Oncology I

1. what is Leucovorin used for? 2. what does High dose methotreate with leucovorin do? 3. effect does leucovorin have with 5-FU?

1. (it is a reduced form of folic acid) is commonly used to rescue cells exposed to folate antagonists (methotrexate) - does not function as a cytotoxic chemotherapy agnet 2. (HDM-L) produces a high complete response rate in CNS lymphomas, and is a part of standard curative therapy for childhood ALL (makes so you can increase the methotrexate dose) 3. it promotes 5-FU inhibition of Thymidylate Synthase- used in colon cancer -is more iffective in colon cancer with leucovorin.

Carcinolytic antibiotics 1. what are some examples of classes of carcinolytic antibiotics? 2. what are general properties/mechanism? 3. most are isolated from what?

1. -Anthracyclines: doxorubicin -Complex glycoproteins: bleomycin 2. -all bind to DNA or DNA associated proteins -all inhibit RNA synthesis (transcription) -some induce DNA strand breaks by free radical production and/or inhibition of topoisomerase II (not binding topoisomerase explicitly, doing thier inhibition through DNA bound state. 3. most are isolated from stroptomyces broths

Drug sensitivity of cancer that grow at different rates doubling times of human tumors with the following types of tumors, what is the doubling time (days) and treatment regimens to go along with it? 1. Burkitts lymphoma choriocarcioma 2. ALL Hodgkins disease 3. Colon 4. Lung 5. Breast 6. based on those what characteristic of doubling time is chemo monotherapy more likely to be able to treat?

1. -Doubling time: 1-1.5 -Treatment Regimen: single/drug/drug combinations 2. -Doubling time: 3-4 days -Treatment regimen: drug combinations 3. -Doubling time: 80-90 -Treatment regimen: surgery/drug combinations 4. -Doubling time: 90-150 -Treatment regimen: surgery/drug combinations 5. -Doubling time: 100-150 -Treatment regimen: surgery/drug combinations

Antimitotics- vinka alkaloids 1. what are some examples? 2. moa? 3. DLTfor vincristine? 4. DLT for vinblastin? 5. Resistance?

1. -Vincristine: hodgkins disease, childhood leukemia -Vinblastin: testicular 2. destabilizes microtubule assembly 3. peripheral neuropathy 4. bone marrow suppression(will still have neuropathy, just isnt DLT) 5. altered tubulin, P-glycoprotein activity (decreased accumulation

1. what are the steps in carcinogenesis? 2. a combination of ________ must occur for carcinogenesis Genetic basis of cancer 3. what is an oncogene? 4. what is a tumor suppressor gene? 5. oncogenes and tumor suppressor genes provide what type of signals that regulate the cell cycle?

1. -initiation -promotion -conversion/transormation -progression 2. mutations 3. a mutated gene that leads to an abnormal protein which drives malignant growth -a normal gene in a cell that has mutated -a gain of function mutation (turns on the pathway) 4. regulate and inhibit inappropriate cellular growth and proliferation (dampens the signal of growth) -the "break on cell division" -A loss of function mutation (most mutations are loss of function) 5. stimulatory and inhibitory signals.

Approved kinase inhibitors 1. how many approved are there? 2. what was the latest addition? then there are >100 kinase inhibitors in phase II/III clinical trials 3. what are they used for? 4. most protein kinase inhibitors target what? Mechanism of Phosphate Transfer 5. the active site is rigid or flexible? 6. what activate the phosphates for hydrolysis?

1. 44 approved protein kinase inhibitors 2. dacomitinib (sep 27, 2018) 3. anti-cancer drugs 4. tyrosine kinases 5. highly rigid 6. magnesium ions

Hormonal Anastrozole 1.what is this and what is it used for? 2. Class? 3. MOA? 4. Tox? Leuprolide: 5. what is thie? 6. MOA and use? 7. Tox? 8. analog?

1. 4th generation of aromatase inhibitor- effective against ER positive breast cancer 2. aromatase inhibitor 3. anastrazle significantly supresses serum estradiol levels. anastrazole inhibits aromatase (CYP19), the enzyme that catalyzes the final step in estrogen production 4. rarely severe adverse reactions -some musculoskeletal toxicity 5. GnRH peptide, used with flutamide 6. acts on pituitary to inhibit FSH and LH release -prostate cancer 7. N/V, hot flashes -may have an initial testosterone surge (ask someone about this) 8. goserelin

Nucleotide analogs - Pyrimidine analog 1. what is the name of the drug in this category? 2. what is it used for? 3. what is the mechanism of action? 4. ADME? 5. What is the DLT? and others? 6. what is the resistance mechanism?

1. 5-fluorouracil (5FU)(efudex) 2. colorectal, breast, gastric, pancreatic colon cancers (35% decrease in recurrance). -used topically for premalignant skin lesions. 3. irreversible inhibition of thymidine synthase (TS). Incorporation into DNA/RNA. Kills in G1 and S -phases. penetrates CNS 4. half life < 20 min, metabolized by cytosine deaminase. (rapidly metabolized) 5. DLT: bone marrow suppression -N/V, GI tox 6. increased/altered TS

5-Fluorouracil it is a widely used drug. 1. what does it resemble? 2. is 5-FU a prodrug or no? 3. what does it require? 4. 5-FU inhibits what enzyme? 5. what does this do? 6. anticancer antimetabolites are prodrugs 7. what is a possible resistance mechanism?

1. 5-fluorouracil structurally resembles uracil and thymine 2. yes it is a prodrug 3. it requres metabolic activation 4. thymidylate synthase (disequilibration nucleotides) 5. stops the conversion of dUMP to dTMP -5-FU then also incorporates into DNA and RNA 6. yes they are 7. downregulation (upregulation) of metabolic enzymes.

Chclophosphamide metabolism 1. what is the name of the toxic metabolite that is created in cyclophosphamide metabolism? 2. what does it do? 3. how is this overcome?

1. Acrolein 2. it is a nephrotoxic and urotoxic metabolite which causes severe hemorrhagic cyctitis in high dose regimens 3. MESNA is delivered with it. this sops up the Acrolein

DJ was diagnosed with stage III colorectal cancer and is s/p colectomy 4 weeks ago and he presents to a medical oncologist for discussion of chemotherapy 1. what is the role of chemotherapy for DJ? -neoadjuvant -adjuvant -palliative -consolidation DJ underwent 6 months of treatment with mFOLFOX-6. He is now 2 years post his initial diagnosis and CT scans demonstrate masses in the brain 2. what is the role of chemotherapy in the brain? -neoadjuvant -adjuvant -palliative -consolidation

1. Adjuvant 2. palliative

Tumor Nomenclature with the following tissues of origin, what are the benign and malignant forms? Lymphoid 1. Bone Marrow 2. Lympohoid Neural 3. Glial 4. Melanocytes Diagnosis and Staging 5. when are cancers mose curable? 6. what is paramount in the cure of cancer? 7. there is an emphasis on what?

