Med Chem II - Exam 2 - Quiz 1

Comparing the nitrogen mustards -mechlorethamine hydrochloride -melphalan -chlorambucil -cyclophosphamide -Ifosfamide -thiotepa -busulfan

*INTRO* 1. Mechlor -the only aliphatic (alkanes, not aromatic rings) nitrogen mustard used currently in the US -[Mechanic (mechlor) Ally (aliphatic) owns the ONLY MUSTARD shop in the US where she's the ONLY ALLY] 2. melphalan [MILF] **NEED TO KNOW NOMENCLATURE -an aromatic (so not alkyl, but ring) nitrogen mustard -less basic (pka = 2.1 of benzamine) and less reactive (Why??) than aliphatic mustards (which have an amine pka of 6.4) -this stability provides greater distribution into CANCER cells and decreased incidence of severe side effects [the MILF is basic, but less basic than Mechanic Ally. MILF is LESS REACTIVE towards getting hit on then mech. ally and more financially STABLE so she CAN (cancer) DISTRIBUTE !more WATER BOTTLES! (greater distribution in body water --> go to side effects) with FEWER SIDE hustles (side effects)] 3. chlorambucil [CB] -n/a 4. CYCLE FAST -MOA: forms the aziridinium ion -[better cycle fast before JAZ RIDs the team of u] 5. Ife -similar to cycle-fast -MOA: forms aziridinium ion (all Nitrogen mustards do) 6. Thiotepa -not available in the US but FDA allows importation -[egyptian goods from queen THIOTEPA cant be found in the US, they have to be IMPORTED] 7. busulfan [buford] -buford is a big boy. he can both MONOALKYLATE, and CROSSLINK dna (2 successive alkylations to form cross-linked) -can form both intra and inter stranded DNA -[its CUFFIN szn, 1 or 2 CUFFS i be needin (1 link, or 2 links to be able to crosslink). i need a BIG BOY (buford). ENTERING my INTROSPECTION era (inter, intra), thinking about the kinda big boy i need) *INDICATION* 1. Mechlor -still used in regimens for cancers of the blood (*Hodgkin's disease, chronic myelocytic leukemia, chronic lymphocytic leukemia*) -safer alternatives are now available -[Mechanic Ally INDICATED that her best CHRONIC customer is HODGEPODGE LUKE who always has a BLOODy CAN-do attitude w/ his MILE-LIMP -myelo, lympho cytic), but Ally still prefers SAFER customers] (Hodgkin's, leukemias, blood cancers) 2. MILF -multiple myeloma -epithelial carcinoma of the ovary [the MILF is indicated to bang MULTIPLE MYLOs and EPIC CARSON over and over again] 3. chlorambucil [Co** Block] -used in the PALLIATIVE (only to relieve symptoms) treatment of chronic lymphocytic leukemia, malignant lymphoma, and Hodgkin's -[boyle be CO** BLOCKing Jake and MiLd (malignant, lymphocytic) LIMPING LUKE (lymphoma, leukemia) with his weird HODGEPODGE of a PALLETTE (palliative)] 4. cycle fast -lymphomas, Hodgkin's -multiple myeloma -leukemias [I cycle-fast on a HODGEPODGE of cycles for the MMLL --> major major league league] ^^all of these treat LYMPHOMAS, MYELOMAS, AND LEUKEMIAS because nitrogen mustards decrease your lymphocytes and those are all blood cancers 5. Ife -used as FIRST LINE THERAPY for TESTICULAR CANCER -[FIRST time i talked to IFE outside of class i TESTED her patience oops] 6. thiotepa -ovarian and breast cancers -papillary carcinoma of the bladder [thiotepa the ancient egyptian queen died from Poisoned COBB salad - papillary carcinoma, ovarian, breast, bladder 7. busulfan -treats CML -chronic myelogenous leukemia -[Buford keeps tryna CALL MY LINE but i like LUKE (leukemia)] *DOSING/ADME* 1. Mechlor -IV -too reactive for oral dosing. needs special handling -[Mechanic Ally's 4th year in business is booming, its getting REACTIVE attention, so she does NOT HAVE MUCH TIME TO TALK (NO oral). she has to SPECIALLY HANDLE all the cars] 2. MILF -oral, but absorption can be erratic. food affects absorption -IV formulation of an HCl salt is available -[MILF's WORDS (oral) can be ERRATIC but FOOD always calms her down. She can be SALTY and HeCkLe (HCl) for FOUR (IV) HOURS] 3. Chlorambucil [CB] -good oral BA (look at that straight chain of butanoic acid) -OBA is decreased when taken with food -both the parent drug and metabolite are ACTIVE -parent drug undergoes BENZYLIC OXIDATION to provide an ACTIVE phenylacetic acid mustard metabolite [boyle the CO** Blocker needs GOOD OBA to eat what he does. jake's OBA DECREASES every time boyle makes him try something gross. boyle the parent is ACTIVE on his treadmill desk and BREATHES OXYGEN (benzylic oxidation) so he can set an example for his SON to be active (active parent, active metabolite)] -ADME: rapid absorption and clearance as metabolites in the urine. 99% ppb -[boyle is 99% PRO-BOUND to jake and will RAPIDLY absorb problems so jake is in the CLEAR] 4. cycle-fast -oral or IV [I got my GRANOLA BAR with LOW PB PERCENTAGE (low ppb) and LIQUID IV to CYCLE-FAST like a PRO (prodrug)] -low ppb -a *prodrug* -carbinolamine (cyclophos with an added OH group) metabolite is transported into cells where it UNRAVELS to the ACTIVE component, bis(chloroethylamine) -SIDE PRODUCT is ACROLEIN which is URO AND NEPHROTOXIC -N-dechloroethylation of the cyclophosphamide by 3A4 and 2B6 produces inactive metabolites and chloroacetaldehyde which is URO AND NEPHROTOXIC (why? cause it alkylates cys, lys, adenosine, and cytidine residues) -[I CYCLEd-FAST like a PROdrug but fell off and UNRAVELED, rolling into two ACTIVE BI'S (active = bis-chloro) and a EUROpean ACROBATIC TOXIC (uro toxic = acrolein) karen's NEPHEW (nephrotoxic) so she yelled at me] 5. Ife -IV only -the two chloroethyl groups are on dif N atoms -similar to cycle-fast. needs metabolic activation like cycle-fast (so its a prodrug) -but its activated MORE SLOWLY than cycle-fast -N-dechloroethylation in the renal tubules to produce inactive metabolites and CHLOROACETALDEHYDE (aziridinium is also produced) -[Ife seems like the 4TH smartest out of their group but still she must be a PRO (prodrug) cause she got into rho chi. but still, that whole group is toxic, producing A ZIRE (dire) (aziridium), CHLORIC/ACIDIC (chloroacetaldehyde) situation for me] 6. thiotepa [thiopetra like cleopetra] -IV only -THIOPHOSHORAMIDE is less reactive than quaternary aziridinium compounds and is classifies as a WEAK ALKYLATOR -thiotepa undergoes OXIDATIVE DESULFURATION, forming an active cytotoxic metabolite called TEPA. -both thiotepa and TEPA can ALKYLATE DNA (cause look at all the aziridinium ions on thiotepa - its def active) -in vivo hydrolysis leads to aziridine which also alkylates DNA -[thiotepa was queen for FOUR YEARS in a row (IV). their TEpA had some ACTIVE alcohol in it. QUEEN THIOTEPA must detOX DE SELF (thiotepa --(ox desulfuration)--> tepa) before drinking some TEpA. but some people like THEO PHOS and his 4 AMIGOS (theophos phor amide) were WEAK ALC EATERS (weak alkylator --> thiophoshoramide) and some people were STRONG (aziridine), but EVERYONE was an ALK EATER (tepa, thiotepa) ] -(look at the molecule, it has four aziridines!!! they need to be protonated to be active, but it shows that at any step of the way, any of the metabolites and even the parent are active and can be alkylators) 7. Buford -IV, oral -[bufford EATS (oral) 4x (IV) as much as phineas] *SIDE EFFECTS* 1. Mechlor -potent vesicant, inadvertent extravasation --> severe painful tissue damage -when accidental exposure to skin occurs, sodium thiosulfate is used to inactivate the drug -*can cause myelogenous leukemia* with extended use due to its mutagenic/carcinogenic effects on bone marrow stem cells -narrow safety margin -[mechanic ally's POTENTIALLY (potent) VESTy (vesicant) husband died, its so PAINFUL that she needs a TISSUE (causes severe tissue damage). SODA THEO helps her inactivate this sadness. mechanic ally LEAKED (leukemia) tears, all over MYLO'S JEANS, CAUSING them to shrink/ NARROW past safety (narrow safety margin)] 2. Melphan/MILF -less nausea and vomiting compared to mechlor -severe myelosuppression common -*mutagenic* and can induce NONLYMPHOCYTIC LEUKEMIA -distributes into body water, therefore toxicity can be higher in dehydrated patients -[MILF is more financially STABLE than mechanic Ally (due to water bottle business + money saving habits, unlike non-limping luke) so she THROWS UP less when she hears her bank account balance. this is cause she DISTRIBUTES MORE WATER to her TOXIC, DEHYDRATED customers. she SUPPRESSES spending MONEY (myelosuppression) due to her money-saving genes (mutagenic). she's trying to INDUCE this money-saving in NON-LIMPING LUKE.] 3. chlorambucil [CB] -can induce nonlymphocytic leukemia -[BOYLE can INDUCE NON-LIMPING LUKE to turn himself in] ^^both boyle and MILF might be made for each other cause they wanna LECTURE non-limping luke (both induce non lymphocytic leukemia) 4. cycle-fast -Acrolein and chloroacetaldehyde [clear-asset] cause considerable toxicities -MENSA, a cytoprotective agent, is used as an adjacent therapy to reduce acrolein-induced toxic effect. it forms adducts with acrolein to create a water-soluble, excretable adduct [they say CYCLING-FAST is a MENS sport but my CLEAR ASSET is my ACROBATIC history that rly almost makes me WATER SOLUBLE] 5. Ife -myelosuppression -hemorrhagic cystitis -Bladder tox, Nephrotox, annd neurotox are significant -Mensa used as a uroprotective agent -[NEU MEN'S style looks BLAD on IFE's NEPHEW -she's toxic so she tells him that and it SUPPRESSES his sMILE (myelo)- at least she's less HEMORRHAGIC to her SISTER (hem. cystitis)] 6. thiotepa -severe myelosuppression -can induce leukopenia, thrombocytopenia, and anemia -[THIOTEPA was a queen that SUPRESSED sMILES (myelosuppression) and LATer (leukopenia, anemia, thrombo), laughter.) *7. Buford* (red on his pdf) -serious bone-marrow HYPOplasia and myelosuppression -recovery from busulfan-induced pancytopenia takes up two years -crosses BBB which can cause seizures -[BUFORD SIEZED the BBq outta my hands as well as PANTSED me (pancytopenia) which is going to take 2 years to recover from. then he yelled about there NOT BEING ENOUGH BONE MARROW Hmmm... (low bone marrow diseases like HYPOplasia and myelosupp)

Mitosis Inhibitors (Antimicrotubule Agents)

-a mitotic inhibitor is a drug that inhibits mitosis, or cell division. -they basically disrupt MICROTUBULES (aka mitosis tubules) -most effective in the M phase

