Fundamentals of Cancer Therapy

what bridges the innate and specific immune systems?

*Antigen presenting cells* (dendritic cells) bridge the innate and specific immune systems and generate primary immune responses. take nonspecific immune data and transfer it to specific immune cells

Doxorubicin MOA

*Intercalates between DNA base-pairs and generates free oxygen radicals*

Phases 1, II, III of Cancer Trials

*Phase I*- Dose escalation to determine safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) --> determines *safety* - side effects & MTD *Phase II*- Determine activity in specific diseases (test group of 20-30 people and determine *response rate*) *Phase III*- *Comparative trials*. e.g., Compare efficacy of ABVD vs. BEACOPP in Hodgkin's lymphoma.

MTX toxicities

*dose dependent* myelosuppression, nausea and vomiting, mucositis, hepatoxicity, neurotoxicity, nephrotoxicity

Bevacizumab MOA & toxicities

*humanized monoclonal antibody against VEGF* Hypertension, impaired wound healing, bowel perforation, proteinuria, pulmonary hemorrhage, CHF, deep venous and arterial thrombosis, pulmonary embolism, other thrombo-embolic events, reversible posterior leukoencephalopathy syndrome (RLS)

Carmustine is in which group?

*nitrosoureas*

how do tumors hide from immune system?

-Decreased MHC class I expression- decreased antigen presentation. -Immunoediting- Loss of target tumor antigens. -Loss of co-stimulatory molecules (B7).

Innate (non-specific) immune system.

-Primitive- found in animals as ancient as sea sponges. -Granulocytes, monocyte-macrophages, natural killer (NK) cells. -Complement proteins. -Non-specifically attack and kill targets. -Have no "memory," thus it confers no long term immunity (you can't transfer the immunity form one organism to the other)

how do tumor cells employ strategies to attenuate immune responses?

-T-regulatory cells (CD4+CD25+FoxP3+), myeloid-derived suppressor cells -Expression of immunosuppressive cytokines and enzymes- TGF-β, VEGF -Expression of negative immune regulatory molecules- CTLA-4, PD-L1.

Rituximab toxicity

1. Cytokine-release syndrome/tumor lysis syndrome (if you have high circulating malignant cell levels) 2. Prolonged and severe lymphopenia, immunosuppression, opportunistic infections, reactivation of viral hepatitis. 3. Severe mucocutaneous reactions (Rituxan®) 4. Pancytopenia/bone marrow failure (CAMPATH®)

2 important TKIs

1. Erlotinib 2. Imatinib

Patients at High Risk of Methotrexate Toxicity

1. Renal dysfunction or concomitant use of other nephrotoxic --> purely really excreted 2. Third space fluid (e.g. pleural effusion, ascites, anasarca) that "reservoirs" methotrexate. 3. Gastrointestinal obstruction 4. Dehydration 5. Acidic urine --> MTX is acidic, if you give an acidic drug you block the excretion 6. Using competing weakly acidic drugs (e.g. aspirin, penicillins) for excretion by kidney

2 types of immunomodulatory drugs

1. Thalidomide 2. Lenalidomide

Sipuleucel-T

4 month improvement in castrate-resistant metastatic prostate cancer, cumbersome to develop vaccine for each patient Toxicity: Infusion reaction, cerebrovascular events, chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting.

trastuzumab indications

Approved for treatment of chemorefractory metastatic breast cancer and in combination with paclitaxel for untreated patients with metastatic disease, and as adjuvant therapy.

best results of Trastuzumab are under what condition?

Best results are seen when patient's tumors are scored 3+ (high) for over expression low expression will not likely respond to this

Topoisomerase I Inhibitors (2)

Camptothecin Derivatives: 1. Topotecan (Hycamptin®) 2. *Irinotecan (Camptosar®)*

Primary resistance to chemo drugs

Cancer cells are not initially susceptible to the drug.

what kind of antibody is rituximab?

Chimeric IgG1 monoclonal antibody.

Trastuzumab toxicity

Congestive heart failure (CHF)/dysfunction, diarrhea cardiac muscle expresses HER2/neu if injured (heart attack or exposure to doxorubicin, not recommended to give doxorubicin with herceptin)

Cell Cycle Non-specific Chemo Agents

Cytotoxic to both cells that are actively cycling as well as to cells in the G0 phase (quiescent)

HER-2/neu expression correlates with what?

HER-2/neu expression correlates with hormone and chemotherapy resistance and a poorer prognosis at every stage in breast cancer.

antidote for MTX toxicity?

High dose methotrexate (>100 mg/m2) requires leucovorin rescue (antidote) --> activated form of folic acid called folinic. high doses often given for primary bone tumors

what kind of antibody is trastuzumab (herceptin)?