1. Benign: none Malignant: Leukemias 2. Benign: none Malignant: Hodgkinds and non hodgkins lymphoma 3. Benign: gliomas Malignant: Gliobastoma, astrocytoma 4. Benign: pigmented nevus Malignant: malignant melanoma 5. in the early stages 6. early detection 7. screening

Antibiotics - Complex Glycopeptides 1. what is the name of the medication in this category? 2. what is it used for? 3. 2hat is the MOA? 4. DLT? -and others 5. Resistance:

1. Bleomycin (mixture of A2 and B2) 2. Head, neck, testes (curvature with vinblastine and cisplatin), uterine, cervix, hodgkins, and non-hodgkins lymphomas 3. DNA and metal binding region. DNA breaks by free radical damage. most suseptible in G2 4. lungs and skin fibrosis -cardiotoxicity, edema, minimal myelosuppression or immunosuppression 5. increased DNA repair, bleomycin hydrolase - not MDR1

Hormone related summary 1. what cancer frequently deomonstrate hormone dependent growth (at least in early stage disease)? 2. what are some classes? 3. t/f the toxicities tend to be more severe?

1. Breast and prostate 2. GnRH agonists -GnRH antagonists -Antiestrogens (including for prevention) --aromatase inhibitors -antiandrogens -corticosteroids 3. false, toxicities tend to be more mild.

1. what are the "Big 4" cancers (as far as prevalence is concerned? 2. what are the 4 harder to treat cancers? (cause the highest rates of death) 3. what are the 4 highest prevalence cancers in utah? 4. what about the highest death rate cancers in utah? 5. what have been the trends in cancer related deaths? 6. why?

1. Breast, Lung and bronchus, Prostate, colorectum 2. Lung and bronchus, Colorectum, Pancreas, Breast 3. Breast, prostate, melanoma of the skin, lung and bronchus 4. lung and bronchus, breast, pancrease, colorectum 5. they are going down 6. probably because it is less cool to smoke. and we have better screening

Laboratory Monitoring 1. what are some things in the lab to monitor *2. Absolute neutrophil count(ANC), how do you calculate this? memorize all of the following calculations 3. Body surface area 4. CrCl 5. Calvert equation 6. IBW male 7. IBW female 8. Corrected calcium

1. CMP, CBC with differential, absolute neutrophil count 2. =WBC x %PMNs+bands =WBC x % Neutrophils =WBC x % gransulocyte 3. sqrt((Ht(cm) x wt(kg))/3600) 4. ((140-age) x weight (IBW vs ABW)(kg))/(SCr x 72)) -then times that by 0.85 for females 5. Carboplatin dose (mg) = AUC x (GFR + 25ml/min) 6. 50 + 2.3 (every inch >5 ft) 7. 45.5 +2.3 (every in >5 ft) 8. (4-albumin)*0.8 +Ca (measured)

Topoisomerase Poison 1. topoisomerase I poisons are what type of derivatives? 2. what about topoisomerase II poisons? 3. what does topoisomerase do? 4. it is essential during what? 5. what does Doxorubicin do to topoisomerase? 6. doxorubicin is toxic to what organ? how?

1. Camptothecin derivatives 2. anthracyclines derivatives 3. cleaves DNA to relieve torsional strain 4. essential during DNA replication 5. stabilizes DNA-topoisomerase complexes -anthracyclines stabilize complex of topo II w/ cleaved DNA 6. cardiotoxic-contractile impairment -anthracyclines can be reduced metabolically -the reduced form can result in reactive oxygen species -causes cardiotoxicity

Cancers 7 warning signs 1. what are they? 8. what to do if you see a warning sign?

1. Change in bowel or bladder habits 2. A sore that does not heal 3. Unusual bleeding or discharge 4. Thickening or lump in breast or elsewhere 5. Indigestion or difficulty swallowing 6. Obvious change in wart or mole 7. Nagging cough or hoarseness 8. See a doctor

Platinum Compounds 1. what are some of the compounds here? 2. tell me about Cisplatin 3. tell me about carboplatin 4. tell me about oxaliplatin 5. Notable ADME: there is something that reduces toxicity here, what is it?

1. Cisplatin, carboplatin, oxaliplatin 2. (platinol) is prototype - functions as a non-cell cycle specific, bifunctional, alkylating agent used in testicular cancer 3. (Paraplatin) less toxic (~45x) than cisplatin but is generally less active 4. (eloxatin) lacks cross-resistance with other platinum compounds - generally less toxic than other platinum compounds 5. Cl- diuresis

Type III inhibitor: Targeting Allosteric Sites 1. what is the name of the agent here? 2. what does targeting allosteric sites provide? 3. where are the allosteric sites in kinases? 4. do all kinases have allosteric sites? 5. these are more challenging to what?

1. Cobimetinib 2. superior selectivity 3. they are frequently adjacent to ATP binding sites 4. no 5. more challenging to develop

More nucleoside analogs 1. what are a couple of nucleoside sugar analogs? and what are they used to treat? 2. what are some purine analogs what are they used for? DNA synthesis pathways 3. most target which pathway, the de novo or the salvage pathway? azathioprine inhibiots purine biosynthesis and methotrexate inhibits pyrimidine biosythesis

1. Cytosine arabinoside (ara-c, cytarabine, cytosar) -hematopoietic disease Gemcitabine (gemzar) -solid tumors 2. all used for hematopoietic disease -6-mercaptopurine (purinethol) -6-thioguanine (tabloid) -Fludarabine (oftorta) -clofarabine (Clofarex) 3. de novo

5-FU pharmacogenetic issue 1. what is the rate limiting enzyme in pyrimidine catabolism? 2. why would a dihydropyrimidine dehydrogenase deficiency be a problem here? 3. what is the name of an oral analog of 5-FU that has the same concerns with DTD deficiency?

1. Dihydropyrimidine dehydrogenase 2. because normally 85% of 5-FU is inactivated and eliminated through this catabolic pathway. so not having this will effectivly increase the dose of the 5-FU -the enzyme activity varies through the population 3. capecitabine

Antibiotic - Anthracyclines 1. what is the medication in this class? 2. what are they used for? 3. MOA? 4. Toxicity (DLT and others) 5. Resistance? 6. what might doxorubicin-polymer conjugantes do?

1. Doxorubicin 2. Breast, head, neck, thyroid, bladder, testes, prostate, ovary, sarcomas, leukemias, and lymphomas 3. DNA intercalator, DNA breaks by free radical damage and Topo-II interferance 4. DLT: cardiotoxicity (total dose, often irreversible)(i.e. once you hit the max dose you dont get any more if it) -myelosupression 5. decreased/altered topo-II, P-glycoprotein activity (decreased accumulation) 6. reduce toxicity, increases targeting

Staging 1. what are some things that go into staging? (4) 5. what is the TNM staging?