VEGRF Inhibitors

1. Sunitinib 2. Vandetanib 3. Axitinib

MEK inhibitors

1. Trametinib 2. cobimetinib

B-Raf inhibitors

1. dabrafenib 2. Sorafenib

antitumor antibiotics - anthracyclines

INDICATION 1. doxorubicin [doxin] -Hematologic cancers and solid tumors of breast, ovary, stomach, bladder and thyroid [bloody bucket on bob st] -a liposomal formulation of doxorubicin (marketed as DOXIL) is used in the treatment of AIDS-related Kaposi sarcoma AND organoplatinum-resistant ovarian cancer -doxil has a v high half life -[the DOXIN SOLIDLY led me to BOB ST (solid tumors of Bob St) where we found a CAN of BLOOD (hematologic cancers). the doxin could sniff anything, even out LIPO (liposomal) in Ms Kaposi the AID (AIDS related Karposi) and the PLATINUM-ORGANIST (organoplatinum-resistant) who CAN OVER-do it (ovarian cancer)] 2. daunorubicin [DANNY BOY] -for treatment of acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) in adults and acute lymphocytic leukemia in children and adults -[danny boy's ADULT parents are NON-LIMPING (non-lymphocytic leukemia) to their ACURA (acute). but Danny boy is LIMPING to A CUTE (acute) girl on CollegeAve (lymphocytic leukemia, acute --> for both Children and Adults)] 3. idarubicin [ida garten] -for acute myeloid leukemia (AML) in adults in combo with other antileukemic drugs -[ida makes A-CUTE MILD LEAK soup in 10 min IN COMBO with a nice grilled cheese sandwich] 4. mitoxantron [MIT] (ONLY A 3-MEM RING SYSTEM at first --> it eventually forms a 4-ring system) -synthetic anthracycline analog indicated for: -acute nonlymphocytic leukemia used in combo -prostate cancer -[synthetic MIT used by LUKE to win a NON-LIMPING COMBO even with his PROSTHETIC CALF (prostate cancer)] 5. bleomycin [BLM] -Hodgkin's and Non-Hodgkin's -squamous cell carcinoma -testicular carcinoma [BLM makes a both HODGEPODGE and NON-HODGEPODGE people SQUEAMISH and TESTY] 6. dactinomycin -Wilms tumor -Ewing's sarcoma -Solid malignancies -[SOLID D-acting on the SWING WILMA, u could have at least SEWn on a smile] 7. mitomycin C -disseminated adenocarcinoma of the stomach or pancreas -given in combo -[MY OH MY, these PANCAKES (pancreas) DISSEMINATED my STOMACH like A-DINO (adenocarcinoma)] MOA 1. doxorubicin -Dual MOA a. TopIIa inhibition b. Hydroxy-free radical-induced DNA strand scission 2. daunorubicin -Dual MOA a. TopIIa inhibition b. Hydroxy-free radical-induced DNA strand scission 3. idarubicin -Dual MOA a. TopIIa inhibition b. Hydroxy-free radical-induced DNA strand scission ^^[Ida brings her doxin to danny boys house, using any MECHANISM to cheer danny who was sad since his classmates were saying his TOP was ii RADICAL!!] 4. mitoxantrone -type IIa Top inhibitor -protonated amines BIND TO anionic phosphate residue on DNA leading to a ternary complex of DRUG-TOPiia-DNA -[that Catch with the MIT brought him 2 the TOP of the charts in the BIG THREE (ternary complex)] -also THESE BIG SIDE CHAINS prevent NADPH from reducing those =O's into OHs and causing free radical production, so MIT is less CARDIO toxic [MITT romney is less CARDIOTOXIC to my heart because i don't find him attractive] 5. bleomycin -antitumor antibiotic isolated from streptomyces verticillus. the drug substance is a mixture of bleomycin A2 and B2 -MOA: intercalates with DNA and causes DNA destruction via cytotoxic free radicals (the structure looks like it would intercalate) -the electron rich disaccharide, imidazole, and pyrimidine bind to Fe2+ -BLM-FE2+ --> BLM-Fe3+-OOH --> free OH radical -the hydroxy radical abstracts a proton from 4' of DNA-ribose causing DNA scission **the hydroxy radical is the BLM Active species that causes the DNA scission -[BLM was a STrEP in the VERTICAL direction (strep verticillus). they have a mix of posters INTERCALATED in BOTH AB buildings (A2, B2 mixture found in the drug). there would be total DESTRUCTON by RADICALS if they INTERCALATED into the AB too] 6. dactinomycin -antitumor antibiotic from strep parvullus -cyclic bis-depsipeptide attached to a substituted phenoxazine core -MOA: binds strongly to DNA thereby inhibiting transcription of DNA and DNA replication [DactiNAmycin] -what functionality causes the strong binding to DNA? --> the PLANAR AROMATIC RING SYSTEM -dactinomycin binds to the guanine portion of DNA intercalating between guanine and cytosine base pairs -the p-benzoquinoneimine REDUCTION by nadph/450 reductase generates hydroxy-free radicals that break SINGLE-STRAND DNA 7. mitomycin C -Antitumor antibiotic isolated from from Streptomyces caespitosus or Streptomyces lavendulae -what is the two-fold mechanism of mito's cytotox? --> hydroxy radical generation and DNA alkylation -activated through a two-electron bioreductive process using NADPH/P450 REDUCTASE and/or NQO1 REDUCTASE (an enzyme EXTENSIVELY EXPRESSED in NEOPLASTIC cells) -hydroxy radicals break single strand DNA -additionally, DNA alkylation occurs at TWO SITES (shown) DOSING/ADME 1. doxorubicin -IV -coadminned with DEXRAZ-OXANE (a chemoprotectant for anthracycline cardiotoxicity). its an ANTIOXIDANT and PRODRUG and IRON-CHELATING AGENT [Dex, RAZ ur hand to take A PIC] -[Doxin gets washed 4(IV) times a year] -[Dex, RAZ ur hand to take A PIC of my DOXIN getting washed 4x a year] 2. daunorubicin -IV -coadminned with DEXRAZ-OXANE -[danny boy's a senior in 4th(IV) year of college] -[Dex, RAZ ur hand to take A PIC of danny boy walking up to that girl] 3. idarubicin -IV -coadminned with DEXRAZ-OXANE -[Ida is a 4x (IV) award winning food network chef] -[Dex, RAZ ur hand to take A PIC of me and ida Garten] 4. mitoxantrone -IV [Mitt Romney is the 4th highest grossing senator] -reduced cardiotoxicity --> less prone to NADPH/CYP450 REDUCTION, so there's a lesser chance of hydroxy-radical formation -no cardiotoxic oxygen radicals (ROS) -has a naphthol quinoxaline ACTIVE METABOLITE which is LESS TOXIC than the parent [i'm less prone to being REDUCED by MITT romney. he is LESS TOXIC TO MY HEART (less cardiotox) so I am LESS RADICAL around him (fewer radicals formed). but NAPPY QUINN is who rly gets me ACTIVE cause he's LESS TOXIC than MITT] 5. bleomycin -IV -rapid absorption following IM, SC, IP administration -nearly complete OBA -[BLM when u think about it, happened about 4 years ago and has been RAPIDLY ABSORBED and now is almost COMPLETELY BIOAVAILABLE] 6. dactinomycin -IV (look at the ridiculous size of the molecule, has to be IV) [i cant believe my acting was D-acting, ive been in acting school for 4 years!! (IV) I want a large ViDeo to see what im doing wrong (large Vd)] -Large Vd [large V-Dactin] 7. mitomycin C -rapidly cleared post IV dosing -[my oh my i havent listened to troye sivan in 4 years] SIDE EFFECTS 1. doxin -*Cardiotoxicity* (a hydroxy-radical mediated effect. same mech contributes in part to its efficacy) -myelosuppression -Nausea/vomiting -Mucositis [Doxin does some RADICAL CARDIO for an MNM candy] 2. daunorubicin -*Cardiotoxicity* (a hydroxy-radical mediated effect. same mech contributes in part to its efficacy) -myelosuppression -Nausea/vomiting -Mucositis [Danny boy does some RADICAL CARDIO for an MNM candy] 3. idarubicin -*Cardiotoxicity* (a hydroxy-radical mediated effect. same mech contributes in part to its efficacy) -myelosuppression -Nausea/vomiting -Mucositis [Ida garten does some RADICAL CARDIO for an MNM candy] 4. mitoxantrone -moderate nausea and vomiting (less severe than other anthracyclines) -bone marrow suppression -[i want to throw up LESS at the sight of MITT ROMNEY he makes my bones shake less (less bone marrow suppression)] 5. bleomycin -*10% of patients develop PNEUMONITIS which can turn into PULMONARY FIBROSIS -1% DIE -does NOT cause bone marrow suppression -[this is dark but george floyd (BLM) prob got pneumonitis and pulm fibrosis from the lack of air. many people think there was ONLY 1% CHANCE HE COULDVE DIED but we all know thats wrong. his death was NOT from SUPPRESSING BONES (no bone marrow suppression), it was from suppressing oxygen] 6. dactinomycin -*toxic rxns due to dactinomycin are frequent and may be severe* -*extravasation danger* -[DactiNAmycin be breakin DNA AND Vessels --> extravasation] [ugh my dactings so bad, i need an extra VACATION to relax] 7. mitomycin C -bone marrow toxicity most common and serious (64%) -produces cumulative myelosuppression -dont memorize these r so dumb

Steroid Hormones

MOA -the free steroid hormones diffuse through the cell membrane and BIND on HIGH AFFINITY receptors. they act as TRANSCRIPTIONAL FACTORS by interaction with specific DNA sites -so the STEROID-RECEPTOR COMPLEX binds to dna as TRANSCRIPTION FACTOR -[STARE-oid at my TRANSCRIPT (transcription factor) to see all Fs] -forms steroid-receptor complexes which TRIGGERS GENE EXPRESSION -protein synthesis (enzymes, receptors, growth factors) occurs as response to steroid hormone resulting in function, growth, and differentiation and playing central roles in normal physiologic processes as well as in many diseases and disorders -so basically: transcription factor binds --> gene activated --> protein produced --> some process in the cell happens BIOSYNTHESIS OF STEROIDS -enzyme deficiencies and associated disorders 1. deficiency or lack of 21-hydroxylase = results in REDUCTION OF CORTISOL synthesis, resulting in EXCESS 17a-HYDROXYPROGESTERONE being formed, leading to virilization (masculinization)???? wtf is this --> sooo 17A is a PRECURSOR to ANDROSTENE AND TESTOSTERONE -thats how it leads to masculinization -SER (smooth endo retic) 2. a defect in 11B-hydroxylation results in large amounts of deoxycorticosterone being formed, which has mineralocorticoid activity, resulting in INCREASED SALT RETENTION AND HYPERTENSION -MITOCHONDRIA 3. if 17a-hydroxylation is defective, production of sex steroids (progesterone, estrogen for women, + adrien the man - androgen) is REDUCED resulting in HYPOGONADISM. in addition, more pregnenolone is DIVERTED (from what?) for the biosynthesis of mineralocorticoids -SER (smooth endo retic) Q: explain the consequences of deficiency of 21-hydroxylase (increased androgen/testosterone and masculinization [21 is when u become a MAN]), 11B-hydroxylase (leads to INCREASED ALDOSTERONE causing salt/water retention and HTN) [all the 11-yo girls wanted to get their shoes from ALDO and it gave all their parents HTN] [11 was also the age everyone was learning MITOCHONDRIA is the powerhouse of the cell)], and 17a-hydroxylase [at 17 is when they really start telling girls to REDUCE SEX to DIVERT PREGNANCY (reduced sex hormones --> hypogonadism, diverted pregnenolone)]

non-steroidal aromatase inhibitors

anastrozole, letrozole SKIPPING

CAR-T (chimeric) -personalized -t cells are collected from a PATIENTS BLOOD via apheresis -t-cells are RE-ENGINEERED in a lab to produce CARs on their surface (chimeric antigen receptors) -these re-engineered cells are then multiplies/expanded -@ the treatment center: patients begin with a short course of chemo called "lymphodepletion" -then the CART is infused into the patient's blood stream, and the car t-cells multiply. then they recognize certain cancer cells and attach to them (the ones that have the antigen that these CARs have been programmed to recognize) -then the CART cells ERADICATE THE TUMOR CELLS -they may also *help guard against recurrence* because they remain in the body months after -called a *living medicine*

*CART CELL IMMUNOTHERAPY* 1. tisagenlecleucel [tis a genuine thing to push a CART] -A CD-19-directed genetically modified autologous T cell immunotherapy -Patients' T-cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) and eliminate all cancer AND NORMAL cells expressing CD-19 2. Axicabtagene Ciloleucel [AXE to the CABBAGE that was in my CARTT of cabbages --> the cabbage guy's cart always gets axed and ruined] -a CD-19-directed genetically modified autologous T-cell immunotherapy -Patients' T-cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) and eliminate all cancer AND NORMAL cells expressing CD-19 *INDICATION* 1. tis a genuine thing to push a CART -acute lymphoblastic leukemia (ALL) 2. AXE to my CABBAGE -large B-cell lymphoma, relapsed or refractory after 2 or more lines of systemic therapy -[cabbage man BE LIMPING LARGE (large b-cell lymphoma) re-LAPs with a re-FRACTURED hip (relapsed or refractory). those avatar kids, at least 2 or more of them, always be causing him trouble systemically (after 2 or more systemic lines)] *PK* 1. tis a genuine thing to push a CART -high distribution into bone marrow -tis-a-genuine is present in blood and bone marrow and is measurable beyond 2 years 2. AXE to my CABBAGE -anti-CD19 car-t cells displayed an INITIAL RAPID EXPANSION followed by a decline to near baseline levels by 3 months post ax-icabtagene ciloleucel infusion *BOXED WARNING* 1. tis a genuine thing to push a CART -*life threatening cytokine release syndrome* -neurological toxicities 2. AXE to my CABBAGE -*life threatening cytokine release syndrome* -neurological toxicities ^^[NAUURRR (neurological) the _Calvin Klein (CKs)__ is threatening to release from my CART] -same BBWs for both CART -get it? cause injecting some random ass cells into your blood can seem like a foreign object and then immune system starts wilin with ck's and they cause so much shock u die *COST CONSIDERATION* 1. tis a genuine thing to push a CART -one time cost: $475,000 2. AXE to my CABBAGE -one time cost: $373,000

Estrogenic Drugs

*CHEMICAL NAMES WE NEED TO KNOW* -estradiol = estrane backbone (no methyl on 10), DBs on 1, 3, 5. but 5DB goes to 10, not 6, so its 5(10). DIOLS --> on C3 its planar, but on C17 its wedge so B --> 3, 17B diol -EE (ethinyl estradiol) = looks like it should be 19-yne but its 20-yne *INDICATION* 1. estradiol (available in VOTE formulations + TOPICAL) (so new pneumonic = T-VOTE) -vasomotor symptoms associated with menopause -vulvar/vaginal atrophy associated with menopause (topical only) -[T-10 seconds to T-VOTE (all formulations of ESTRADIOL) on the MEANest (menopause) Vacuum-Motor (vasomotor) so it could win a VERY VERY (vulv, vag) nice TROPHY (atrophy) and a TROPICAL (topical only) vacation] 2. estradiol cypionate (prodrug of estradiol) -hypogonadism -moderate to severe vasomotor symptoms associated with menopause -[charlene ESTRADA CYPS on her tea like a pro (cypionate is a prodrug) while yelling GO-HIPPO (hypogonadism), use ur MOD-SEVERE VASOMOTOR skills and dont PAUSE (menopause)] 3. ethinyl estradiol (EE) -hypogonadism -moderate to severe vasomotor symptoms associated with menopause -[ETHICAL ESTRADA (ethinyl estrada), charlene ESTRADA CYPS on her tea while yelling GO-HIPPO (hypogonadism), use ur MOD-SEVERE VASOMOTOR skills and dont PAUSE (menopause), like a PRO (prodrug)] 4. mestranol -mestranol and EE are used primarily in oral contraceptive combo formulations -hypogonadism 5. Quinestrol aka ethinylestradiol cyclopentyl ether (EECPE) *ADME* 1. estradiol -Poor OBA (5%). it is conjugated in the intestine and eliminated. then, what is absorbed is rapidly OXIDIZED in the liver (estrone) -[poor estradOBA] 2. estradiol cypionate (prodrug of estradiol) -the ester PRODRUG is deposited in tissue and slowly released into blood where it gets HYDROLYZED to estradiol (2 OHs) [self explanatory. prodrug --> metabolite. tissue --> blood] -IM injection at monthly intervals, slow release form also available -[Estrada CYPS and sends recap Instant Message (IM) to interns every month, and she is never SLOW to RELEASE her tasks on time (slow release). but then she blows her nose in TISSUE but slowly comes out BLOOD] 3. ethinyl estradiol (EE) -oral or injection -metabolically more stable than estradiol -how does the C17 ethynyl group help stability? --> prevents oxidation by making the C17-OH tertiary. without oxidation, the molecule stays stable -considerably more potent than estradiol -rapidly and completely absorbed after oral administration -undergoes first-pass metabolism to O-glucuronide and sulfate derivatives -[O I S P A F EE --> OI, pay the SPA F(EE) ethical estrada --> oral, injection, stable, potent, absorbed (well, rapidly, and completely), first pass, EE] 4. mestranol -[OIT] oral, injectible, topical 5. Quinestrol aka ethinylestradiol cyclopentyl ether (EECPE) -oral weekly dosing -[I only TALK (oral) to QUIN on our STROLL (quinestrol) once a week (weekly)] *WARNINGS* 1. estradiol -N/A 2. estradiol cypionate (prodrug of estradiol) -BBW: Estrogens have been reported to increase risk of endometrial carcinoma in postmenopausal women -[estrada cyppin on her BLACK TEA from the BLACK BOX while releasing RISKY END-MEAT CARDS (increased risk of endometrial carcinoma) to women in the PM (post menopausal women) 3. ethinyl estradiol (EE) -n/a

antimetabolites - *pyrimidine antagonists* ********************************************* -pyrimidine antagonists inhibit the biosynthesis of the pyrimidine dTMP -they inhibit THYMIDYLATE SYNTHASE (TS) (carries out the rate limiting step in producing dTMP) -without dTMP, DNA synthesis cannot occur dUMP = deoxyURIDINE MP (precursor to T, just add a methyl) dTMP = deoxyT MP TS = thymidylate synthase = adds a methyl to dUMP, making dTMP THF = tetrahydrofolate SYNTHESIS OF DTMP -THF is kinda like home base -dUMP truck comes to this home base where it gets methylated -TS is also here at home base to help dUMP turn into dTMP -ALL THREE OF THESE COMPONENTS ARE NECESSARY FOR DTMP PRODUCTION *5,10-THF gets regenerated and it can be used over and over again -5-10 means theres bonds between 5 and 10 that are pushed onto dUMP to give it a methyl