1. Extent of the disease 2. Prognistic information 3. Involves: x-rays, CT, MRI, ultrasounds, bone marrow biopsy, lumbar puncture, PET scanning 4. TNM staging 5. -T: Tumor (size of mass) -N: nodes (nodal involvement) -M: metastases (presence or absence)

Nitrogen Mustards Common Toxicities 1. what is the common dose limiting toxicity? 2. is Mechlorethamine delayed or rapid type? 3. how about Cyclophosphamide? 4. What other toxicities do these have? 5. what are some common resistance mechanisms?

1. Frequently hematological - Myelosuppression 2. delayed type 3. rapid type 4. -GI: N/V -CNS: Fever, chills, fatigue 5. Many; increase DNA repair pathways.

Hormones Degrarelix 1. what is this? 2. what does it do? 3. is there a testosterone surge initially? 4. what used for? Antiandrogens Biclutamide 5. what is this? 6. MOA? 7. Toxicity?

1. GnRH antagonist 2. immediate onset of action; more rapid suppression of testosterone than leuprolide 3. no 4. FDA approved Dec 2008 for prostate cancer 5. long lasting oral nonsteroidal antiandrogen -metastatic prostatic carcinoma 6. inhibits the uptake and/or nuclear binding of testosterone and dihydrotestosterone by prostatic tussue -most effective when combined with LHRH agonists 7. rarely severe adverse reactions.

Diagnosis 1. what are some different components of the diagnosis? (8) 9. which two are distinct from a regular workup?

1. HPI (weight loss, pain, duration of CC, other s/sx 2. PMH (predisposing factors) 3. Social History (tobacco, alcohol) 4. Family History (Hx of cancers in family) 5. Physical Exam 6. Labs (CBC, electrolytes, creatinine, LFTs) 7. Radiology 8. Biopsy 9. Radiology and biopsy

Role of chemotherapy 1. what are some of the different roles and what do they mean?

1. Induction chemotherapy: treatment of disease to achieve remission Consolidation chemotherapy: given after induction to control microscopic disease Maintenance chemotherapy: given over long term basis to maintain remission salvage chemotherapy: chemotherapy given after relapse Adjuvant chemotherapy: reduce local and distant recurrance after surgery Neoadjuvant chemotherapy: prior to surgical resection to improve results Primary Chemotherapy -palliation in advanced disease -curative in select diseases

Antimitotics - Epothilones 1. what is the name of a drug here? 2. MOA? 3. Tox? 4. ADME? 5. Resistance new class of antimitotics with a distinct tubulin binding mode

1. Ixabepilone: brease cancer (refractory or resistant) 2. stabilizes microtubule assembly; Microtubule binding differs from that of taxanes 3. myelosuppression, peripheral neutopathy, hypersensitivity reactions 4. Administered IV, cleared by the liver (CYP3A4) 5. Low Susceptibility to altered tubulin and the -glycoprotein and MRP1 efflux pumps

Folate Antimetabolites 1. what are two different drugs in this category? 2. what are they used to treat? 3. what is the mechanism? 4. ADME? 5. Toxicity? 6. what are some resistance mechanisms?

1. Methotrexate and amethopterin 2. trophoblastic choriocarcinoma, ALL, burkitts lymphoma 3. hihydrofolate reductase inhibitor: inhibits dTMP synthesis 4. polyglutamation of MTX concentrates drug in the cell 5. bone marrow, GI, ranl alopecia, teratogen 6. increased/altered DHFR (gene duplication), decreased uptake

Platinum Compounds Toxicity 1. what is the DLT of Cisplatin 2. what is the DLT for Carboplatin 3. what is the DLT for oxaliplatin? 4. what is a resistance mechanism here?

1. Nephrotoxicity, neurotoxicity and ototoxicity -less marrow toxicity 2. myelosuprression (thrombocytomenia - less neuro a dn nephrotoxic) 3. peripheral neuropathy (throat) 4. multiple mechanisms

Second generation Bcr-Abl inhibitors 1. what are some examples? 2. which of them is a multikinase inhibitor? 3. what type of inhibitor is dasatinib? 4. which of them is more potent that imatinib? 5. both nilotinib and dasatinib interact with what?

1. Nilotinib, dasatinib 2. dasatinib 3. a type I kinase inhibitor 4. nilotinib -hydrophobic rather than hydrogen bonds (less sensitive to resistance mutations) 5. Thr315

Antifolates 1. what are 4 medications in this category? 2. what does pemetrexed stop? 3. what about raltitrexed 4. what about pralatrexate? 5. what about methotrexate? 6. antifolates inhibit _______ _______ ______ on several levels 7. t/f approved antifolates have the same mechanisms of action?

1. Pemetrexed, raltitrexed, pralatrexed, methotrexate 2. Purine biosynthesis, thymidylate synthase, dihydrofolate reductase 3. thymidylate synthetase 4. dihydrofolate reductase 5. dihydrofolate reductase 6. inhibit nucleotide metabolism 7. false, approved antifolates have distinct mechanisms of action

Third generation Bcr-Abl Inhibitors 1. what is one? 2. this is the only Bcr-Abl inhibitor effective for what? 3. why is this? Different Resistance Patterns 4. t/f Each Bcr-Able kinase has distinct profile of resistance mechanisms 5. which of the agents is least resillient to resistance mutations? 6. ponatinib is the Bcr-Abl inhibitor least susceptible to resistance mutations. would it not make sense to just put all patients on panatinib?

1. Ponatinib 2. T315I mutants 3. the aalkyne group bypasses Thr315 position 4. true 5. imatinib (first line) 6. dont want to develop resistance to it. This concept is similar to the issue of antibiotic resistance.

Enzymatic phosphorylation 1. what are the two types of kinases that he specified? 2. how many protein kinases are there? 3. how many proteintyrosine kinases are there? 4. they and many more enzymes contain what kind of binding pockets?

1. Serine/threonine kinase and tyrosine kinase 2. >500 3. >90 and there are also small-molecule kinases 4. ATP binding pockets.

Moving toward precision medicine 1. what are the pillars of cancer care? 2. t/f anticancer therapeutics are rapidly evolving 3. why does chemo fail? 4. what is a therapeutic index? 5. the therapeutic index is narrow or wide for most anti cancer drugs? 6. what are the implications for dosing and schedule?

1. Surgery, radiotherapy, cytotoxic chemotherapy, precision therapy, immunotherapy 2. true 3. resistance, late treatment, toxicity, etc. 4. the degree of separation between toxic and therapeutic doses 5. narrow 6. they need to be very precise because they are very nearly toxic.

1. what is a rare example of where 1 mutation can cause cancer? 2. what is an example of a medication that targets CML? Tumor Suppressor Gene 3. what is the example? 4. what does it do? 5. it is known as the "_________ of the genome" 6. inactivation of P53 allows for what?

1. The Philidelphia gene, where a changed chromosome 22 combines with a broken off chromosome 9 to create a bcr-abl -Chronic Myelogenous Leukemia (CML) 2. Imatinib -it binds to the kinase domain inside the cells and stops cell signalling from happning 3. P53 4. Responsible for negative regulation in the cell cycle -allows the cell to halt for repairs, corrections, and responses to external signals -loss of control of normal cell growth 5. guardian 6. mutation

Factors affecting response 1. what are some? (7) look back at the chart in the slide called performance status

1. Tumor burden 2. tumor-cell heterogeneity 3. drug resistance 4. dose intensity 5. patient specific factors 6. pharmacogenomics 7. performance status

Vinca Alkaloids just go back and look at them again. I dont want to draw them. too complicated. 1. what are some examples? 2. what do they come from? 3. what do vinca alkaloids interfere with? 4. at high concentrations they do what? 5. at low concentrations they do what?

1. Vincristine, vinorelbine, vinblastine 2. Rosy periwinkle 3. microtubule dynamics 4. they bind to alphabeta-tubulin dimers and destabilize microtubules 5. interfere with microtubule dynamics

1. what is cancer? 2. what are some traits of cancer cells?

1. a general name for >100 different diseases -cells that are less interested in fixing mistakes 2. loss of genomic control -increased mutation rates Cells grow out of control -replicate in absence of growth signal -resist apoptosis Cells invade local tissue -contact independence (loose thier contact dependence) Form distant metastases -epidermal mesenchymal transformation (can differentiate) -anchorage independence Angiogenesis -ability to grow vasculature (this is how we see the cancer cells) Immortatilty -telomere extension

Alkylating agents 1. what are they? 2. what are some of the subtypes? 3. what is the general property/mechanism? 4. what are some general types of alkylating agents?

1. a large lass of antinneoplastics 2. nitrogen mustards, nitrosureas, platinum compounds 3. all are electrophilic molecules that covalently modify nucleophilic molecules in cells -DNA- most important adduct for anticancer properties- inhibits cell cycling and promotes cell death 4. monofunctional -cause single strand DNA breaks Bifunctional (much better) -inhibit DNA replication and transcription by crosslinking DNA -crosslinking is much more challening to fix

Intercalator Drugs: structural features 1. Mitoxantrone, what is it? 2. what are some other exampels of the intercalators? 3. what is the name of the part of the structure that intercalates? DNA binding of doxorubicin 4. what does the anthracycline core do? 5. what does the protonated amine do?

1. a rationally designed intercalator anti-cancer agent 2. doxorubicin, daunorubicin, epirubicin, idarubicin 3. anthracycline 4. intercalates between two neighboring base pairs 5. electrostatic attraction of protonated amine and polyanionic backbone

1. Nitrogen mustard mechanism of action, how does it work on a molecular level? 2. what is the most often attacked position on the DNA base? 3. what is the Nitrosurea MOA? these are dirty drugs, they hit oa lot of different things, number of side effects. Alkylating agents: in reality there are multiple MOAs that target DNA 4. what are cisplatin and carmustine?

1. activation by making the triangle thing with the nitrogen -then nucleophilic attack of unstable aziridine ring by electron donor (these cold be -SH of protein, -N of protein or DNA base, -O of DNA base of phosphate) 2. the N-7 position on the DNA 3. does the same type of thing as the nitrogen mustards, except that it produces an alkylated DNA and a Carbamoylated protein 4. alkylating agents

Optimization by advanced formulations 1. what is abraxane? 2. what is marqibo? many natural products are present as liposomal/nanoparticle formulations 3. what types of side effects would you expect to be mainly reduced for abraxane ralative to taxol?

1. albumin nanoparticle of paclitaxel 2. vincristine liposomes 3. increased bioavailability and decreased injection site reaction

Metabolites and their antimetabolites 1. what do they do? 2. are they orally active or are they prodrugs? 3. what are some toxicities? 4. what are the general drug classes?

1. antimetabolites resemble cellular metabolites and act to interfere with DNA synthesis or the synthesis of DNA precursors (need cells to be dividing) -these are classical cell cycle specific anticancer agnets. 2. most are prodrugs what must be activated through incorporation into the normal biosynthetic pathways. 3. only partially selective to tumor cell - toxic to all rapidly dividing normal cells -bone marrow and intestinal epithelium are particularly sensitive 4. antifolates and antinucleotide analogs.

Paradigm Shift Classical oncology does what in the following 1. attacks what? 2. is it used alone or incombination? 3. how effective in the late stage? 4. what are the toxicities like? Modern oncology does what in the following? 5. what does it target? 6. combine with what? 7. High efficacy for targeting what? what is the ramification of this?

1. attacks rapidly dividing cells 2. used alone or in combination 3. late stage disease minimally treated 4. broad toxicities 5. target discrete pathways 6. combine with cytotoxic therapy 7. high efficacy for targeting tumor cells and less toxicity

Discovery of Cisplatin 1. how was is discovered? 2. how it Cisplatin activated? 3. what does cisplatin do once ti is activated? 4. what is the the most reactive position in DNA? 5. what does Cisplatin do to the double helix?

1. barnett rosenberg -studied the effect of electrical fild of cell growth -used platinum electrodes immersed in bacterium medium -cell division of E. coli was curtailed -the effect of was linked to traces of platinum leaked into solution that had formed cisplatin 2. by aquation -by exchange of chloride to water ligand for activity 3. binds to DNA -forms intert coordination complexes -amine ligands stabilize complex by hydrogen bonds -formation of intrastrand cross links 4. Guanine N-7 5. distorts it. Cisplatin intra-strand cross links distort the geometry of double stranded DNA bending the duplex

Cell cycle Specificity there are cell cycle specific drugs that act in cycle specific phases 1. cell cycle nonspecific drugs act effectively following what? 2. what can be used to act in G1 to S phase? 3. what about S phase specific? 4. what about s phase specific self limiting? 5. M phase?

1. bolus injection 2. CDK4/6 inhibitor (palbociclib, abemaciclib, ribociclib) 3. cytosine arabinoside, hydroxyurea, irinotecan, topotecan 4. 6-mercaptomurine, methotrexate

Natural product summary 1. what are the classes? 2. is the toxicity uniform? Targeted cancer therapeutics Hormonal agents 3. Tamoxifen, what is it used for? 4. MOA? 5. Tox? 6. what are some others?

1. broad variety of microbial and plant sources that target many distinct cellular processes -antibiotics: target DNA -Topoisomerase inhibitors: result in DNA strand breaks -antimitotics -target microtubule function 2. toxicity is not uniform - even within subgroups 3. estrogen receptor positive breast cancer -Antiestrogen SERM (synthetic estrogen receptor modulators) 4. block estrogen response -inhibits G1 to S transition 5. rarely severe adverse reactions to tamoxifen include vasomotor symptoms (hot flushes), N/V and vaginal bleeding. Tamoxifen also increases the incidence of endometrial cancer by two to three fold 6. raloxifen, fulvestrant -these work differently --> but they're used for ER positive breast cancer as well.