*Intro* 1. 5FU [so at C5, theres a fluorine. otherwise it looks exactly like uracil] (this F inhibits the whole process of TS turning it into dTMP) -pyrimidine antagonist (looks like uracil except it has 5-F) -prodrug -5FU is the prodrug (not active) -to become active, 5FU needs to turn into 5F-dUMP (5FU without a monophosphate attached = no activity. monophosphate must be attached, AND de-oxy must happen at C2 --> therefore, *deoxy*-U-*monophosphate* (both are uracils, but only dUMP can be a substrate for TS and give the drug activity) -[only the dump truck can arrive at home base (THF) and mingle with TS (trash sorters)] 2. floxuridine (FUDR) [flocks] -n/a 3. Capecitabine -n/a *MOA* 1. 5FU -TS inhibitor (TI) -acts as a False substrate that mimics 5-dUMP (F) -irreversible inhibition of TS (I) -formation of an irreversible ternary complex of TS, THF, and 5-FU (IT = irreversible ternary) -ternary complex does NOT lead to 5F-dTMP because normally, there is an H where the F is, and the H can be ejected. but the F cannot be ejected (F not ejected) -5F-dUTP (monophosphorylation --> triphosphorylation) - lets say 5f-dump is just floating around and instead of binding to THF, it gets phosphorylated 2 more times --> this is also a false base that can get INCORPORATED IN DNA and stop chain elongation (triphosphate U gets incorporated into DNA, chain termination) -[5 FU's to IT teFITI, 5FUs to Dana] -[IT teFITI. TP incorporated into Dana's CHAIN, STOPPED her from elongating it with more charms.] -[irreversible ternary, false (substrate for TS), TS inhibitor. (5FdU) TP/triphosphate incorporated into, DNA, stops chain elongation] 2. floxuridine (FUDR) [it's the U and the ribose, just not the phosphorous] -converted in vivo into 5-F-dUMP (same as the active form of 5FU) -all that happens is that it gets converted into monophosphate form (active 5F-DUMP) (cause only the dump truck can reach the active THF site) -TS inhibitor (TI) -acts as a False substrate that mimics 5-dUMP (F) -irreversible inhibition of TS (I) -formation of an irreversible ternary complex of TS, THF, and 5-FU (IT = irreversible ternary) -ternary complex does NOT lead to 5F-dTMP because normally, there is an H where the F is, and the H can be ejected. but the F cannot be ejected (F not ejected) -essentially the same pneumonics as 5-FU -[5 FU's to IT teFITI, 5FUs to Dana] -[IT teFITI. TP incorporated into Dana's CHAIN, STOPPED her from elongating it with more charms.] -[irreversible ternary, false (substrate for TS), TS inhibitor. (5FdU) TP/triphosphate incorporated into, DNA, stops chain elongation] *they just become 5F-dUMP in different ways* 3. Capecitabine -orally active prodrug of 5-FU (its this long chain attached to 5-FU) which is converted in vivo to the active 5F-dUMP -rest of MOAs are the same as above [u have the capacity to speak up and be ORALLY ACTIVE and say 5-FU to all cops] *DOSING* 1. 5FU -IV -[4th (IV) time Dana's parents took her to see teFITI on vaca. she said 5 FUs to u tefiti.] 2. floxuridine (FUDR) -IV, regional arterial infusion [so many people FLOX to the RAIV (regional arterial IV)] 3. Capecitabine -ORAL -[u have the capacity to SPEAK UP (oral)] *Indications* 1. 5FU -IV palliative treatment of colorectal, breast, stomach, and pancreatic cancers (C B S P) -topical treatment for actinic or solar keratosis -[on the CuSP of saying 5thFU to this B*TCH who should be my PAL (palliative), already 4 (IV) were said] [colored the beast's stomach with a pink crayon] -[screaming 5FUs to the sun. coloring the sun (solar) topically (topical) like acne (actinis) on the face] 2. floxuridine (FUDR) -palliative treatment of GI adenocarcinoma metastatic to the liver -[GIA C. flox to the RAIV] 3. Capecitabine -first line therapy in patients with colorectal cancer -[these new COLORBLIND (colorectal) glasses gave me the CAPACITY to SEE for the FIRST TIME (first line therapy) -also used alone or in combo w/ docetaxel in patients with metastatic breast cancer -[u have the capacity to be alone (can be used alone) like a mega-beast-candidate (for metastatic breast cancer) or with combo of friends for the next DOCE months (can be used in combo with docetaxel)] *ADME/SIDE EFFECTS* 1. 5FU -dihydropyrimidine dehydrogenase (DHPDH) causes most 5FU metabolism in the liver -how does a polymorphism of DHPDH affect toxicity? --> low/deficient enzyme = higher 5FU levels --> life threatening consequences -[did he pay da hydrogenase-guy? if not 5FUs to him] 2. floxuridine (FUDR) -caution with impaired hepatic/renal function -can be removed by dialysis (25%-50%) -lower potential for nausea/vomiting -[HR (hepatic renal adjustment) increasing as the maze runners FLOX towards the DIAL (dialysis) to escape the maze. only 25-50% escape. low ENVY (N/V) tho, just sadness.] what is the safety benefit of FUDR, compared to 5FU? -its PK is not impacted by dihydropyrimidine DH (DHPDP) (no 5FU to be metabolized) 3. Capecitabine -can cause a potentially disabling disorder called *hand and foot syndrome* -*potentially lethal DDI with warfarin* due to 2C9 inhibition -negative food effect -[capacity to get blown up by C9 in this war (ddi with warfarin due to 2c9 inhibition by capecitabine) OR become a HAND AND FOOT servant (hand/foot syndrome) who never gets food (negative food effect) - but its your capacity to choose. which will it be?]

miscellaneous pt 1

*Intro* 1. Hydroxyurea -hydroxyurea is a drug with a 100-year history -looks like urea (NON) with a hydroxy on it -its MUTAGENIC [oh ur hea? lets go to muTANGO CLASSto in the CAR (mutagenic, clastogenic, carcinogenic) 2. Bortezomib [bort] -n/a 3. Olaparib [olaf] -BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins BRCA1 and BRCA2 -inherited mutations in BRCA1 and BRCA2 account for about 20-25% of inherited breast cancers and 15% of ovarian cancers -so BRCA mutations cause both *breast cancer and ovarian cancer* -the cancer cells use poly ADP ribose polymerase (PARP) to repair their DNA -and *BRCA1/2 mutated genes have a UNIQUE DEPENDENCY on PARP* to repair damaged DNA in cancer cells -[OLAF helped INHIBIT THE PERP (PARP) Hanz from getting away (olaf is a parp inhibitor). Hanz Perp was supposed to join the DNAs of two lines (PARP repairs DNA). Hanz was the leader of BrrCavalry (BRCA), a group that was just as evil as the MUTATED IVORY BEAST (mutated BRCA causes ovarian/breast cancer) that elsa created. the BrrCav had a unique dependency on Hanz the perp (PARP), but now that he's in jail, the BrrCav can't use him.] 4. Idelalisib [Ideal Adele] -n/a 5. L-Asparaginase and Peg-Asparaginase -L-asp is an enzyme isolated from e. coli -[Little gASP --> e.coli in the chipotle?? but chipotle is ma laifee] *MOA* 1. Hydroxyurea (OH-urea) [Oh, ur he'a] -inhibits *ribonucleotide reductase* aka RIB-RED (the enzyme that REDUCES RNA (2 OHs - [rihanna says oh oh oh]) into DNA (1 OH - [OH dang]) -therefore, it stops the conversion of RNA into DNA -[Oh, ur He'a (urea) to help me paint the room RIB-RED?] 2. Bortezomib [aBORT the TRASH --> works with 26S proteosome, the trash can of the cell] -REVERSIBLE inhibitor of the 26S proteosome in mammalian cells -in normal cells. dysfunctional proteins are tagged for degradation with ubiquitin -the 26S proteosome degrades those ubiquitinated proteins -inhibition of the 26S proteasome prevents this targeted proteolysis, leading to cell death -26S is the garbage disposer of the cell. by inhibiting it, the garbage builds up and causes cell death -[aBORT this 26th prototype (26s proteosome inhibitor), its TRASH! abort it! bring its death! (causes cell death) onto the next one! number 27] 3. Olaparib -PARP inhibitor -[OLAF helped INHIBIT THE PERP (PARP) Hanz from getting away (olaf is a parp inhibitor)] 4. Idelalisib [ideal adele] -inhibitor of the PI3K( ) which is highly expressed in malignant lymphoid B-cells -PI3K( ) inhibition results in apoptosis of malignant tumor cells -also inhibits chemokine signaling pathways CXCR4 and CXCR5 (these are receptors) -[similar to how there are an ABUNDANCE of PIK-3s at Burger king (PI3K is highly expressed in malignant B-cells), ADELE has an IDEAL Pick-3 (pi3k) of her top three POP (apoptosis-causer) songs from singer charlie XCX (CXC), but it wouldnt hurt to pick a 4th and 5th (CXCR4/5 inhibition)] 5. L-Asparaginase (Elspar) and Peg-Asparaginase -L-asparaginase converts L-asparagine into L-aspartic acid + NH4+ --> [L-asparaGINA got turned into an L-asPARTY amMONIAC by the new drug "GINASE"] -L-asparaginase (elspar) MOA is based on SELECTIVE KILLING OF LEUKEMIA cells due to DEPLETION OF ASPARAGINE since its all getting turned into asparty -[don't mess with L-asparaGINASE, the new drug on the street, it will get u like it SELECTIVELY KILLED LUKE (leukemia) and DEPLETED the life outta asparaGINA (selective killing of leukemia cells by depleting L-asparaGINA)] -remember that this drug is just a ton of this enzyme GINASE that turns all the L-asparaGINA into PARTYING MANIACS - thus it depletes the cell of L-asparaGINA *Indications* 1. Hydroxyurea -carcinoma of the head and neck with concomitant radiation therapy -chronic myeloid leukemia (CML) -[OH, ur he'a? ur gonna have to INDICATE that with a __CaMeL scream (CML)__ next time or something cause ur so short i can barely see ur HEAD AND NECK] 2. Bortezomib -multiple myeloma -mantle cell lymphoma -[abort abort! neil found the MMs we keep on the mantle] 3. Olaparib -BRCA-mutated ovarian cancer -BRCA-mutated, HER2 negative metastatic breast cancer -simple indications: [At first people thought OLAF was an IVORY BEAST (ovarian, breast cancer) but actually the mutated ivory beast that else created was evil, just like the BrrCav (mutated BRCA - induced ovarian and breast cancer)] -including genes: [Brr-Cav is MUTE (mutated BRCA), its OVER for them (ovarian cancer). since the supposed meta beast (MBC) OLAF stopped them from NEGATIVELY killing HER2 aka elsa (her2-neg metastatic breast cancer)] 4. Idelalisib -chronic lymphocytic leukemia (CLL) -follicular B-cell non-Hodgkin lymphoma (FB NHL) -small lymphocytic lymphoma (SLL) [Ideal adele follows the FB NHL page, CaLL her SiLLy] 5. L-Asparaginase and Peg-Asparaginase -a component of a multi-agent chemo regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) [L-AsparaGINASE is part of a secret FBI group of multiple-agents (part of a multi-agent regimen) and they are ALL obsessed with her. GINAs gonna get ALL the money, and ALL the cute limping lukes] *ADME* 1. Hydroxyurea -excellent OBA (the molecules is so simple, just a small alkyl chain) -serum levels peak within 2 hours of consuming the capsules [oh ur hea? at this EXCELLENT BOBA place to EAT? no CAP? (oral capsules)] 2. Bortezomib -IV -[this is ONLY the 4th (IV ONLY) time neil found our MMs and we had] to aBORT 3. Olaparib -Oral -[OLAF is always singing (oral) about summer] 4. Idelalisib -oral -[adele has an amazing VOICE (oral)] 5. L-Asparaginase and Peg-Asparaginase -n/a *AEs* 1. Hydroxyurea -BBW = hydroxyurea is *mutagenic* and CLASTOGENIC which implies a carcinogenic risk to humans -[oh ur hea? come take this muTANGO CLASSto with me, lets get in the black-box (bbw) CAR (carcinogenic)] 2. Bortezomib -diarrhea, nausea, peripheral neuropathy -[neil saw those old ass MMs on the mantle we were supposed to abort out of his PERIPHERY, then they gave him VOM/DIARRHEA. him eating them has me PeeVeD] 3. Olaparib -n/a 4. Idelalisib -n/a 5. L-Asparaginase and Peg-Asparaginase -anaphylaxis (A) -serious allergic rxns (S) -thrombosis (T) -fulminant glucose intolerance (F) -[the drug L-asparaGINASE works FAST --> it'll getchya] -[i wonder if FREMULON GINA has a glucose allergy]

Comparing the Nitrosoureas (N=O) = all are UNSTABLE compoundS that DECOMPOSE READILY in AQUEOUS ENVIRONMENT to form HIGHLY REACTIVE CARBOCATIONS that ALKYLATE dna

*Intro* 1. carmustine -What are the possible reactive intermediates of Carmustine? a. a vinyl cation that is highly reactive b. 2-chloroethylisocyanate c. 2-chloroethylamine d. some random molecule -all are potential alkylating reactive intermediates -need to know the structures i guess [VILE CAT (vinyl cation) stuck in the CAR that MUST have riders is being HIGHLY REACTIVE and wants to get out] 2. lomustine -n/a 3. streptozosin -why is streptozosin water soluble? = it contains an N-nitroso urea -what is the reactive alkylating species? = Diazomethane --> a potent methylating agent -the water soluble N-nitroso is ISLET-SPECIFIC. thats how its used for metastatic islet-cell carcinoma (meta. pancreatic neuroendocrine tumors) -[i drink my "ISS LIT" (islet-specific N-nitroso) N-NITRO WATER SOLUTION (N-nitroso makes it water soluble) for my STREP. it was either my DNA or METH AGENT (potent methylating agent) DIAZ's METH (diazomethane) that gave me STREP] 4. dacarbazine and temozolomide -GO BACK - SUPER COMPLICATED SLIDES 5. dacarbazine -n/a 6. temozolomide -n/a 7. procarbazine -gets metabolized to METHYL RADICALS that can alkylate -what are 2 reactive intermediates that you have learned so far that can ALKYLATE?? --> CATIONS AND RADICALS -so this drug is known as a DNA methylating agent -[the PRO-CARB EATER is RADICALLY against METH. both METH AND ALC can f up ur DNA (DNA alkylating/methylating agent using methyl radicals)] *Indication* 1. carmustine -used as a SINGLE agent OR in COMBO therapy for: -brain tumors -multiple myeloma (in combo w/ prednisone) -Hodgkin's -Non-Hodgkin's lymphomas [BT MM P H NHL. BMHN [each CAR MUST be ridden by a SINGLE or a COMBO, none can be empty. when the BooM (brain tum, MM) PLAYS (MM, in combo w PREDNISONE), HOLD/HOG (hodgkins) the NEW (non-hodgkin's) safety handle] 2. lomustine -primary and metastatic brain tumor (makes sense cause it can cross BBB) -Hodgkins as a secondary therapy in combo with other drugs -[Lombardo is indicated to be messed up in the BRAIN in the PM (at night) (primary, metastatic) and always says a HODGEPODGE of things SECONDARY to his COMBO of initial words] 3. streptozosin [indicated that ISS LIT] -metastatic islet cell carcinoma aka metastatic pancreatic neuroendocrine tumor -[if u can remember that this drug is islet-cell specific, u can remember the indication] 4. dacarbazine and temozolomide 5. dacarbazine -hodgkins -malignant melanoma 6. temozolomide -adult patients newly diagnosed with glioblastoma multiforme -given concomitantly with radiotherapy and then as a maintenance treatment -also for refractory anaplastic astrocytoma 7. procarbazine -hodgkins MOPP: -first combination therapy that achieved high cure rate for Hodgkin's (developed by NCI) *ADME/DOSING* 1. carmustine -IV or implant (Gliadel wafer) -IV is given no sooner than every 6 weeks [tn on the ride where each CAR MUST have someone in it, a 4th (IV) person accidentally imPLANTED (Implant) their GHIRADELI WAFERS in someone's face] -lipid soluble, transverses BBB -carmustine degrades in 15 minutes -CSF > 50% of levels in plasma [BBs must transverse the "you must be this tall to ride" in order to get in a ride where the CAR MUST be full] 2. lomustine [LOM] -stable enough for *oral dosing* in capsule form -why can lomustine treat brain tumors? cause it is HIGHLY LIPID SOLUBLE and can cross the BBB [LOMbardo CAPPED (capsule) that he was STABLE and actually SPOKE (stable enough for oral dosing) psychotically. he murdered then CROSSED the BBB state lines all while SOLIDIFYING his LIPS (lipid soluble) and keeping em shut] 3. streptozosin -IV -islet specific [4th (IV) time getting STREP, ISS LIT] 4. dacarbazine and temozolomide 5. dacarbazine -IV -[da car backed into 4 cars today (IV)] 6. temozolomide -oral capsules in patients with glioblastoma -IV form also available -[TIME to DOZE-O while these GLEE-BLASTers SING (oral) at me. this is the FOURTH (IV) assembly where im going to dozo.] 7. procarbazine -oral -*adminned as part of a multidrug regimen known as MOPP regimen that is capable of curing almost 70% of patients with advanced-stage Hodgkin lymphoma* -MOPP: 1. Mechlorethamine, an alkylating agent (Mechlor - mechanic ally) 2. Vincristine (Oncovin), a mitosis inhibitor 3. Prednisone, a steroid 4. Procarbazine, a *DNA methylating* agent ADME of MOPP: -rapid and complete absorption -crosses BBB -[PRO CARB EATERRR (oral) RAPIDLY ABSORBS his BBQ (rapid absorption, crosses BBB) then cleans up his HODGEPODGE of a mess 70% successfully with a MOPP] *Side effects* 1. carmustine -Bone marrow toxicity -delayed myelosuppression -emesis (rapid onset); prior admin of anti-emetics is useful -acute pulmonary toxicity -[i left my BEADed necklace from my BONY hand in that CUTE car cause i had to throw up - emesis. now getting it back will be DELAYED. in the ride where the CAR MUST have people in it] 2. lomustine -delayed bone marrow suppression -carcinogenicity [Lombardo was DELAYED in SUPPRESSING the BONES of the man he killed so CARSON (carcinogenicity) the cop got him] 3. streptozosin -cumulative renal toxicity -DNA damage induces *activation of poly ADP-ribosylation* which can lead to diabetes induction also -therefore, strep is used to generate ANIMAL MODELS OF DIABETIC NEUROPATHY [getting STREP 4x must be due to DNA DAMAGE. my body's REAL TOXIC (renal tox). thats why i need PADded PR (poly adp ribo) ACTIVATED at all times so people don't find out and my DAY doesnt BEAT (dia betes) me to the ground. they will use me in ANIMAL STUDIES if they do] 4. dacarbazine and temozolomide 5. dacarbazine -emesis > 90% -vomiting -anorexia [da car seemed it was backing up for EVA and EVA. when i looked inside to see who was driving, it was some anorexic girl who looked like she was gonna be sick] 6. temozolomide -neutropenia and thrombocytopenia -[TIME to DOZE-O for the NT (night) ya peens (penias)] 7. procarbazine -*associated with serious toxicity* MOPP: -emesis (60-90%) -leukopenia -strong MAO inhibitor leading to potentially fatal DDI and drug-food interactions [the PRO-CARB EATER is SERIOUS about staying away from TOXIC (associated with serious toxicity) FOODS and DRUGS cause they could INTERACT and INTERFERE with his success (drug/food interactions)]

DNA polymerase and Chain elongation inhibitors

*Intro* 4. Cytarabine (sitar) -what is the structural difference between cytarabine and cytidine? = cytarabine has an arabinose instead of a ribose 5. Gemcitabine (Gem-sitting) -structure is similar to cytarabine but with a gem-difluoro group at C3 -what is the active form of gemcitabine? = the TP form [actively throwing TP at gem sitter and sitar player] 1. Fludarabine Phosphate (PRODRUG) -an arabinoside [arab flood arab - wait it has "arab" in the name] -marketed as the monophosphate nucleotide -*phosphate gets cleaved off rapidly in the bloodstream* -[choppin off phosphorous (rapid cleavage of PO4) heads of innocents in the BLOODBATH that is the ARAB FLOOD] -[the FLUD was a PRO (prodrug) for rich arabs] Why is flud marketed as a phosphate? to improve aqueous solubility for IV administration -[cleaving off phosphorous heads means more blood means improved aqueous solubility means better LIVES (Iv) for the gross rich arabs who just want to see the poor and innocent die (improved solubility for IV)] -active compound = *2-fluoro-ara-ATP* -and deoxycytidine kinase (DCK) is the enzyme that creates this active compound -so FLUD --(DCK)--> 2F-ara-ATP [be more active u 2-F(luoro)AT-Piece of Shi --> the arab FLUD D*CKS (DCK enzyme) said this to me] *MOA* 4. Cytarabine (sitar) -acts as a false substrate for DNA polymerase -can get incorporated into DNA and terminate chain elongation -inhibits DNA AND RNA polymerase and nucleotide reductases -active in the S phase of the cell cycle 5. Gemcitabine (Gem-sitting) -DNA polymerase inhibitor -false substrate for DNA polymerase -Gem-cit DIPHOSPHATE also inhibits RIB-RED -[while gem-sitting some DiPsh*t kids make me see RIB RED] 1. Fludarabine Phosphate -inhibits DNA polymerase -inhibits ribonucleotide reductase -[one sec I'm taking DA-best-NAp (DNA) PROLLY (DNA poly) of my life, next sec I wake up to RIB-RED corpses everywhere cause that's what arab flood did] ^^Basically all MOAs: -DNA poly inhibitors -Chain terminators [DPICT perfect] *but with gem-sitting, also DP inhibits Rib Red -[FLUDding our GEM-SITTING activities with sitar music is the MECHANISM to DePICT a horrible night (flud, gemsit, sitar = dpict] [and what makes it WORSE is that gem-sitting may also bring DIPshts who make me see rib-red (gem-sit-DP inhibits Rib Red)] *Indication* 4. Cytarabine (sitar) -acute nonlymphocytic leukemia -meningeal leukemia (available as an intrathecal administration for this) -[sitar indicated for mANLy MaLes] 5. Gemcitabine (Gem-sitting) -in combo with carboplatin for treatment of patients with advanced ovarian cancer -in combo with paclitaxel for first line treatment of patients with metastatic breast cancer -combo with cisplatin for first line treatment of non-small cell lung cancer -first line treatment for adenocarcinoma of the pancreas -[gem sitters found out that: a. carbs are over (carboplatin, ovarian cancer) b. u can get first place PACMAN as a girl cause they oggle ur Bs (paclitaxel, breast cancer) c. no-small feat to sell Linguini to someone who prefers cis plate (cisplatin, non small cell lung cancer) d. gem sitting is first way to a-DINE on Pancakes (first line, adenocarcinoma of pancreas) ] 1. flud -B cell chronic lymphocytic leukemia -B CLL -[the flud makers, B-eware, we'll CaLL god] *Dosing* 4. Cytarabine (sitar) -IV 5. Gemcitabine (Gem-sitting) -IV 1. flud -IV [the arabs all have 4 (IV) side hoes] *Side effects* 4. Cytarabine (sitar) -n/a 5. Gemcitabine (Gem-sitting) -n/a 1. flud -called "AIDS in a bottle" due to it's significant immunosuppressive activity -[arabs can be racist so arab FLUD included a lot of gays cause they thought the gays were "AIDS in a bottle"] *ADME* 4. Cytarabine (sitar) -n/a 5. Gemcitabine (Gem-sitting) -longer t1/2 than sitar -Gemsitting = 19 hours, sitar = 3.6 hours -likely due to presence of the GEM-DIFLUOROMETHYLENE GROUP -[we can tolerate sitting gems for longer than hearing the sitar cause gem sitting offers DA FLOORINGLY good METH (difluoromethylene gives better half life)] 1. flud -F on C2 helps it be resistant to degradation -[the Factories were mysteriously resistant to degradation in the arab FLUD]

Anti estrogens (blocking estrogens) [SERM!! hand her over you FIEND (fene, phene)]

*MOA* 1. tamoxifen -SERM (selective estrogen receptor modulator) (estrogen antagonist) 2. toremifene -SERM 3. clomiphene -SERM -the E/Z mixture has estrogenic and anti-estrogenic activity -these are GEOMETRIC isomers 4. raloxifene -SERM -acts as an estrogen AGONIST in osteoblasts/clasts and ANTAGONIST in breast/uterine receptors -makes sense cause it treats low bone volume and overactive breast cancer *Indication* 1. tamoxifen -breast cancer 2. toremifene -breast cancer 3. clomiphene -fertility drug 4. raloxifene -osteoporosis -breast cancer *Dosing* 1. tamoxifen -oral -minor metabolite endoxifen (has an extra OH at the top) makes it more *pOHtent* than the parent 2. toremifene -oral 3. clomiphene -oral 4. raloxifene -n/a *Warnings* 1. tamoxifen -tamoxifen resistance can occur -on prolonged treatment, agonist property takes over and tamoxifen feeds the tumor 2. toremifene -BBW = QTC prolongation 3. clomiphene -n/a 4. raloxifene -less resistance than tamoxifen

Macromolecular Anticancer agents - MoABs

*intro* 1. Alemtuzumab [alum] -humanized IgG1 MoAb [see "zu" in name --> zuu the dog is humanized cause he's part off the family] [IgG1 --> says he's been the oG since day 1] 2. Bevacizumab [bevel] -humanized IgG1 moAB (see "zu") -[point the BEVEL up --> has been the OG message since day 1] 3. Cetuximab [set tux] -chimeric monoclonal antibody (xi) 4. Panitumumab [PAN it 2 u] -human MAB (tum "u") 5. Rituximab -chimeric "xi" 6. Trastuzumab -humanized "zu" 7. Blinatumomab [Bling] -new class of MoAb known as BiTE = bi-specific T-cell engager -it links the CD19 on B-cells to CD3 on T cells --> allows T-cells to recognize/attack cancerous B cells [got BLING in that Bite] 8. Ramucirumab -fully HUMAN "u" MoAB *Therapeutic Uses* 1. Alemtuzumab -second line therapy for B-cell CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) -for people who have B-CLL who have been treated with alkylating agents and who have failed fludarabine therapy -[the ALUM donated all his money back to the school so now he has to BUY a crappy CeLL phone --> BCLL. PLUS he's the SECOND LINE on his mom's plan pffttt. he tried to get money first by FLOODING cookies with ALK-based icing but that didnt work, so now this is his next best option] -Off label: T-cell-prolymphocytic leukemia (T-PLL), an aggressive tumor for which no standard treatment exists -[the ALUM ripped OFF THE LABEL of his new crappy phone and let it TOPPLLE to the ground] 2. Bevacizumab -metastatic colon cancer in combo with standard chemotherapy [metaSTABBED me in the COLON with the BEVEL using the COMBO that is STANDARD for baby KEEM (chemo) OVER and OVER again (ovarian)] -ovarian cancer 3. Cetuximab -indicated for K-ras* mutation-negative (wild-type), EGFR-expressing colorectal cancer and for head and neck cancer -[Color of my Retina (colorectal) that u can see on my HEAD above my NECK is turning red with anger that my SET TUX looks KRAS and WILD cause there's EGG FR on my tux] -can only be used in people where Kras is NOT MUTATED, where its WILD TYPE -cause in 2012 they approved THERASCREEN KRAS TEST - which tested if your kras was mutated or not -KRAS IS A PROTO ONCOGENE. KRAS MUTATION IS VERY PREDICTIVE OF POOR RESPONSE TO CETUXIMAB -[if your set tux is lookin MUTATED AND KRAS, people will have a POOR RESPONSE to your cet tux] 4. Panitumumab -for treatment of EGFR-expressing metastatic colorectal cancer with disease progression despite prior treatment -so for metastatic colorectal cancer that expressed EGFR that is spreading even tho u gave it treatment -[first treatment didn't work (progression despite prior treatment) so we PANNED IT 2 U. now u can record superheros in the METAverse eating EGGS FR (egfr-expressive) through a COLOR-CORRECTED (colorectal) lense] 5. Rituximab [ritu] -CLL, non-Hodgkin lymphoma, rheumatoid arthritis -[CaLL the non-hodgepodge kids ONLY to eat RITU in our ARTHI-ROOM (rheum arthritis)] 6. Trastuzumab -in combo *with paclitaxel* for first-line treatment of HER2-overexpressing metastatic breast cancer -as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens [??] -HER2 overexpressing metastatic gastric cancer [do you trust HER 2? ik PAC MAN and MS.PAC MAN are a TRUSTING COMBO (paclitaxel/trust combo) when using META (metastatic) strats to end those ghosts like BEASTS CAN (breast cancer). trust me to take care of KATIE when she has GASTRITIS (gastric cancer)] 7. Blinatumomab -philadelphia chromosome-negative relapsed or refractory B-cell-precursor acute lymphoblastic leukemia (BCPALL that does not have philadelphia chromosome) -[i got my BLING CUT PAID ALL the way down in North Carolina since PHILADELPHIA has no bling for my bite] 8. Ramucirumab -colorectal cancer, metastatic -gastric cancer, advanced or metastatic (can be given as a single agent or with paclitaxel) -non-small cell lung cancer in combo with docetaxel [when they RAMMED me into the COLOFUL METAVERSE (metastatic colorectal), i was PACKIN some ADVANCED META GAS which is why im SINGLE (single or w paclitaxel --> advanced or metastatic gastric cancer). NO SMALL FEAT to be able to BREATHE in there for DOCE/12 hours (non-small cell, lung cancer, docetaxel)] *MOA* 1. Alemtuzumab -*Binds to CD52* (an antigen on the surface of mature lymphocytes). when drug binds to CD52, lymphocytes (cancerous blood cells) undergo cellular lysis -[ALUM lives in his mom's house and found grandma's old CD from '52 in the attic] 2. Bevacizumab -inhibits VEGF-A (which stimulates tumor blood vessel formation aka angiogenesis) -bevel directly binds to VEGF to form a protein complex which is incapable of further binding to VEGF receptors -[BLOCKING ANGIE (blocks angiogenesis) from injecting gross VEG(A)N- Frosting (VEGF-A) into the cupcakes using a BEVEL] 3. Cetuximab -binds specifically to the extracellular domain of EGFR -[EGG FR? on my SET TUX?? looks so KRAS and i look WILD and ungroomed (for wild-type KRAS) 4. Panitumumab -binds to the extracellular domain the EGFR*, preventing its activation -EGFR* = ErbB-1 and HER1 in humans [pan it 2 u to record superheros in the metaverse eating EGGS FR] 5. Rituximab -binds to CD20 located on B-cells. -*RITU destroys B cells* and is therefore used to treat diseases which are characterized by B cell PROLIFERATION or DYSFUNCTION (lymphomas, leukemias, transplant rejection, and some autoimmune disorders) -[parents have all CONTROL DESPITE me being 20 (CD20), they're still calling me to eat RITU in the arthi room and urging me to DESTROY B's on my report card and only get As] 6. Trastuzumab [trust u] -binds to EGFR2 (aka HER2/neu or ErbB2) -HER2 is amplified in 20-30% of early-stage breast cancers and has been associated with poor prognosis. -trastu has been shown to INHIBIT THE PROLIFERATION of human tumor cells that OVEREXPRESS HER2 -[we trust U, but do u trust HER2? she stole all ur EGGS FR, and for the 2ND time too!! (EGFR2). she even used all the wrong ERBS for the 2nd time too. she ate all ur eggs and [HER2] could BLOCK u like a PRO-LIFTER [binds EGFR2, blocks proliferation of cells that overexpress HER2] *binds to and blocks two dif things 7. Blinatumomab -new class of MoAb known as BiTE = bi-specific T-cell engager -it links the CD19 on B-cells to CD3 on T cells --> allows T-cells to recognize/attack cancerous B cells [got BLING in that Bite] 8. Ramucirumab -binds to vascular endothelial growth factor RECEEPTOR 2 (VEGFR2) -needed to block angiogenesis -[RAM some VEG FR in ur 2nd RECIPE (vegfr 2 receptor) of quesadillas sonu geez, then block ANGIE (block angiogenesis) from espanol chopped] *Side effects/warnings* 1. Alemtuzumab -BBW = [BRIM = alum is full to the BRIM with excuses of how he's about to get a new job and move out] -B = bone marrow suppression -R = REMS - its on REMS -I = infusion reactions that can be fatal -M = malignancies can be caused 2. Bevacizumab -BBW = GI perforations, surgery, wound healing complications, hemorrhage [i got GIPped on my WiSH that I could stab back the person who stabbed me with a bevel in a BLACK BOX] 3. Cetuximab -BBW = infusion reaction and cardiopulmonary arrest - closely monitor serum electrolytes -[im gonna get the CIS (cardiopulm arrest, infusion rxn, serum electrolytes) to investigate who got EGG FR on my set BLACK (bbw) tux] 4. Panitumumab -BBW = dermatologic toxicities, infusion reactions [zoom in with the BLACK BOX camera we panned to u - zoom in on spidermans DERM skin!! so smooth. this will surely INFUSE a RXN in the crowd, they love tom holland] 5. Rituximab -BBW = fatal infusion rxn, tumor lysis syndrome resulting in acute renal failure, mucocutaneous reactions and leukoencephalopathy -[F, T, A M L - all this RITU is giving me FAT LiMbs - i should take it to go in a BLACK BOX] 6. Trastuzumab -BBW = cardiomyopathy, infusion reactions, pulmonary toxicity -[i cant TRUST U when u took that PIC of me] 7. Blinatumomab -AEs (no BBW): Myelosuppression, serious and often fatal infections, hepatotox -[i Bling up MY FISH too (myelo, fatal infection serious hepatotox)] 8. Ramucirumab -BBW = risk of hemorrhage, including severe and sometimes fatal hemorrhagic events -[Ram Rammed into me causing me to hemorrhage and my BBL (BBW) to pop]