Important Concepts 1. protein kinases are drivers of what? 2. inhibiotrs of protein kinases are important for the treatment of what? 3. t/f there is one type of kinase inhibitor 4. most kinase inhibitors bind where? 5. there is a challenge to find selective or nonselective kinase inhibitors? 6. drug resistance often involves what? 7. allosteric and covalent inhibitors can enhance what?

1. cancer growth 2. cancer (they are anticancer drugs) 3. false there are different types of kinase inhibiotrs 4. the ATP-binding pocket 5. selective 6. point mutations 7. selectivity

Tumor growth and chemotherapy 1. what are some things to consider here? 2. what is a gompertzian curve? Principles of tumor growth and chemo 3. what is the log cell-kill hypothesis? 4. what is a gomperzian model?

1. cell cycle dependence -growth fraction percentage -log-kill efficacy -time to resistance -time to cure 2. its a curve of some kind, a principle of tumor growth and chemotherapy. 3. a given chemotherapy is predicted to kill a constant fraction of cells as opposed to a constant number - 1st order kinetics -inverse relation between cell number and curability 4. response to chemo depends on position on growth curve

Response Criteria what do the following mean? 1. Complete response 2. Partial response 3. stable response 4. progression 5. what are some clinical trial endpoints?

1. disappearance of all cancer w/o evidence of new disease for at least 1 month after treatment 2. 50% or greater decrease in tumor size or objective tumor markers and no evidence of new disease w/in 1 month 3. neither grows or shrinks by 25% 4. 25% increase in tumor size or development of new lesions 5. -OS: overall survival -DFS: disease free survival -RFS: relapse free survival -ORR: overall response rate -TTP: time to tumor progression -PFS: progression free interval

Vinca Alkaloid mechanism 1. what do they do? Antimitotics - Taxanes 2. what are some examples? Paclitaxel - breast, ovary. lung, head and neck 3. MOA? 4. DLT? -other tox? 5. ADME? 6. Resistance?

1. dont allow assembly of microtubules: cannot separate sister chromatids. cell senses too much DNA and enters death pathways 2. Paclitaxel and docetaxel (synthetic analog to paclitaxel) 3. stabilizes microtubule assembly "mitotic spindle poison" 4. DLT: Myelosupression -peripheral neuropathy, allergic reactions to injection are a problem 5. administered IV, cleared by the liver, susceptible to MDR 6. altered tubulin, P-glycoprotein activity (decreased accumulation)

Bone marrow suppression following therapy 1. Rapid recovery, what is this associated with? 2. Delayed recovery: what is this associated with? Toxicities 3. what is a dose related toxicity? 4. what is a cumulative toxicity? 5. what are some other chemotherapy toxicities? may want to go back and look at the slide titled, "pediatric leukemia - a success story for oncology"

1. drugs: cyclophosphamide, methotrexate, vinblastin, Ara-C 2. Drugs/treatments: BCNU, Melphalan, irradiation 3. increasing the dose increases toxicity 4. each dose increases the odds of developing specific toxicities. 5. N/V, mucositis, alopecia, neurotoxicity, cardiotoxicity, hepatotoxicity, pulmonary toxicity, renal toxicity, nail toxicity, skin toxicity, infertility, carcinogenesis

topoisomerase inhibitors - pure topo-II inhibitor 1. what is the name of the medication here? 2. what is it used for? 3. MOA? 4. Tox? 5. ADME? 6. Resistance?

1. etoposide 2. testicular (PEB), small cell lung cancer 3. stabilizes Topo-II DNA complex. cuases double strand break 4. DLT: bone marrow -nausea, diarrhea, RISK of secondary neoplasia 5. Administered po and IV, largely cleared by the kidney 6. p-glycoprotein activity (decreased accumulation)

Taxane and Epothilone mechanism 1. these dont allow for what? Another example of a natural product 2. what is L-asparaginase? 3. what is the MOA? 4. what is the ADME? 5. Use? 6. Toxicity? 7. resistance?

1. for the disassembly of microtubules: cell becomes clogged up with microtubules and enters death pathways. 2. an enzyme commonly purified from microbial sources 3. hydrolyzes L-asperagine to aspartic acid and ammonia - depletes L-asparagine. cytotoxicity due to protein synthesis inhibition 4. does not cross the BBB - still depletes L-asparagine in CNS 5. treatment of acute lymphocytic leukemia (ALL) 6. hypersensitivity reactions toxicities due to inhibition of hepatic protein synthesis, CNS toxicities (more in adults that children) 7. expression of L-asparagine synthetase in tumor cells.

Types of kinase inhibitors 1. how many different types are there? 2. what does Type I do? 3. Type II? 4. type III? 5. type IV? he says we should know the four types

1. four 2. binds ATP-Pocket of active conformation 3. binds ATP pocket of Inactive conformation 4. binds allosteric site (often pocket adjacent to active site) 5. binds to distant site (e.g. protein-protein interaction inhibitor)

Pathology of Cancer cells 1. these are based on what? 2. there are two different kinds of pathology, what would they be and what do they mean? Tumor Nomenclature with the following tissues of origin, what are the benign and malignant forms? Epithelial 3. surface epithelial 4. glandular Connective 5. bone 6. Smooth Muscle

1. frozen section, needle biopsy 2. Benign-freckles, moles, fatty lumps -stay in one place -do not invade surrounding tissue Malignant -have no clear cut boarder -con spread to other parts of the body 3. Benign: Papilloma Malignant: Carcinoma 4. Benign: Adenoma Malignant: Adenocarcinoma 5. Benign: Osteoma Malignant: Osteosarcoma 6. Benign: Leiomyoma Malignant: Leiomyosarcoma

Biological Perspective of cancer problem Cancer has select phenotypes 1. cancer arises from genetic lesions that cause an excess of cell growth or division, with inadequate cell death, what are some of these types of diseases? 2. what are some of the different mechanisms that cancer cells work?

1. genetic diseases, developmental disease, metabolic disease, stem cell disease 3. resisting cell death (proapoptotic BH3 mimetics), -sustaining proliferative signalling (EGFR inhibitors), -evading growth suppressors (Cyclin dependent kinase inhibitors), -activating invasion and metastasis (inhibitors of HGF/c-Met), -enabling replicative immortality (telomerase inhibitors), -inducing angiogenesis (inhibitors of VEGF signalling) -deregulating cellular energetics (aerobic glycolysis inhibitors) -avoiding immune destruction (Immune activating anti-CTLA4 mAb) -genome instability and mutation (PARP inhibitors) -tumor-promoting inflammation (Selective anti-inflammatory drugs)

Growth and development of heterogeneity in cancer 1. is cancer homo or heterogeneous 2. clonal in origin, many additional changes happen during tumor progression and escape what? differences in accumulated mutation rate 3. may take ____ ____ to develop into clinical tumor Pathways to cancer 4. is it a loss of function or gain of function that leads to cancer?