Mitosis Inhibitors (antimicrotubule agents) = Taxanes ************************************************ What do taxanes do -they bind to B-tubulin when it is POLYMERIZED or ELONGATED -["we're in for the ELONGATED-haul, polly] -so, by binding, it prevents the depolymerization -as a result, the microtubule cannot shorten

*intro* 1. paclitaxel -a NATURAL product isolated from the PACific yew tree (brev) -[Pac man comes NATURALLY to mama] 2. docetaxel -synthetic (baccata tree) 3. cabazitaxel -synthetic (baccata tree) -the triple meth version of DOCE [cabbies use 3x the amount of meth] --> lower PGP resistance and BBB penetration [cabbie, take me to the brookly bridge (BBB)] *MOA* 1. paclitaxel -prevents depolymerization (shortening) of microtubule -[mama suggests that we should PREVENT DEEPALI (prevents depolym) from using our PACMAN machine] 2. docetaxel -prevents depolymerization -[teacher, prevent deepali from sleeping next to my #doce sleeping bag] 3. cabazitaxel -taxane -prevents depol -[cabbie, put ur foot on the gas and PREVENT DEEPALI from catching up to me] *Indication* 1. paclitaxel -first line for advanced ovarian and non-small cell lung cancer (NSCLC) in combo with cisplatin -for anthracycline resistant metastatic breast cancer (alone or in combo with capecitabine) -[pacman, firstly, is NOT-SMALL, OR OVERrated (non-small cell, ovarian cancer) even tho its hard to see on a CIS-PLATE with tons of other games in one place.] -[tell the pacman player u have the CAPACITY to move out of that ANTHRAX basement that used to be ur mom's who died of breast cancer (combo of pac and capacity for anthracycline-resistant breast cancer)] -what is the advantage of paclitaxel-capecitabine combo therapy? = pac can upregulate thymidine phosphorylase (which activates capecitabine) 2. docetaxel -breast cancer -also for NSCL cancer, prostate cancer, gastric cancer, and head and neck cancer [BPH GN Non-small] -[preK teacher with BPH told us lights out. i said GN and knocked in my non-small sleeping back #doce] 3. cabazitaxel -docetaxel resistant metastatic prostate cancer -[the pros (prostate cancer) smoke meth like cabbies to get PGC off their ass (to reduce PGP resistance, like what happens in DOCE] *Dosing/ADME* 1. paclitaxel -IV -DDIs with drugs metabbed by 2C8 -due to poor solubility, a mixture of water, alcohol, and cremophor EL is used. -cremophor EL causes hypersensitivity which can be reduced by pretreatment with dexamethasone and antihistamines -[pac man machines have POOR SOLUBILITY - watch out for basement flooding] -[we are going to go watch PACMAN gamers CREAM each other lIVe (IV) (given with cremophor) and blow each other up with C8 (DDIs with 2C8)] 2. docetaxel -IV -has a C10-OH (instead of a methoxy like paclitaxel) giving it better solubility -efflux by PGP causes resistance -[PGC effluxed (pgp efflux) our DOCE-lunch time and replaced it with 10'oclock- OH god (doce has 10-OH not 10-methoxy like pac --> better sol) just let us LIVE! (IV)] 3. cabazitaxel -IV -[cabbies LIVE exciting LIVES (IV IV IVVV) *SIDE EFFECTS* 1. paclitaxel -main mechanism of resistance to this drug: cellular efflux by Pgp -[PGC effluxed our pac man machine from the break room] -hypersensitivity, myelosuppression -there's an albumin-bound form that doesn't have the hypersensitivity -FDA pregnancy risk category D teratogen -[pregnant lady got a D+ on her pac man playing skills, she got sensitive and started calling for myelo (sensitivity, myelosuppression), he told her new ALBUM is out so quit the sensitivity (albumin-bound form has less sensitivity)] 2. docetaxel -same as pac -[pregnant lady got a D+ on her pac man playing skills, she got sensitive and started calling for myelo (sensitivity, myelosuppression), he told her new ALBUM is out with DOCE songs (docetaxel) so quit the sensitivity (albumin-bound form has less sensitivity)] 3. cabazitaxel -[pregnant lady got a D+ on her pac man playing skills, she got sensitive and started calling for myelo (sensitivity, myelosuppression) to get the CAB (cabbie), he told her new ALBUM is out with DOCE songs (docetaxel) so quit the sensitivity (albumin-bound form has less sensitivity)]

Mitosis Inhibitors (antimicrotubule agents) = Vinca Alkaloids ************************************************** -these inhibit POLYMERIZATION of microtubules, NOT DEPOLYMERIZATION -so these inhibit POLLY not deepali -[Vinny has a parrot named polly]

*intro* 1. vincristine -natural 2. vinblastine -natural -*blocks GTP binding to a/B tubulin heterodimer* -[vinBLAST into the GATES (GTP) of the AB --> the academic building] 3. vinorelbine -[i have semi-synthetic teeth vinORALLY] *MOA for all* [Vinny has a parrot named POLLY - inhibits tubule polymerization] *DOSING FOR ALL* [IV --> VINCA backwards is IV] *ADME* -rapid distribution to tissues -vincristine has the longest t1/2 -do not cross BBB -[vinCRISTY can TALK for the longest t1/2 about the stupidest sh**. she's so dumb, no info ever gets past her BBB] *AES* -all are severe vesicants -[VINNY VESICANTS] *Resistance* -PGP efflux -[vinny's in PGC and they're trying to EFFLUX him]

Antibody drug conjugates (ADCs)

*not sure if i have to know what kind of linkers used for each one* *Intro* 1. brentuximab vedotin -chimeric antibody drug conjugate (ADC) "xi" -[Brent was a dark child (ADC)] 2. enfortumab vedotin [en fortune 500] -fully human ADC conjugated with MMAE* (monomethyl auristatin E) (u could tell by the name -vedotin) via a proteolytically cleavable linker -"u" -[en this FORTUNE 500 is A DARK COMPANY (ADC) 3. Adotrastuzumab Emtansine (seems like any MAB with a second part to the name is an ADC) -humanized ADC -trastuzumab conjugated with a cytotoxic drug EMTANSINE (aka MERTANSINE or DM1) via some modified linker -[tell this is conjugated to emtansine from the name] -[tell this is trastuzumab in part cause of the name as well] -"zu" -[EM, ur TAN is lookin like a MERmaid TAN, ull get 1 DM tn ill tell u that] 4. Fam-trastuzumab deruxtecan -humanized ADC "zu" -u can tell its an ADC by looking at the name 5. Gemtuzumab ozogamicin [gem rush for bozo's --> cali] -humanized ADC -"zu" -tell its an ADC from the name -this MoAb is conjugated with CALICHEAMICIN (a small molecule that breaks DS-DNA) -[the BOZO rushed to CALI for the GEM-RUSH (gold-rush) (ozogam, calichea, gemtuzumab)] -[CALI is ITCHY with people full of DESperation in their DNA (DS DNA)] 6. Ibritumomab tiuxetan [I'm a BRIT in a TiuX - how jake would say "tux" - JAMES BOND!] -A murine ADC (radioimmunotherapy) --> "mo" = mouse -tiux is a chelator to which radioactive isotope (yttrium-90 or indium-111) are added. and now tiux is conjugated to I-BRIT -[james bond says "i want to be a MURINE biologist" over the ACTIVE RADIO (its radiotherapy that uses radioactive isotopes), while hovering over the INDIAN ATRIUM (indium, yttrium) in his CHILL TUX (tiux is a chelator)] 7. Tositumomab -"mo" = murine -a murine IgG2a ADC that is covalently bound to radionuclide iodine-131. -iodine 131 emits both beta and gamma radiation, causing cell death -[tossing (tositumomab) a GRuB-INVITATION TO DINE (gamma, radiation, beta) (tosit. covalently bound to iodine-131, making it an ADC) atchya for level 2a of the GRAND (igG 2a) asian-dinner food Court (ADC)] *Indications* 1. brentuximab vedotin -anaplastic large cell lymphoma ALCL -Hodgkin's -[Brent drinks a HODGEPODGE of ALCohoLs with LARGE ANNA] 2. enfortumab -urotherlial cancer, locally advanced or metastatic -[UR OTHELIA? the en fortune 500 women's products company?] 3. Adotratsuzumab Emtansine -HER2+ breast cancer patients who have failed to respond to trastuzumab and taxane -[the first round of evaluating how he TREATS HER 2 was TAXING (taxane), but now we are trying AGAIN. this time we are bringing in EMILY, cause he treats HER SO POSITIVELY (2nd try to treat HER2 POSITIVE breast cancer) (after using taxane and trastuzumab and they didn't work) 4. Fam-trastuzumab deruxtecan -HER2+ breast cancer -[Fam, u TRUSTED HER2? are u POSITIVE?] 5. Gemtuzumab -acute myeloid leukemia (AML) -[the gem-rush ALTERED MY LIFE forever] 6. Ibritumomab tiuxetan -B-cell non-hodgkin's lymphoma -[James bond is a Brit (Bcell) - NO HODGEPODGINESS allowed (non-hodgkin's)] 7. Tositumomab -CD-20 POSITIVE, non-Hodgkin's lymphoma -BBW: serious allergic reactions (including anaphylaxis), prolonged and severe cytopenias, and radiation exposure -ARC -[this dumb 20YO just positively TOSSED IT -my 20yoCD - (tositumomab is for CD-20 positive cancers) into the closing doors of a BLACK BUS at ARC (BBWs = ARC). me, someone who has NO time for HODGEPODGINESS, am infuriated (tosit treats non-Hodgkin's lymphoma)] MOA 1. brentuximab vedotin -binds to cell surface CD30 on tumor cells -the MAB BRENT is LINKED TO the antiMITOTIC agent monomethyl auristatin E (MMAE) which is reflected by "vedotin" via a linker -the antibody portion attaches to the CD30, delivering the antimitotic MMAE (cause the tumor internalizes it) which is THE PART RESPONSIBLE FOR ANTI-TUMOR ACTVITIY -MMAE inhibits MICROTUBULE POLYMERATION (similar to vincas) -the peptide linker is Cit-Val and there are 4 MMAE's per IgG (don't think we need to know this - check quiz) -[Brent is in MMA due to a VENDETTA - mmae is "vedotin"] -[MMA PROLLY (polym) gives Micro-Tubes of steroids to its winners, not TUMS. the MMA is ANTI-TUMS (anti-tumor activity of this ADC is due to MMAE only. IgG is simply able to recognize and bind to tumor cells)] 2. enfortumab [fortune 500] -binds to nectin-4, an adhesion protein highly expressed on several solid tumors -subsequent to binding the drug is internalized, and proteolysis release MMAE intracellularly where it INHIBITS MICROTUBULE POLYMERIZATION -[en fortune 500s they PROLLY watch MMAE all day long and hand out MICRO-TUBES of cocaine (mmae is the part with anti tumor activity that inhibits microtubule polym) -[NECK beard who was a SOLID 4/ ten was BOUND to me as i roamed the FORTUNE500 company] 3. Adotratsuzumab Emtansine -binds to HER2/neu (EGFR2) RECEPTOR, enters the cell where emtansine is released and INHIBITS TUBULE POLYMERIZATION (its also an antimitotic like vincas) -[Ado, u threw EGGS FR at my car 2X (ado binds to egfr2), and now ur going to treat HER (emily) like that 2 (EGFR2 is basically HER2)?? EMILY u should PROLLY INHIBIT him from being able to get his TUBES of sperm (B99 reference) ever again (emily is the part that inhibits polymerization of tubules)] 4. Fam-trastuzumab -Fam trastuzumab binds to the HER2/neu receptor -[Fam, u treated HER 2 well considering she was so NEU] -deruxtecan is a camptothecin analog. the N-acylated exatecan is 10-fold more potent than SN-38, the active metabolite of irinotecan. -exatecan is a TOPOISOMERASE I inhibitor -[FAM (fam-trastuzumab), EXACTLY (exatecan) what were u and DERICK (deruxtecan) doing with only ONE of u with ur TOPs on (top1 inhibitor)? Derick from camp (derick is an analog of camptothecin) ?? he is EXACTLY 10X more potent at getting girls than SN-38 from Irene's (irinotecan) camp (derick/exact is 10x more potent than SN-38)] 5. Gemtuzumab -binds to the CD33 antigen. this antigen is expressed on the surface of leukemia blasts in more than 80% of patients with AML (gem-rush altered my life) -after binding, its internalized and calicheamicin is released and goes to break DS DNA -[do you think people of CALIFORNIAN DESCENT even lived past 33 back during the times of the gem-rush (CD33 binding of gem)] 6. Ibritumomab tiuxetan -binds to CD20 antigen found on normal and malignant B cells -CD20 is expressed on >90% of malignant B cells in non-hodgkins so this is a great target -*the antibody part binding to CD20 allows radiation from the attached isotope (mostly beta-emission) to kill the cell and nearby cells as well (wowowo)* -in addition, the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and apoptosis -together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells 1. James bond binds to CD20 -[james bond leaves 20ppl cut and dry, cut and dead] 2. iodine-131 releases radiation (mostly beta emission) 3. antibody part, I-brit tiux, activates ADCC and CDC, triggering apoptosis -CD20, radiation, ADCC, CDC, apoptosis -[20 belligerent ACDC CD's are found at the CDC- always ACDC music RADIATING down the halls that make my ears want to POP, pls JAMES BOND come sneak in and turn it off] 7. Tositumomab -Binds to CD20 antigen which is found on the surface of both normal and malignant B cells -[this dumb 20YO just positively TOSSED IT -my 20yoCD - into the closing doors of a BLACK BUS at ARC. and i have NO time for hodgepodginess. (tositumomab binds to CD-20 so it can help treat CD-20 positive non-hodgkins B-cell lymphoma)]

antimetabolites - purine antagonists ***************************************** PURINE ANTAGS = -MOA: inhibit the de novo synthesis of GMP and AMP -Pure Mina the GiMP goes down the rAMP] -the rate-limiting enzyme that allows the synthesis of purine nucleotides in cancer cells is GLUTAMINE AMIDO-PHOSPHORIBOSYL TRANSFERASE (target for mercaptopurine) -lets call it [GAPT] -[murky captain leaves his crew aGAPT with his strange ways] what rxn is carried out by GAPT -it AMINATES (adds amino) to a RIBOSE on C2 -the formylation rxn catalyzed by glycine amide ribonucleotide transformylase (GAR transformylase): -REQUIRES 10-FORMYL THF to donate a formyl group -[GARy the PURE ANTAGONIST (purine antagonists) requires 10 formal THick F*CKS (10Formyl THF)] --> emphasis on FORMYL because this group DONATES the formyl group to GAR transformylase -the production of AMP and GMP (pure mina the gimp goes up a ramp) requires 10Formyl THF and GAR to add formyl to our ribose -and the murky captain... leaves his crew aGAPT --> glutamine AP transferase is the target of mercaptopurine THIOPURINE ANTIMETABOLITES =?? thiol-containing purines -6-TG (thioGUANINE) looks like guanine, (has the NH2 at the bottom)!! in the 6th position where =O usually is, tho, its replaced with an SH (a thiol) -6-murky-captain does not have an NH2

- both are *prodrugs* that must be converted to RIBONUCLEOTIDES by hypoxanthine guanine phosphoribosyl transferase (HGPRT) before they gain activity -[the murky pirate and the _____ are both PROS] -PRODRUGS --(HGPRT)--> active ribonucleotide analogs -prodrugs = NUKE analogs -what we need = RIBOnukes -so: HGRPT (hagrupt) =HAGRUPTLY ADDS the ribose to the nukes/drugs (like hagrid adds ribs to his nuclear-sized plate.) -as SOON as the ribose gets added, the molecules is active. any intermediate containing ribose gets activated -[the second those ribs touch hagrid's plate, his salivation is ACTIVATED] *u need to hagruptly add ribs in order for salivation to activate -THEN, when these prodrugs are ribosylated by HGRPT, they are just monophosphorylated. this molecule itself can inhibit AMP and GMP just fine by inhibiting certain enzymes (like 6-murky captain inhibits aGAPT, so AMP and GMP can't be formed). however, they can be further phosphorylated into TRIPHOSPHATE where they can compete with A/G-triphosphate for incorporation into DNA (or RNA, depending on how many OHs), and then stop chain elongation ------------------------------------------------------- *MOA* 1. 6-MP (murky captain) -inhibits the de novo synthesis of purine nukes (AMP, GMP) -how? by INHIBITING GAPT, the rate-limiting enzyme that synthesizes AMP/GMP -[the murky captain sends PURE mina the GIMP off the RAMP cause he wanted her to walk the plank (6MP inhibits purines AMP/GMP)] -[for a LIMITED RATE, the murky captain can leave your whole crew aGAPT and INHIBIT any misbehavior (inhibits GAPT, rate-limiting step)] -6-MP triphosphate incorporates into RNA and DNA -[if u TRY to FOSTER a relationship with the MURKY CAPTAIN he'll have u RUNNING saying DANG (triphosphate 6-MP incorporates into RNA/DNA] *since the MAIN mechanism is inhibiting GAPT to inhibit synthesis of AMP/GMP (rather than incorporation into DNA/RNA as triphosphate), there is a LOWER RISK for mutagenesis and secondary malignancy compared to 6-TG -[murky captain offers low risk that your crew will Mutate and Succumb-toMalignancy (low risk of mutagenesis and secondary malig. compared to 6-TG, which focuses on an enzyme more downstream)] -MECHANISM OF RESISTANCE = deficiency in the activating enzyme HGRPT (ahh so the cancer cells will start limiting their production of HGRPT so it can't ribosylate these drugs) -[the cancerous crews at sea will form a RESISTANCE to hagrid and will BAN HAGRID because he hagruptly adds all their ribs to his plate and they're sick of it (cancer cells can form a resistance to 6-MP by reducing HGRPT so it can't activate the drug) 2. 6-TG (thigh gap?) -inhibits de novo synthesis of AMP/GMP by inhibiting aGAPT (rate-limiting step) -the *active form 6-TGTP* (adding a triphosphate) gets incorporated into RNA. -the active form deoxy-6-TGTP gets incorporated into DNA -higher chance of mutagenesis because its easier for this drug to target getting incorporated into RNA/DNA -[my 6-thigh gap left mouths aGAPT lol, i got INCORPORATED into many RUNNING/DANCING groups bc of it and cause of my TIGHT-PILATES (triphosphate) form (greater incorporation into RNA/DNA when it's in TP form] *Indication* 1. 6-MP -ALL, AML -[ALL i AM-Looking for on these waters of the murky captain (6-MP) is hagrid, someone INDICATED he would be here (6-MP indicated for ALL, AML (acute lymph/myelo leukemia)] 2. 6-TG -nonlymphocytic leukemias -[my thigh gap and non-limping gets LOOKS] *Dosing* 1. 6-MP -oral -but absorption can be erratic and is reduced by the presence of food -[murky captain's hostage HAGRID EATS ribs (oral). but he eats em so hagruptly and ERRATICALY that the PRESENCE OF THE FOOD is REDUCED quickly (6-MP is oral, erratic absorption, reduced absorption in presence of food) -[murky captain YELLS ERRATICALLY and reduces everyone's rations of food] 2. 6-TG -oral, but absorption is variable -[i always here people WHISPERING (oral) about my thigh gap] *Side Effects* 1. 6-MP -bone marrow suppression -major metabolizing enzyme is Thiopurine S-methyl transferase (TPMT) --> patients with inherited little or no TMPT activity are at risk of increased PURINETHOL toxicity and usually require substantial dose reduction -[Side effect of murky captain is his NO room in his TEMPERMENT (TPMT) for increased toxicity among crew members, he'll start hitting/suppressing u with a BONE (bone marrow supp)] (little-no TMPT = increased toxicity) 2. 6-TG -TMPT deficiency causes serious myelosuppression -[i have zero room in my temperment for these rumors about my thigh gap, i will suppress u with MY-LOW kick]

Immune checkpoint inhibitors

- immune checkpoints are there to MINIMIZE any collateral damage from a defective cell process - can be either stimulatory or inhibitory factors - inhibitory: PDL 1 or PDL2 bind to PD1 [l = LIGAND] -[if the PEDAL is in a certain position, it INHIBITS you from being able to ride the bike] - inhibitory: CD80 and cd86 bind to CTLA4 -stimulatory: CD80/86 bind to CD28 - nvm, theyre not inhibiting from BINDING, they actually DO BIND and then cause INHIBITION OR ACTIVATION OF T CELLS - whereas, for stimulatory: binding will ACTIVATE T CELLS so inhibitory and stimulatory refer to its effect on T CELLS tumors can SUPPRESS THE ACTIVATION OF T CELLS by secteting inhibitory factors like PDL2, PDL2 or CD80 And 86. these ligands then go to T CELL receptors and bind to them, causing them to become inactivated - because these inhibitory checkpoints are FACTOR-RECEPTOR interactions, they can be blocked from binding by antibodies -ANTIBODIES bind to CD80/86 AND PDL1/PDL2 so that these factors can no longer bind to THE RECEPTORS ON T CELLS: PD1 and CTLA4 -remember that CD28 is the only stimulatory receptor. ctla4 and pd1 are inhibitory -also remember that these "inhibitory factors" are STILL BOUND TO THE CANCER CELLS - so these cancer cells are "expressing" inhibitory factors that can bind to T-cells and inactivate them so antibodies are used to INHIBIT these immune checkpoint factors - therefore they are IMMUNE CHECKPOINT INHIBITORS -ALL MABs are IV -remember that a PDL1 inhibitor will bind to the site where it's supposed to connect with the PD1 receptor on a t-cell

Steroid Structure

-Basic ring system contains four fused rings: three six-membered rings and one 5-mem ring -the saturated ring systems are TRANSfused -often substituted at various carbons: C3, C10, C13, and C17 -what is the major structural difference between ESTROGEN and OTHER STEROIDAL HORMONES? --> estrogen's A-RING is AROMATIC -[ESTER has a great AROMA]

the role of the immune system in fighting cancer

-cancer cells produce tumor antigens on their surfaces -antigen-bound APCs (antigen presenting cells) activate B cells and T cells -t cells activated by APC multiply and seek out and destroy tumor antigens -when activated by APC, B cells become plasma cells that make antibodies. these antibodies mark tumor cells for elimination -dying cancer cells release additional antigens, propagating the cancer immunity cycle -*APCs, B cells, and T cells and NK cells interacting with the TUMOR ANTIGENS are the CORE COMPONENTS of the immune response that work to eliminate cancer cells* -cancer can actually RESULT from a compromised immune system -so we want to boost the immune system -cancer immunotherapy is then aimed at boosting our immune system -*cancer immunotherapy is the "fifth pillar" of cancer treatment* CANCER IMMUNOTHERAPY -the immune response cannot always eliminate all cancer cells -sometimes an EQM IS REACHED where the tumor is CONTAINED but not destroyed -then the tumor MUTATES and EVADES THE IMMUNE SYSTEM as its growing -the GOAL of immune therapy is to RESTORE THE IMMUNE SYSTEM so that it can eliminate the cancer

classification of cancer

-cancers are classified by the TYPE of CELL that the tumor cells resemble and are therefore presumed to be the ORIGIN of the tumor. -types include: 1. carcinoma = cancer derived from EPITHELIAL CELLS [epic carson] -includes many of the most common cancers in the elderly -includes cancers of the breast, prostate, lung, pancreas, and colon [BP, has carson gotten his LiPCheck yet?] 2. sarcoma = cancer derived from CONNECTIVE tissue [i want to CONNECT my fist to SARCONA's face] (bone, cartilage, fat, nerves) 3. lymphoma and leukemia = cancer derived from HEMATOPOEITEC cells that LEAVE the bone marrow and MATURE in the lymph nodes/blood -leukemia is the most common type of cancer in kids (30%) 4. germ cell tumor = cancers derived from pluripotent cells , most often presenting in the TESTICLE OR OVARY 5. blastoma = cancers derived from IMMATURE, UNDIFFERENTIATED cells or embryonic tissue -blastomas are more common in children than older adults

What are nitrogen mustards? (they are CARBON BASED ALKYLATING AGENTS unlike platinating agents)

-carbon based alkylating agents (unlike platinum based) -*cytotoxic* chemotherapy drugs (remember that cytotoxic chemicals are not cell-cycle specific and they are more toxic to G1 and S phases) -*Non-specific DNA alkylating agents* -originally used in chemical warfare because they are powerful and persistent blister agents (vesicants) -decreases number of lymphocytes (for people exposed to them that actually survive) (is this MYELOSUPPRESSION?) -nitrogen mustards were studied at Yale for the treatment of lymphoma (overproduction, rapid, of lymphocytes) -any molecule with an N, and Chlorine atoms on the 2nd carbon from the N Nitrogen mustards get decomposed into inactive compounds in aqueous media -the 3-mem ring (aziridinium) intermediate is a potent alkylating agent, but eventually it turns into a compound where both the Cls are OHs and this is not an alkylating agent (its inactive) -this metabolism happens when the nitrogen is NOT PROTONATED (at a higher pH) -so to prevent metabolism, the drug is stored at a LOWER pH so that the nitrogen will remain protonated (low pH = more acidic = more proton = more protonated) -at phys pH unprotonated drug cyclizes to reactive aziridinium intermediate which is a potent alkylating agent MOA -bis-alkylating agent via reactive aziridinium reactive intermediate (potent alkylating agent) -form DNA cross-links, preventing DNA transcription and DNA replication (so the cross linking prevents DNA from being able to go further in its processes) -the DNA adducts that form by the interaction with the N-7 of guanine are chemically unstable -these adducts can undergo either depurination (loss purine from ribose-phosphate) of DNA or destruction of the purine base

Naming of Unsaturated Steroids (meaning theres some double bonds in the rings)

-double bonds are specified with the number of the position from which it starts, followed by -ene -if the double bond can be drawn in only one direction, only the starting position needs to be specified -double bonds can also be indicated by a capital delta with the position(s) of the bond specified by superscripted numbers -if however, a double bond is formed to any position other than the next higher numbered carbon, or if it can be drawn in two different directions, then the end of the double bond also needs to be specified -so 8-->9 does not need to be specified as 8(9) -but 8--> 14 does need to be specified as 8(14) -5a-Cholest-8(14)-ene = 5a-DELTA^8(14)-cholestene

metastatic cascade

-in general, anticancer therapy is most effective if initiated when the tumor is growing aggressively but is small -conversely, slow-growing tumors with a high percentage of cells remaining in G0 (ie non-small cell lung cancer) are often nonresponsive to cell cycle-specific chemo (think, lung cancer takes a very long time to develop. a tumor could be growing very slowly) -metastasis = process by which MALIGNANT cells leave the parent tumor and MIGRATE to distant sites and invade NEW TISSUE -the primary metastatic media are blood and lymph fluids -metastatic cascade = when cells DETACH from the basement membrane, INVADE the capillary wall, travel through bloodstream until they eventually ADHERE to capillary wall, ESCAPE from blood vessel (the capillary) (aka EXTRAVASATION --> created those red splotchy rashes), and PROLIFERATE to form METASTASES -there are many opportunities within the metastatic cascade ^^ for the body's immune system to launch a SUCCESSFUL attack and kill those cells. -so basically, tumor cells break off from their tumor, travel through the bloodstream (one of the metastatic media) and attach to a new site, then proliferate into a new tumor

Epothilone: Ixabepilone

-inhibits microtubule depolymerization -IXAB = a semisynthetic epothilone B (natural molecule) analog -IXAB's LACTAM group gives it better water solubility and stability (so, epothilone has O-C=O. IXAB is NH-C=O --> NH gives it a charge making it more H2O sol) -low susceptibility to PGP drug resistance -used in combo with capecitabine for metastatic breast cancer -peripheral neuropathy, neutropenia -BBW with impaired hepatic function -[the IX (ICK's) of ABE - he's lactose (lactam) and his AMIGOS (amino) r too - they are more soluble to water, not milk (better water sol). he's unbothered that he got EFFLUXED from his apt by PGC (low susceptibility to PGP resistance.) icky abe now only has capacity (capacetabine) to go live in mom's BLACK-BOX HECTIC (hepatic impaired BBW) basement who died of breast cancer (BC)] -[icky abe went to PENN state --> PEripheral neuro, neutropenia]

tumorigenesis

-normal cells grow, divide (mitosis, only a few times) and die (apoptosis) in an orderly fashion -cancer cells grow and divide uncontrollably and do not undergo apoptosis (death) what are the 2 genetic factors that control tumorigenesis? 1. proto-oncogenes become oncogenes 2. tumor suppressors get inhibited -proto-oncogenes are the normal versions, they come Pre- (before) the cancerous oncogene. they code for normal proteins that help regulate cell growth and differentiation. they are involved in signal transduction and execution of mitogenic signals through their protein products -examples: italicized --> ras, wnt, myc, erk, trk (they can be capital or lowercase) -oncogenes = formed via spontaneous point mutation, inherited germline mutation, misregulated protein expression, or chromosomal translocation [CIMS] -tumor suppressor genes, such as p53, p21, pINK4A, and Rb are inhibited. this leads to tumors. as an example, loss of p53 tumor suppressor gene is found in ~50% of human cancers