1. heterogeneous 2. immune surveillance 3. 30 years 4. loss of function OR gain of function can occur in different sequence eventually leading to unregulated cell growth

Development of imatinib 1. what was the process?

1. high-through put screening hit for protein kinase C -phenylaminopyrimidine (weak inhibitor, small size, simple synthesis) -then improved in vivo potency by adding a 6-ring with a nitrogen in it -then inhibition of tyrosine kinases when added an amide on the right side -then selective against PKC by adding a methyl onto one of the rings -then you get imatinib by turning the amide into a ring with two nitrogens and a methyl --soluble (mesylate salt) high K, and low mutagenicity

Other hormone/hormone related Prednisone 1. what is this used for? 2. class? 3. MOA? 4. Tox?

1. hodgkins disease, acute lynphocytic leukemia (ALL), lymphomas 2. corticosteroids 3. antianabolic effects 4. cushingoid symptoms

Covalent Inhibitors 1. what is the name of a covalent inhibitor? 2. how? 3. what does it inhibit? what is it used for? 4. what about acalabrutinib? 5. osimertinib? 6. afatinib? 7. targeting the ATP binding site with covalent reactions enhances what?

1. ibrutinib (imbruvica) 2. the michael addition makes it irreverisbly bond? 3. Burtons tyrosine kinase -Lymphomas 4. another example of a covalent inhibitor -burton tyrosine kinase -chronic lymphoid leukemia 5. another example of a covalent inhibitor -EGFR -non-small cell lung cancer 6. another example of a covalent inhibitor -EGFR/Her2 -Non-small cell lung cancer. 7. selectivity

Clinical antimetabolites 1. anticancer antimetabolites predominantly do what? 2. purine and pyrimidine antimetabolites are also incorporated into what? 3. what are three kinds of antimetabolites?

1. inhibit nucleotide metabolism 2. DNA 3. antifolates, purine analogs, pyrimidine analogs

Mercaptopurine drugs 1. do they affect enzymes? 2. what else do they do? 3. what do they require for degredation? 4. there is a DDI with what drug? 5. a combination of 5-FU prodrug and uracil is an orally available drug combination for cancer chemotherapy approved in >50 countries (not in the USA). the purpose of uracil is to increase the K for 5-FU, what is the rational? 6. what are the names of a couple of the mercaptopurine drugs?

1. inhibit several metabolic enzymes (e.g. IMP dehydrogenase) 2. incorporation into DNA, methylation, and futile mismatch repair mechanism 3. xanthine oxidase 4. allopurinol 5. to saturate DPD 6. 6-mercaptopurine (6-MP)(purinethol), 6-thioguanine (6-TG)

Pyrimidine analogs with different MOA 1. what does Cytarabine do? 2. how about Aza nucleoside derivatives? why does that matter?

1. inhibits DNA chain elongation, DNA synthesis and repair; inhibits ribonucleotide reductase with reduced formation of dNTPs; incorporation of cytarabine triphosphate into DNA 2. They inhibit DNA methylation (epigenetic alteration that modifies transcription) 3. DNA methylation shuts down the sites of transription, when there is a lot of methylation it is likely a cancer state -when there is less methylation it is likely an active stranscription site.

Inhibition of thymidylate synthase 1. what does thymidylate synthase do? 2. why does it not just followa different pathway to get what it needs after thymidylate synthase is inhibited? 3. 5-FU acts as what for thymidylate synthase? 4. 5-FU substituent prevents the elimination step through what mechanism? 5. what is a possible resistance mechanism?

1. it converts dUMP to TMP 2. it is the only biosynthetic pathway for formation of thymidines 3. a substrate 4. Covalent irreversible inhibitor 5. amplification of thymidylate synthase

Targeted agents 1. what are two different kinds of targeted agents? Protein kinase as targets 2. what are kinases essential for? 3. what are tyrosine protein kinases important for? 4. aberrant kinase activity can result in what? 5. what to kinases do? 6. where does the phosphate originate? 7. what reverses the phosphorylation?

1. kinase inhibitors and antibodies. 2. for numerous cell signalling pathways 3. mitotic signalling 4. uncontrolled growth 5. they phosphoylate proteins on Tyr, Ser, and Thr residues 6. ATP 7. phosphatases

General Concepts Tubulin Poisons 1. are large or small? 2. are synthetic or natural? 3. what do they inhibit? 4. are thier properties optimal or suboptimal? 5. they are frequently administered as what?

1. large and complex 2. natural products or derivatives thereof 3. inhibit polymerization and depolymerization of microtubules 4. have supoptimal properties (pharmacokinetic, biodistribution, oral bioavailability) 5. are frequently administered as advanced formulas

Staging 1. what is stage I? 2. Stage II? 3. Stage III? 4. Stage IV? 5. tell me what T3N1M0 means and what the stage of cancer would be?

1. localized tumor 2. local and regional extension 3. local and regional extension 4. distant metastases 5. Moderate to large size mass, regional lymph node involvement and not distant metastases = Stage III

Kinase active site 1. what is it like? 2. what is the inactive conformation? 3. what is the active conformation?

1. look at the slide again -N-lobe on top with a P loop -gatekeeper (what is the significance here?) - a hinge region that connects the N lobe to the C lobe. -an A-loop on the C lobe and a DFG (dont know what that is) -and something that says cat. Asp 2. A-loop partially occupies the ATP binding pocket, substrate binding site blocked, DGF flipped outwards 3. A-loop folded onto ATP binding site, DGF flipped inwards with ASP coordinating to magnesium, P-loop binds phosphates

Metastasis: Lethal mechanism of cancer spread 1. primary neopolasm spreads to distant sights through what? implications for drug dosing and accessibility 2. what does metastasis do to survival rates? Tumor Perfusion 3. the further from the vessel, the lower the concentration of oxygen, nutrients and ______ implications for drug dosing and accessibility Resistance to Chemotherapy 4. what are some mechanisms that lead to resistance to chemo?

1. lymphatics or blood vessels and establishes new tumors 2. decreases them 3. drugs 4. -Decrease in cellular uptake or increase in efflux for drugs --multidrug resistance MDR; P-glycoprotein active trasnport of organic molecules. -increased proficiency of repair DNA -increase in levels of target enzyme -alterations in target enzyme -decrease in drug activation.

In-Vivo Activation 1. Cyclophosphamide requires what? 2. what are the 3 steps? 3. what is the name of the component that can cause bladder issues? Chemistry of Cisplatin 4. what type of a complex is cisplatin? 5. what do the chloride ligands do? 6. what do the amine ligands do?

1. metabolic activation 2. 1)oxidation, 2)opening of hemi-animal, 3) beta-elimination 3. acrolein (propenal) 4. square-planar Pt(ii) coordination complex 5. they can be replaced by water and eventually biomolecules 6. they are relatively inert

antimetabolites are anticancer drugs 1. what is an antimetabolite? 2. the metabolism in cancer cells is altered, why do we care about this? 3. what are some examples?

1. molecule resembling a metabolite and inhibiting a metabolic step 2. it can be exploited for therapeutics 3. -Warburg effect -upregulation of purine/pyrimidine biosynthesis

Nitrogen Mustards 1. what is the history of these? 2. what is the prototype nitrogen mustard? 3. what is the name of a drug in this category that is widely used with activity against many tumors? 4. what does it require for bioactivation?

1. mustard gas 2. Mechlorethamine (Mustargan) -Combinations: MOPP -Chlorambucil (leukeran) 3. Cyclophosphamide (cytoxan) -Combinations: CHOP, CMF, etc -Ifosfamide (isophosphamide, Ifex) 4. Requires CYP bioactivation

Resistance 37% of patients have unacceptable outcomes at year 8 on imatinib 1. what plays an important role in imatinib resistance? 2. where do they cluster? 3. what are some other resistance mechanisms? 4. where is the gatekeeper mutation?

1. mutations 2. mutations cluster in P-loop, A-loop, and hinge region 3. drug efflux, gene amplification, other kinase pathways 4. T315I

Alkylating agents Summary: 1. what are the subtypes again? 2. what do they do? 3. they can be bifunctional or monofunctional, which are which? 4. toxicities depend on the particular compound, what are some common ones?

1. nitrogen mustards, nitrosureas, platinum compounds 2. they are electrophilic compounds that react with DNA 3. -Bifunctional: nitrogen mustards and platinum compounds (these are more challenging for the cell to deal with) -Monofunctional: many nitrosureas 4. -many have severe bone marrow suppression -platinum compounds tend to show more renal toxicities.

Examples of Alkylating agents 1. what are some of the different kinds? 2. in general how do these work? Chemical Warfare Therapeutics 3. what is mustard gas Mechanism of Nitrogen mustards 4. the amine group is a good what? 5. ultimately what do nitrogen mustards do to cause damage?

1. nitrogen mustards, nitrosureas, triazenes, platinum drugs, misc. 2. alkylating agnets, cause DNA damage, Cell cycle-specific damage response, apoptosis of cancer cells. 3. a chemical warfare agent used in WWII 4. it is a good nuceophile 5. interstrand/intrastrand cross link (this is very difficult to be repaired) -alternatively DNA-protein cross-link or glutathione adduct

1. was paclitaxel designed to be a drug? Natural product toxins are designed to protect organisms from predators 2. they often have poor what? 3. what are some of the poor pharmacokinetic and pharmacodynamics of paclitaxel?

1. no 2. pharmacokinetic and pharmacodynamic properties 3. -limited quantities are available(~3 trees per patient) -poor water solubility (10-20micromolar) -low oral bioavailability (6.5%) -lipophilic molecules --requres solvent --causes allergic reactions -inefficient tumor delivery -hepatobiliary excretion

1. Etoposide is an anticancer medication whose mechanism of action involves stabilization of DNA-topoisomerase II complexes in analogy with doxorubicin. would you expect cardiotoxicity to be a major side effect? 2. t/f DNA binding drugs are often natural products DNA binding drugs... 3. t/f generally dont have intercalating moieties? 4. t/f interfere with DNA-replication 5. t/f often stabilize complexes of DNA and topoisomerase?

1. no doesn't have the quinone structure so wouldnt expect to form toxic structure to cardio cells. 2. true 3. false, they generally do 4. true 5. true

Resistance: MDR/cancer stem cells 1. are all cancer cells equal? 2. MDR expression is observed in what cells? Tumor evolution and resistance 3. how might this happen?

1. no, there are intrinsic differences to proliferate and form tumors in vivo -a subset of cancer cells have the ability to renew 2. in stem cells and after drug selection 3. initiation of the cancer cell, then heterogeneity is introduced before detection, then treatment A comes along to knock out most of them, maybe one stays that is resistant and the primary tumor might grow from that.

Antimetabolites 1. toxicities? 2. what are some resistance mechanisms? antimetabolite summary 3. what are classical what types of agents? 4. what do they require? 5. what are the two different classes? 6. what o they inhibit? 7. toxicities?

1. only partially selective to tumor cell - toxic to all rapidly dividing normal cells -bone marrow and intestinal epithelium are particularly sensitive 2. most are produrgs - alterations in metabolic pathways that must be activated through incorporation into the normal biosynthetic pathways. 3. cell cycle dependent agents. 4. require bioactivation 5. -antifolates -antibucleotide analogs 6. inhibit enzymes required for DNA for DNA precursors and DNA synthesis 7. toxicities extend to tissues with higher rates of cellular turnover.

Toxicity Considerations 1. Cancer drugs can be extremely toxic agents, what might this effect? 2. the drug therapeutic outcome is limited by what? Hematoligic toxicities 3. what is a common dose limiting toxicity here? 4. what might arise due to myelosuppression?

1. organ function is frequently effected by illness (e.g. tumor infiltration, hepatitis), age, prior injury of therapy 2. -metabolic capacity of the liver, kidney (pharmacogenomics) -ability to produce blood cells (bone marrow reserve) -ability of the GI tract to recover. 3. myelosupression 4. anemia, thrombocytopenia, neutropenia

Taxanes 1. what are some examples? 2. what do taxanes do? 3. stabilized microtubule inhibition of mitosis leads to what? Taxanes: natural products as tubulin binders 4. Tubulin poisons are mostly what? 5. why natural products?

1. paclitaxel (taxol), Docetaxel (better water solubility, easier synthesis) 2. block microtubule depolymerization -taxanes bind to the inner surface of microtubules and stabilize them 3. cell death 4. natural products (pacific yew) 5. -the tubulin small molecule pockets are large and wide and many interactions are required for potent binding -synthetic drug discovery methods are inefficient to identify such drugs -nature has substantial evolutionary pressure to develop toxins (rather than drugs)

Degredation of 5-FU 1. 5-FU is degraded by what process? 2. what is the enzyme that does this? 3. what % of 5-FU is deactivated by DPD? 4. oral K is ______ and _________ 5. does it have a fast or a short half life?

1. pyrimidine catabolism 2. dihydropyrimidine dehydrogenase (DPD) -rapidly converts 5-FU into 5-fuorodihydrouracil 3. >80% 4. Low and unpredictable 5. short

1. Topo-II mechanism, what happens with etoposide? Topoisomerase Inhibitor: Pure Topo-I Inhibitor 2. what is the name of the medication here? 3. MOA? 4. use? 5. DLT? -other tox? 6. ADME? 7. analogs?