Platinating Agents

-so we know they only bind to A and G -we know that platinating agents and nitrogen mustards are the only two agents that can have crosslinking of two strands -and we know that there are two types of cross linking: inter and intra So, with this info, what are the different linked adducts we can form? -d(GpG) - two G's same strand - intra -d(ApG) - A intra'd to G -d(ApA) - two A's intra's --> no, not one of the examples -d(GpXpG) - two G's that are sepp'ed by another base are linked -interstrand cross link where actually Pt is not only linked to a G on strand 1 but also C on a strand 2 specific site of attachment of platinating agents on DNA -N^7 position of A and G -interstrand products = 90% -intrastrand products = 5% -DNA mechanisms are usually unable to correct the damage from platinating agents so it typically causes CELL CYCLE ARREST and APOPTOSIS -ALL currently marketed drugs are platinating agents with Pt(II) complexes and a SQUARE PLANAR GEOMETRY -although, an octahedral Pt(IV) complex is currently undergoing clin trials

what are antimetabolites

-these drugs inhibit specific, normal metabolic processes -they inhibit DNA SYNTHESIS -*can inhibit the enzymes that synthesize nucleotides* -can arrest chain elongation by *incorporation into DNA* as false substrates -classifies according to the type of nukes they inhibit: -purine antagonists (inhibit the biosynthesis of AMP and GMP (AG)) -pyrimidine antagonists (inhibit the biosynthesis of dTMP --> not C?) -antimetabolites are active in S phase (DNA synthesis phase)

tumor specific monoclonal antibodies

-these mabs are tumor specific (called MoAbs) -they target tumor ANTIGENS or tumor cell surface RECEPTORS -the antibody-antigen complex recruits endogenous immunomodulator and cell-destroying cytokines (like MPs and killer T-cells) to fight the cancer -humanized or chimeric moAbs = they reduce the risk of the immune response backfiring and attacking the drug cause they make it seem like the drug is endogenous to humans -humanized = it was non human but they EDITED THE PROTEINS to make it seem human -BBW for most MoABs --> the BBWs for MoABS are [THIC] T = tumor lysis syndrome H = hypersensitivity rxn, hemorrhage, hepatotoxicity I = infection, infusion reaction C = cytopenia, cardiomyopathy, cardiopulmonary arrest Fab = antigen binding site --> binds to antigens Fc = crystallizeable region --> sticks to cell receptors or complement -all moABS have the ending -mab -ximab = chimeric -umab = human -zumab = humanized -li/lim (liximab) = immune/immunomodulator -tu (tuximab) = tumor -les = infectious lesions -cir = CV -vir = viral -bac = bacterial went from: -fully MOUSE antibody --> chimeric (large part of the fork was mouse) --> humanized (small part of the fork was mouse) --> fully human

Estrogens

-three main estrogens: 17B-estradiol (wedge, OH on C17), estrone, and estriol -17B-estradiol --> estrone --> estriol -17B-estradiol is the estrogen that is PRODUCED in the greatest amounts in the body. undergoes rapid OXICATION (OH--> =O) into estrone -estrone = largest concentration in PLASMA -estriol is present in the greatest concentration in the urine Q: how are insoluble estrogens (and other steroids) cleared from the plasma? -estrogens are INSOLUBLE in water and HIGHLY PPB. they are cleared as WATER-SOLUBLE GLUCURONIDE and SULFATE CONJUGATES [CLEAR ester away from GLUE, shes SULFURICALLY clumsy] general therapeutic uses of estrogens -estradiol = in oral (tablet), transdermal (patch), vaginal (ring) [VOTE for therapeutic use of estradiol = vaginal, oral, transderm, ESTRADIOL] -use in prepubertal females to treat: gonad dysgenesis, EXCESSIVE height (no way), genital infections Use during reproductive years -to treat various conditions related to menstrual disorders, infertility, pregnancy, derm disorders, endometriosis -*FOR CONTRACEPTION - COMBO OF ESTROGEN/PROGESTOGEN therapy Use during post-menopause -post-menopausal syndrome -HORMONE-DEPENDENT BREAST CANCER -OSTEOPEROSIS (bc estrogen promotes activity of osteoblasts) Used IN MEN to treat -prostate cancer -sexual dysfunction so ESTRADIOL [vote] can be used for -contraception -hormone-dependent breast cancer -osteoporosis (activates osteoblasts) -prostate cancer [lets VOTE who estra-DIEs on CHOPped] --> contraception, hormone dependent BC, osteo, prostate cancer

Conjugated Estrogens

-what are two unique estrogenic compounds excreted in the urine of pregnant mares? = EQUILENIN AND EQUELIN (as their sodium sulfate conjugates = -[urine be smellin salty and sulfurous in pregnant 'MERicans, take some ELIQUIS (sodium sulfate -equelins (estrogen compounds) found in pregnant mares)] -eliquins are used in estrogen preparations, like premarin -oral, IV, IM -poor OBA -indication: treats uterine bleeding -BBW = can cause endometrial cancer, breast cancer, and CV disorders

Multiple Tyrosine Kinase Inhib

1. Afatinib

ALK Inhibs

1. Ceritinib 2. Brigatinib 3. Gilteritinib

BTK Inhibitors

1. Ibrutinib

Tyrosine kinase inhibitors (NRTKIs) -Bcr-Abl Inhibitors

1. Imatinib 2. Nilotinib 3. Dasatinib

Tumor-Agonistic Receptor Kinase Inhibitors

1. Larotrectinib 2. Palbociclib 3. Abemaciclib

JAK Inhibitor

1. Ruxolitinib

hallmarks of cancer

1. Sustaining proliferative signaling 2. Evading growth suppressors 3. Activating invasion and metastasis (tumor travelling) 4. Enabling replicative immortality 5. Inducing angiogenesis (blood vessel growth around tumors to provide nutrients) 6. Resisting cell death -this succession of genetic changes takes place which confer the cancer cell its malignant characteristics -loss of checkpoints between parts of the cell cycle contributes to tumorigenesis

what are the 2 fates of alkylated DNA?

1. depurination (loss of the purine) 2. hydrolysis of the purine

RTKIs: EGFR and EGFR/HER2 Inhibs

1. erlotinib 2. gefitinib 3. Lapatinib 4. Osimertinib

physiological effects of sex steroids

1. estrogens --> [eSECONDARY-gens] -female secondary sex characteristics/feminizing effects -development of reproductive tract 2. progesterone --> [primary =progesterone] -primary effect is on uterus -endometrium: secretory effects -myometrium: stop spontaneous rhythmic contraction -during pregnancy, placenta produces large amounts of progesterone. sends -ve feedback signal to hypothalamus to stop FSH and LH production 3. androgens -male secondary sex characteristics -differentiation and growth of male reproductive organs

Antimetabolites - Antifolates

1. methotrexate 2. pemetrexed

miscellaneous Antimetabolite

1. pentostatin

So many mechs literally called "miscellaneous agents"

5. Belinostat -HATs unravel the chromatin, allowing transcription -HDACs deacetylate (but your butt gets closer to the seat) and CONDENSE chromatin, blocking transcription -HDACs have so many substrates, so blocking them can induce apoptosis through many mechanisms -Belina is a HDAC inhibitor (aka a HDAI) -so it BLOCKS deacetylation, leading to acetylation and even hyperacetylation -this in turn leads to hypertransctiption, growth arrest in cancer cells, and then APOPTOSIS of cancer cells -normal cells are LESS SUCEPTIBLE to HDAIs -may promote p53 by expressing p21 -[belinda blocks historical DAQuiris. she'll aPOPtose u if she sees u with an old one. but normal kids are less affected/scared by belinda] *hydroxamic acid derivative [belinda is so DRAMATIC] 6. Panobinostat [Pan and trash bin] -hydroxamic acid derivative [dramatic] -[pan and Trash BIN is so DRAMATIC] 7. Glasdegib -the hedgehog pathway is important for the maintenance and regeneration of adult tissues -[hedgehog can maintain and regenerate its spikes] -in cancers, this pathway is over-activated along with activation of "smoothened" (SMO) - a protein crucial in hedgehog signal transduction -[hedgehogs ROLL so SMOOTHLY] -Hedgehog pathway inhibitor (by inhibiting SMO activation) -[GLASS inhibits hedgehog (pathway) by inhibiting his SMOoth roll ACTIVITY (activation)] 8. Ivosidenib -theres this gene called IDH1 -mutation of IDH1 occurs in 6.6% of AML patients [tAMiL IDLI gene] -so, we want to INHIBIT this gene since mutation of the gene is ONCOGENIC -Ivosid is an IDH1 inhibitor -[I VONT Tamil idli - also the structure has this square in it that looks like an idli] *Therapeutic Uses* 5. Belinostat -treatment of relapsed or refractory *peripheral T-cell lymphoma* -["Back (peripheral) up with the fake fractured/relapsed (refractory/relapsed) limp (lymphoma) TORY (T-cell)" said Belinda "i can see right through ur fake act even through my PERIPHERY (peripheral T-cell lymphoma)] 6. Panobinostat -Multiple myeloma -[Pan BIN and everyone else in the class says MMMM to chicken] 7. Glasdegib -newly diagnosed acute myeloid leukemia in combo with low-dose CYTARABINE -[I want to trim the hedgehog's spikes to give him A CUTE MILD LOOK (AML), then i want to play the sitar (cytarabine) for him] 8. Ivosidenib -acute myeloid leukemia - AML (in people with a susceptible IDH1 mutation) -[i vont tAMiL (AML) IDLI (in people with IDH1 mutation)] *MOA* 5. Belinostat -HDAC inhibitor (HDAI) -[Belinda inhibits Historical (histone) DAQuiris (DAC), only new recipes at her party] -so it promotes transcription 6. Panobinostat -HDAC inhibitor -[Bin hates any historical things including DAQuiris, she only wants new things, what a brat] 7. Glasdegib -Hedgehog pathway inhibitor (by inhibiting SMO activation) -[the hedgehog rolled in the GLASS inhibiting its ability to roll smoothly (inhibits SMO)] 8. Ivosidenib -IDH1 inhibitor -[i vont tamil idli] *ADME*/*Dosing* 5. Belinostat -Oral -[Belinda TOLD (oral) T to back up with the limp] -[belinda never SHUTS UP (oral) about how much she hates HISTORICAL DAQuiris] 6. Panobinostat -Oral -[BIN talks (oral) a lot about Nari] -[BIN never shuts up about how much she hates OLD HISTORICAL DAQuiris] 7. Glasdegib -oral -[I want to FEED my hedgehog who stepped in glass some leaves so he can EAT] 8. Ivosidenib -oral -[i vont to EAT tamil idli] ^^ALL ORAL, maybe look at the structures to see why? *Side effects* 5. Belinostat -Significant DDIs exist -Cardiovascular Edema -QT prolongation -dermatologic skin rash -[Belinda things she's a QT but she just gives everyone a skin rash. only person who likes her is her SIGNIFICANT DiDI who's HEART SWELLS (CV edema)] ^we won't need to know this in detail dude 6. Panobinostat -severe diarrhea -fatal/ischemic events -[I hope BIN (who sucks the oxygen out of every room from how much sh she talks -ischemic) gets severe diarrhea] 7. Glasdegib -BOXED warning: embryo/fetal toxicity -[mama BLACK BELT (bbw) hedgehog was worried i was being TOXIC to her embryo/fetus baby hedgehog so she attacked me] 8. Ivosidenib -can cause "differentiation syndrome" which can be fatal if not treated -boxed warning -[i cant DIFFERENTIATE between tamil idli and guju idli but at least its ON THE BOX (boxed warning)]

Ring fusion geometry and the terms "a" and "B"

5a-androstane = TRANS = PARALLEL = planar molecule = or on normal structures, alpha points DOWN [trAns] 5B-androstane = the A ring (with the C5) is CIS = PERPENDICULAR A-RING compared to rest of molecule = or on normal structures, B points UP [beta get up] [CIS, B- real] -ORRR if a substituent (or hydrogen) is BELOW THE PLANE of rings, it is assigned ALPHA -if its AT OR ABOVE the plane of rings, its Beta *the stereochem of Carbon 5 must always be included in the name of the steroid *a and B should only be used with customary drawings, NOT when structures are rotated 180-deg -if molecule is trans (parallel), u name it like so: 5a-androstane --> A/B trans, B/C trans, C/D trans -if molecule at C5 is cis (5B-androstane), u name it like A/B cis, B/C trans, C/D trans *5a-androstane is more stable than 5b-androstane

Cisplatin (Platinating Agent) Carboplatin (Platinating Agent) Oxaliplatin (Platinating Agent)

Cis = the Cl's are on the same side, and the NH2's/NH3's are also on the same side -so to tell the structure, just look for the one that's cis *Therapeutic Uses* 1. cisplatin [put it all on the SAME PLATE, idc if the eggs touch the potato and the ketchup] -metastatic testicular tumors IN COMBO with other anticancer agents OR post surgery, OR radiotherapy [CPR needed after "are eggs MEAT? TEST with bena] -metastatic ovarian tumors IN COMBO with others, or with post surgery, or radiotherapy [CPR needed after "are eggs OVEReasy (ovarian) MEAT? TEST with bena] -SINGLE AGENT for advanced bladder cancer not amenable to surgery or radiotherapy [my cis plate is so ADVANCELY BlAD that boys will remain UNAMENABLE to me, SR, and i shall remain SINGLE foreva] 2. carboplatin [carbo-load the plate] -ovarian carcinoma (epithelial tissue) IN COMBO with CYCLOPHOSPHAMIDE -[Carson (carcinoma) CARBO-LOADS (carboplatin) his PLATE with eggs OVEReasy (ovarian) in COMBO with his CYCLING (cyclophos) routine to stay fit] 3. oxaliplatin (ox "Al") -stage III colon cancer -advanced colorectal cancer either alone or in combo with 5-fluorouracil -[the ox Al CAN (cancer) run across 3 STAGES when he smells COLOGNE (colon cancer). he's ADVANCED in his COLORING both alone and with 5yo FURleen (5-FU)] *Dosing* 1. cisplatin -IV infusion -hydrate patients for 24 hours with Cl-containing solutions to increase urine output (BC ITS NEPHROTOXIC = [TOXIC ADU]) -vesicant = beware of EXTRAVASATION risk -CAUTION = no established antidote; dialysis (blood filtering) is ineffective due to HIGH PPB (PLASMA protein binding) (protein-bound drugs cannot be filtered out, they cant pass through the membrane) -[need 4 (IV) extra vacations (extravasation/ vesicant) when dealing with TOXIC NEPHEW ADU (nephrotoxic) for even 24 hours (hydrate with saline for 24 hours, to increase urine output), especially when his extra-pb-PB SANDWICH (extra/high ppb) TOUCHES other things on his CIS-PLATE (cisplatin). there NO ANTIDOTE (no antidote to the cisplatin toxicity) to get him to DIAL (dialysis no work) back his tantrums] *CISPLATIN COMA SAP* = C =cumulative renal tox that's severe, chemoprotectant needed. O = ototox. M = myelosuppression. A = Amifostine the chemoprotectant S = sodium thiosulfate (makes cisplatin into a water soluble adduct, inactivating it) A = anaphylactic rxns, aluminum (cannot be given). P = platinating agents can't be given with aluminum needles 2. carbo-load -n/a 3. ox al -n/a *ADME* 1. cisplatin -high ppb [aarav doesn't like his high ppb sandwich touching the rest of his cis plate] -slow elimination of Pt -cisplatin forms a REACTIVE INTERMEDIATE --> a diaquo form, where both Cl-'s are replaced with H2O. this intermediate is FAR MORE REACTIVE than cisplatin. (this intermediate is formed by HYDRATION reaction, not an enzyme-mediated transformation). by reactive, he means that it cross links to DNA much easier -[two drops of water (diaquo- very reactive) spilled on my cisplate and i dont care, im not very reactive, (but the diaquo IS RLY REACTIVE) that it's touching my food] 2. carbo load -also forms a diaquo reactive intermediate (same as cisplatin) -carbo load has milder side effects than cisplatin because it takes LONGER to form the diaquo (look at how much bulkier the molecules is compared to cisplatin) -[the CARBO LOADING guy is doing great in life - he has FEWER SIDE HOES than people who still cry about their food touching on cisplate (fewer side effects than cisplatin) and it takes him longer to have to pee (longer to form diaquo)] 3. oxaliplatin -*High Vd* (440L!) (Vd of 7 is enough to send it into tissues) -[we got a HIGH quality VIDeo (high Vd) of the ox Al runnin across stages]

what is mechanism of cardiotoxicity of anthracyclines??? slide 12 anticancer part 2 -the reduction of anthracyclines causes SUPEROXIDE RADICALS to form -CATALASE is important to help get rid of these superoxide radicals by turning them into water and oxygen -but cardiac tissue lacks catalase, so you get a buildup of cardiotoxic metabolites -additionally, reduction of C13 C=O on anthracyclines turns into SECONDARY ALCOHOL METABOLITES that INHIBIT Ca2+. Mg-ATPase, and Na/K pump leading to CHRONIC MYOPATHY AND CHF -WHAT IS FENTON RXN H2O2 + Fe2+ --> hydroxy-radical + OH- + Fe3+ -WHATS UP WITH DEXRAZOXANE- HOW DOES IT REDUCE ANTHRACYCLINE CARDIOTOX -dex raz is a CHEMOPROTECTANT for anthracycline toxicity -*its an antioxidant, and prodrug iron chelating agent that's coadminned with anthracyclines*