1. results in Topo II covalently modified to DNA and double strand breaks 2. Itinotecan (camptosar) 3. pure topoisomerase I poison source: derivatives of camptothecin 4. colorectal cancer, and small cell and non small cell lung cancer, -also has shown positive responses several other cancers 5. DLT: bone marrow suppression -GI tox, secere diarrhea (lets us know the drug is working) 6. Administered IV, cleared by the kidney 7. topotecan

Super alkylators 1. these are some of the most what? pyrrolobenzodiazepines these agents are interesting for antibody-drug conjugates 2. cyclophosphamide and isofamide can lead to hemorrhagic cystitis as a serious side effect because the side product acrylamide can react with the bladder epithelium. mesna can be co administered to prevent this outcome. propose a mechanism of action for mesna

1. some of the most toxic compounds are DNA alkylators 2. sH will attack the acrolein and make it no longer toxic

Topo-I cleavable complex cellular effects of topo I inhibitors in dividing and non-dividing cells 1. what is the role of SN-38? Antimitotic agents 2. what are some general properties/mechanism? 3. what are general types of antimitotics? 4. what are some classes of stabilizers? 5. what is a class of destabilizer?

1. stabilizes the enzyme-DNA complex and prevents the religation of the single strand breaks created by the enzyme, which are converted to double strand breakd upon collusion with a replication fork during the S phase (for collision model) 2. disrupt chromosomal dynamics -disrupt cellular machinery necessary for DNA replicaiton and mitosis 3. Microtubule inhibitors -stabilizers -destabilizers 4. -Taxanes -epothilones 5. vinca alkaloids

Anticancer (purine/pyrimidine) antimetabolites 1. are or arent structurally similar to natural metabolites? 2. they require what in order to work? 3. they rely on a single or several mechanisms of action? 4. what are they degraded by? 5. epigenetic drugs reverse suppression of tumor suppressor

1. structurally very close to the natureal metabolites 2. metabolic activation 3. several mechanisms of action -inhibition of nucleotide metabolism, incorporation into DNA, incorporation into RNA 4. nucleotide catabolism 5. yep

The pharmacist role 1. what are they? 2. what are some different treatment modalities?

1. supportive care issues -verification of chemotherapy dosing -pharmacology and pharmacokinetics -nutritional support -pain management -infection -nausea/vomiting -research protocols -patient education -insurance coverage. 2. Surgery: diagnosis and treatment, treatment of choise for solid tumors Radiation: management of cancer (surgery and radiation are for local regional control Chemotherapy biological/targeted therapy

Bcr-Able Drives Chronic Myeloid Leukemia 1. what is the name of the gene that causes this? 2. what happens? 3. Bcr-Abl is responsible for what types of leukemia? 4. what do Bcr-Abl inhibitors do for thier patients?

1. the Philadelphia chromosome 2. chromosomal rearrangements (philadelphia chromosome) result in constitutively active tyrosine kinase: Bcr-Abl 3. for almost all chronic myeloid leukemia (CML) 4. significantly increases the lifetime of CML patients.

Challenge of Selectivity 1. what makes selective inhibition challenging here? 2. is it possible? 3. some approved FDA protein kinases are unselective, what is this referred to as? Multikinase inhibitors as therapeutics 4. what does sunitinib do? 5. what is it approved for? 6. what does the lack of selectivity cause? 7. this makes single-nucleotide mutation less effective as what?

1. the conserved active site of protein kinases 2. multiple reports demonstrate that selective inhibition is possible 3. multi-kinase inhibitors 4. inhibits multiple kinases of different types -PDFGR, VGFR, c-KIT, RET 5. renal cell carcinoma and gastrointestinal stromal tumors 6. side effects 7. a resistance mechanism

Do targeted therapies improve survival?

1. they are not curative, but make the disease more manageable

Microtubule poisons 1. what are microtubules? 2. what do they form in the cell? 3. what inhibiting them do? 4. how might they be inhibited? 5. what are some characteristics of the binding sites?

1. they are tubular polymers formed from alphabeta tubulin dimers 2. they form cytoskeleton and mitotic spindles -they are dynamic during mitosis 3. inhibition of microtubule (de)polymerization is cytotoxic 4. small molecules can bind to microtubules and alphabeta-tubulin at different sites and inhibit microtubule (de)polymerization (spindle toxins) 5. they are large and wide requireing large, complex molecules for binding.

5-FU Prodrugs 1. several prodrugs have been developed, why? 2. what is the name of one of these 5-FU prodrugs? 3. several purine/pyrimidine antimetabolites (e.g. 5-FU, gemcitabine) are incorporated into DNA causing what?

1. they improve bioavailability and enable oral administration 2. . Capecitabine (this is really a prodrug of a prodrug) 3. either replication stalling or DNA-damage

Cell cycle 1. what is doubling time? 2. what is the growth fraction? 3. what happens in the S phase? 4. what happens in the G2 phase? 5. M? 6. G1?

1. time to double cell population 2. fraction of cells in the cell cycle. 3. replication of DNA genome 4. synthesis of cellular components for mitosis 5. Mitosis 6. synthesis of cellular components needed for DNA synthesis

1. Camptothecin, what does it target and what are some characteristics? 2. Irinotecan, what does it target and what are some characteristics? 3. Camptothecin analogues stabilize what? topoisomerase inhibition at replication fork 4. topoisomerase I inhibition leads to what?

1. topoisomerase I poison; poor water solubility, albumin binding 2. topoisomerase I, prodrug: enhances solubility, reduce off-target toxicity 3. DNA-topoisimerase I complex, prevent religation of DNA -interaction with neighboring nucleobases, -covalent intermedicate (DNA cleavage site) -hydrogen bonding to topoisomerase I 4. stalled replication forks and double strand breaks.

Classes of chemotherapeutics 1. what is a chemotherapeutic? 2. what are 4 classes and what do they do?

1. toxins that are more active in dividing than resting cells. 2. Antimetabolites: inhibit metabolism 3. DNA- alkylators: induce DNA-damage response 4. DNA binders, topoisomerase poisons: stall DNA-replication 5. Microtubule poisons: inhibit cytokinesis

Binding og imatinib to Bcr-Abl 1. imatinib inhibits what type of kinase? 2. what is essential for selectivity? 3. what moiety makes important binding contributions? General Design Principles 4. there is frequent interaction with which region? 5. what is responsible for selectivity? 6. what gets targeted alot? 7. there is frequent bind to what? 8. what structural features will they likely have?

1. type II 2. Hydrogen bond to Th315 3. piperazine moiety 4. -frequent interaction with hinge region 5. -gatekeeper responsible for selectivity 6. -targeting hydrophobic pocket 7.-binding to allosteric pocket close to ATP binding site 8. adenine like structural features

Signal transduction inhibitors 1. what falls into this category? 2. what is an example of a medication here? 3. what does imatinib do? 4. tox? 5. Resistance? 6. what are some others? 7. we inhibit not only the enzyme, but what else?

1. tyrosine kinase inhibitors 2. Imatinib 3. Bcr-Abl/c-kit kinase inhibitor (CML, GIST) 4. generally mild -N/V, edema and muscle cramps, neutropenia and thrombocytopenia, cardiomyopathy 5. alterations in kinase expression or mutations in kinase 6. nilotinib, dasatinib, bosutinib, ponatinib 7. all of the down stream effects