DEXRAZOXANE -chelates Fe2+ which is needed for the hydroxy-radical forming [DEX, RAZZLE me while im sick with anthrax :((( ] FENTON RXN -since cardiotox is caused by hydroxy radical, this is perfect -dex can penetrate cardiac tissue where it gets hydrolyzed to amide-carboxylate which is a STRONG FE2+ CHELATOR

Immune Checkpoint Inhibitors (cancer immunotherapy) AntiCTLA4 mAb AntiPD1 mAbs AntiPDL1 MABS

IPNAA [tIP? Naa] N IP A A P -[i pile, pam bro, nevel, aztec, abel ave [ip pb [nevel bypasses the immune checkpoint and tracks the IP of abel to see which aztecan PB he uses] -these are all MABS ^^those were moABs kk - all MABS are IV***** *MOA* 1. ipilimumab [i-pile] -binds to the *CTLA-4* INHIBITORY cell receptor on t-cells in order to BLOCK any INHIBITORY FACTORS (like CD80/86) from binding to CTLA-4 -therefore, it allows T-cells to remain free from any inhibitory molecules, increasing T-cell activity -[I PILE up the BINDERS containing info on citations so i can CITE LATE AT NIGHT --> (i-pile blocks CTLA-4, preventing CD80/86 from binding, allowing T-cells to remain active)] down below: both the PEDOS are PD1 blockers 2. Pembrolizumab [Pam bro? she's hot --> what everyone tells Jim. THE OFFICE] (everyone is so UNRESPECTABLE to pam) -humanized "zu" -Pambro is an antibody to the PD1 receptor that blocks the binding PDL1 or PDL2 to the T cell, allowing T-cell activation -[Pam, bro, watch out for PeDos [PD1] like michael and that other gross guy --> really put the PEDAL to the metal [PDL1/2] to get away from them if u have to] 3. Nivolumab [nevel] -human MAB "u" -blocks the PDL1 or PDL2 binding to T-cells by blocking the PD1 receptor -[Nevel was a PeDo for sure, carly had to put the pedal to the medal to get away from him] down below: Aztecs on Abel Ave are both PDL1 inhibitors aka PUDDLES 4. Atezolizumab [Aztec] -zu = humanized -now this one binds to the INHIBITORY FACTOR ON CANCER CELLS --> PDL1 -blocks PDL1 stopping the cancer cell from being able to bind to PD1 on t-cell -[the aztecs had to deal with PUDDLES blocking their way cause they had no bridges and deal with CANCER cause they had no treatments (binds to PDL1 ligand on cancer cells) 5. Avelumab [Abel Ave aka AVEL] -human "u" -MAB -binds to PDL1 blocking the cancer cell from binding to PD1 on the tumor cell -[many PUDDLES on abel ave, its ok cause the weeknd don't mind seeing his reflection] *Indications* 1. ipilimumab -unresectable metastatic melanoma -BBW = severe immune rxns -[i pile on the UMMs during my presentation, and my teacher asks what the heck im even trying to INDICATE] 2. Pembrolizumab -unresectable or metastatic melanoma (if ipilimumab + BRAF inhibitor doesn't work first) -non small cell lung cancer [Pam works in an office where NO SMALL office could SELL more paper and LUNGE into more sales than this one (non small cell lung cancer). plus you'll always hear kevin going UMM in the background for ambiance] 3. Nivolumab -unresectable or metastatic melanoma (if ipilimumab + BRAF inhibitor doesn't work first) -non small cell lung cancer -[Nevel's being recruited as an actor into the OFFICE to work with Pam --> [Pam works in an office where NO SMALL office could SELL more paper and LUNGE into more sales than this one (non small cell lung cancer). plus you'll always hear kevin going UMM in the background for ambiance] 4. Atezolizumab -metastatic NSCLC (non small cell lung cancer) -Urothelial carcinoma -used when patients already had Pt-chemotherapy but disease still progressed -[Aztecs were INDICATED to live at the same time as OTHELIA (urothelial cancer) yet they built PRISONS with spacious, NON-SMALL cells - what a META strat (metastatic NSCLC)] 5. Avelumab -treatment of MERKLE CELL carcinoma -first line treatment of advanced renal cell carcinoma in combo with axitinib -[when the weeknd looks at his face in the puddles on abel ave, its MURKY. but he looks at him self and goes "i just wanna be a REAL KID" and put an AXE to this life :(((((((( (renal cell carcinoma in combo with AXEitinib)] *AEs* 1. ipilimumab -severe and fatal immune-mediated adverse effects may occur (severe immune reactions) -[the more you PILE ON the charm, the more likely u gain immunity] 2. Pembrolizumab -severe and fatal immune-mediated adverse rxns may occur -[PAM has IMMUNITY according to michael, theres very little she can do wrong] 3. Nivolumab -severe and fatal immune-mediated adverse rxns 4. Atezolizumab severe and fatal immune-mediated adverse rxns 5. Avelumab -severe and fatal immune-mediated adverse rxns *Dose* 5. Avelumab -800 mg IV once every 2 weeks ???

Steroid Nomenclature

Most steroids will belong to ONE OF FOUR ring systems [CAPE] -big -android on meth with no side hustlers (2 methyls, no side chain) -preganant with twins (HAS a 2-carb side chain) -estrane (missing methyl at c10, no side chain) 1. Cholestane (C1-C27) -one methyl at C10, one at C13 -has an 8 carbon side chain -each ring is TRANS-fused to the consecutive one -the two methyl groups on C10 and C13 are not part of the original base structure so they receive the numbers *C18 AND C19* NAMING/DRAWING the structure -any carbon with a WEDGE is pointing UP and is named (Beta) (B) -any carbon with a DASH means that group is pointing DOWN and is named (a) (alpha) -ALTERNATING STEREOCHEM EXISTS BETWEEN ADJACENT CHIRAL CARBONS FROM C10-C13 (our two methyl placeholders) -so in order from C10--> C13: this is the order: C10, C9, C8, C14, C13. and this is also the order: up down up down up / B a B a B (go straight across from the left to right, then up) -[Beta get UP] **C5 configuration (right under C10) MUST BE SPECIFIED AS (a) or (B) in the name of cholestane --> 5a-cholestane or 5B-cholestane 2. Androstane -C1-C19 -has the two methyl groups at C10 and C13, but no 8-carbon side chain at C-17 -Androgens have a androSTANE skeleton -[ANDROID very much works like its ON METH (both 10 and 13 have methyls) but NO SIDE HUSTLERS be selling androids, only apple (no side chain)] 3. Pregnane -C1-C21 -has the two methyl groups, and a 2-carbon side chain at C-17 -Progestins and adrenocorticoids have pregnane skeleton -[PREGANANANT with 2 TWINS that I have to carry around like an annoying side chain at 17 yo (2-carbon side chain at C-17)] 4. Estrane -C1-C18 -No methyl at C10, no side chain at C-17 -Estrogens have an estrane skeleton -[bellatrix ESTRANGE forgot to take her ESTROGEN and she DOESNT TAKE METH (no methyl at C10, only a H)]

Non steroidal estrogens

SKIPPING

steroid hormones

Sex steroid hormones -Female sex steroids = 1. Estrogens, 2. progestins [my fave female artist released her first EP] -male sex steroids = 3. androgens [male adrian] Adrenocorticoids = 4. mineralocorticoids, 5. glucocorticoids 1. estrogens = look like estrone: no methyl on C10 2. progestERONE = look like pregnane - have an UNSATURATED ketone in the A-ring (meaning right next to the ketone on C3 theres another DB) 3. androgens = 2 methyls no side chain = methyl on C10 AND OH on C17 (combo of these two) 4. mineralocorticoids = progestin-like unsaturated-ketone A-ring AND 21-OH. often 11-OH (so pregnane backbone) 5. glucocorticoids = progestin-like unsaturated ketone A ring PLUS 17a and 11B OH groups (so pregnane backbone)

topoisomerase poisons -so sometimes in cells, DNA gets very tangled like a necklace and you cant untangle it, so it becomes stuck like that and inactivated -topirosiomerase proteins cut this DNA to untangle it and then restitch it back together -TopIIa cuts BOTH strands of DNA, top1a cuts only one strand of DNA -in cancer cells we want to INHIBIT top proteins so the cancer DNA can stay tangled.

[CIT, ET] 1. camptothecin (natural, not yet synthetic) -top I inhibitor/poison -active in S phase [works on DNA so most active in S phase] -derived from chinese xi shu happy tree -[i remember when i used to go to camp amongst the xi shu chinese happy trees (natural product). we had limited water SOLUTIONS out in the wild tho (limited water sol). i got poison ivy on ONE TOP at Camp (Top1 inhib)] -limited water solubility so they had to add synthetic analogs to increase the water solubility in future drugs 2. Irinotecan -prodrug -synthetic analog of camptothecin -better solubility (as a prodrug) --> remember? BUT STILL IV -turns into active metabolite SN-38 (eqm favors creation of SN-38 over other metabolites due to PREFERENTIAL PROTEIN BINDING) -Top I inhibitor -S phase -glucuronidation and sulfation can befall it -first line treatment for metastatic colorectal cancer -BBW = delayed diarrhea due to anticholinergic effect -life threatening toxicity from campto in patients deficient in the UGT1A1 enzyme (or other UGTs) because then it can't glucuronidate and then it becomes toxic -has a hydroxy acid metabolite that still has a little bit of activty -[our rhino (irinotecan) SAFARI NIGHT (SN-38) brought COLOR BACK INTO MY RETINAS for the first time and brought color to our LIVES (colorectal cancer, first line, IV).] -[irino got rhino-tazed (structure) like a pro (prodrug)] -[my UGGS (UGT1A1 polys) got ruined on RHINO safari night and i got POISON ivy on ONE TOP (top i poison)] -[in rhino safari night there was no where to use the bathroom so i had to DELAY my DIARRHEA (delayed diarrhea)] 3. topotecan (right in the name -> TOP-otecan - top1 inhibitor) -Top I inhibitor -S phase -Iv (SOC --> SCLC, ovarian, cervical cancers) and oral (relapsed SCLC) -BBW = it causes myelosuppression so its USE-LIMITING (otherwise u'll kill off all ur bone marrow cells). also, cannot be given with other bone-marrow suppressing drugs -NO known UGT1A1 polymorphism -has a hydroxy acid metabolite that has NO ACTIVITY -[Top1otecan wants to TOP-OFF ur bone marrow cells for good (very myelosuppression) if u dont put a SOC (indications) i it. -[for the 4th time (IV), put a soc in it. limit ur use of words (use limiting)] 4. etoposide and Teniposide (podophyllotoxin-derived TopIIa Inhibitors) [two drugs, top 2 a inhibitor] -[they TOP u off TWICE and toss u to the etopoSIDE/tenipoSIDE with DOUBLE DAMAGE - two drugs - top2 inhibitors] -podophyllin-derived Top IIa poison -S phase -IV, oral [shut ur mouth or ill end ur LIVES by topping u off and tossing u to the etopoSIDE] -SCLC, refractory testicular cancer -synthetic glycosidic derivatives of podophyllotoxin (isolated from american Mandrake) [the mandrake will e-topple u over TWO TIMES OVER (top-II inhibitors) with his PODOs (podophyllin-derived)] -these drugs have a "1-epi" structure version of podphyllin where the 1-OH is glycosylated camp, irino, top, etoposide n/a IV IV and oral IV and oral ^^they'll top u off and end ur live

Carbon Based Alkylating agents and Platinum based alkylating agents -orgo diagrams

alkylation you have a C-X (C is pos. charged, X is neg. charged) -another atom can take the place of X (usually S, O, or N) platination -you have a platinum group attached to two NH2s and 2 Xs (usually two Cl-s) -a Y atom (usually S O N or OH) comes and displaces the Cl, one after another --> so platination can occur twice

what are the antitumor antibiotics? what are the anthracyclines??

antitumor antibiotics -NATURAL products isolated from streptomyces genus of bacteria or semi-synthetic natural product analogs that BLOCK DNA REPLICATION OR TRANSCRIPTION ****** these are the mechanisms by which they do so: -topoisomerase IIa (topIIa) POISONS (anthracyclines -cytotoxic free radicals generators (bleomycin) -DNA alkylating antibiotics, similar to NITROGEN MUSTARDS (mitomycin) -prevent transcription by binding to DNA (dactinomycin) WHAT BE ANTHRACYCLINES??? -topIIa POSIONSSSS -isolated from streptomyces bacterium -have a TWO-FOLD MOA: a. Inhibition of TopIIa = once bound to topIIa, the ternary complex of DRUG-TOPIIA-DNA (wait so TopIIa is already bound to DNA, but on top of this, the drug binds to topIIa, creating a ternary complex) --> allows CLEAVAGE of bound DNA but BLOCKS the RESEALING of the cleaved DNA b. hydroxy free radical-induced DNA strand scission SOOO, DNA gets cut in one of 2 ways with this anthracyclines: 1. the ternary complex does it 2. hydroxy-free radicals do it ALSO THE ANTHRAS LOOK LIKE TETRACYCLINES

leukemia classifications

any cancer of blood cells or bone marrow cells 1. myelogenous leukemia -affects granulocytes and monocytes (M,G MG) -major myelogenous leukemias = ACUTE myelogenous (granulocytic) leukemia) (AML) and CHRONIC myelogenous (granulocytic) leukemia (CML) 2. lymphocytic (lymphoblastic) leukemia -affects lymphocytes -major lymphocytic leukemias = ACUTE lymphocytic (lymphoblastic) leukemia (ALL) and CHRONIC lymphocytic leukemia (CLL)

Production of sex steroids

female: -FSH promotes development of follicles. follicles release ESTROGEN [falling for FISHY ester and hoping we produce some sex steroids]. -LH rise causes formation of corpus luteum. CORPUS LUTEUM PRODUCES PROGESTERONE [habeas CORPUS is PROGRESS - when u talk law to me i produce sex hormones] male: -testosterone produced by leydig cells in testes, stimulated by LH -[LEAVE HIM (LH) to DIG (leydig) himself into a hole since he doesnt want to study for his TEST (testosterone)]

AntiCancer Drugs 1. Platinating/Alkylating Agents General

what is an alkylating agent? -something that forms STABLE BONDS with the PURINE BASES (A and G) in DNA [alkylating/platinating --> Pt is a metal, so is Ag --> A and G are the bases these agents bind to] Two classes of these CYTOTOXIC AGENTS -platinum-based (aka platinating agents) -carbon based (aka alkylating agents) these agents are NOT cell-cycle specific. they can bind to the DNA at any cycle -however, they are more toxic at G1 and S phases (why? because DNA amount is growing so there's more TARGET present) these agents produce *reactive chemical intermediates* -they are reactive cause they're ELECTROPHILIC (slightly positively charged) MOA -forms STABLE BONDS with A and G of DNA -they can also REACT WITH RNA and CRITICAL PROTEINS what are BIFUNCTIONAL alkylating agents? -they not only form stable bonds with A and G, but they can CROSSLINK nucleotides -examples: platinating agents and nitrogen mustards what are the MONOFUNCTIONAL ALKYLATING AGENTS? -nitrosoureas, dacarbazine, procarbazine, temozolomide (nitros, dacarb, procarb, tem) what are the two kinds of DNA cross linking? -intrastrand and interstrand -intra is... -inter is... (within same strand, between two dif strands)