Humanized IgG1 mouse monoclonal antibody

why is it is difficult to vaccinate against tumors?

Immunological tolerance- tumors are recognized by the immune system as "self" and not as foreign, and therefore not rejected. The tumor is you, very hard to distinguish yourself as not self, hard to get immune system to attack a tumor Tumors employ numerous strategies to hide from the immune system. Tumor cells employ strategies to attenuate immune responses.

Rituximab increased response rates

Increased response rates in re-treatment and in combination with chemotherapy

common toxicities seen in all monoclonal antibodies

Infusion reactions- fevers, chills, rash, blood pressure changes, pruritis, dyspnea, chest pain, nausea, headache, anaphylaxis. Less likely with "humanized" antibodies.

Bortezomib MOA, toxicities, indications

Inhibits 26S proteosome and decreases nuclear NF-κB activity Indication: Multiple myeloma, B-cell mantle cell lymphoma Toxicity: Neuropathy, nausea, vomiting, myelosuppression, orthostatic hypotension.

Antigen Processing, Presentation, T-cell Activation and T-cell Mediated Tumor Cell Killing

MHC Class 1 presents antigen you have a cancer cell expressing a foreign antigen, it's chopped & presented as small peptides in the surface, will intact with specific T cell activating

multiple MOAs of trastuzumab

Multiple mechanisms of action: receptor blockade, down-modulation, ADCC, sensitization, anti-proliferative, inhibition of angiogenic factors, synergy with chemotherapy

Thalidomide indications & toxicity

Oral agent Indication: Multiple myeloma Toxicity: Teratogenic, neurotoxic

Lenalidomide indications & toxicity

Oral agent Indication: Myeloma and myelodysplastic syndromes Toxicity: Teratogenic, myelosuppression, risk of second cancers

Specific immune system-

Recognizes and targets specific antigens/epitopes and has *memory.* -*Humoral immune system*- composed of B-cells and plasma cells that produce specialized glycoproteins called antibodies that target specific antigens -*Cellular immune system*- T cells- immune system regulation and targeted killing. -CD4+ T cells: "helper" T cells, T-regulatory cells -CD8+ T cells: cytolytic T-lymphocytes (CTL) or "killer" T cells.

cetixumab toxicities

Severe anaphylaxis, skin rash, acne, folliculitis, diarrhea, abdominal pain, lung inflammation, *hypomagnesemia*

trastuzumab target

Targets HER-2/neu (ErbB2) a member of the EGFR family.

Mitoxantrone toxicity

Toxicity: myelosuppression, cardiotoxic, blue-green secretions (urine)

cetixumab targets what?

antibody directed against EGFR

most sensitive organ to chemo therapy?

bone marrow

Impact of Rituximab on Survival of Patients with DLBCL

dramatic increase in survival pre and post rituximab after the introduction of rituximab you have prob close to 40% improvement in survival of patients with DLBCL which had a poor prognosis in the past

Erlotinib targets what?

epidermal growth factor receptor

Negative Checkpoint Blockade

in certain chronic infections in mice, the mouse's immune system develop T cell exhaustion. it knew the mouse was infected but could not respond they recognized this signaling system called PDL1 and PD1 (programmed death ligand). these viral infected cells unregulated PDL1 on the cell surface which shut off T cells it's recognize now that 50% of human cancers up regulates PDL1. when PDL1 engages with PD1 (its receptor on the T cell), it turns off the T cell response. T cell becomes exhausted. antibodies have been developed to block this interaction Nivolumab & Pembrolizumab - they work the same but dose is different in patients whose tumors have high levels of PDL1 on surface, their response rates are close to 65%. even if they don't express PDL1, 15% of patients will respond

Pseudoprogression

in some patients taking Nivolumab & Pembrolizum, the immune cells (once activated by blocking the system) flood into the tumor and cause tumor swelling --> this looks like what appears as bone metastasis on imaging

Rituximab half life

long 1/2 life - because of huge molecular size they hang around in the body for a long time. also slowly metabolized, especially in the kidney

How are Monoclonal Antibodies Made?

original way: take human tumor antigens (either expressed in vitro translation or grinding up tumor), immunizing a mouse/rat/rabbit, harvesting the spleen and then taking the B-cells from the spleen and then assaying them for producing the antibody that you are interested in and then immortalizing them in a hybridoma by fusing them with a myeloma cell and then produces lots of a specific monoclonal antibody

HER-2/neu is over expressed is what % of breast cancers?

over expressed in 20-30% of breast cancers.

Prophylactic Vaccines for cancer

prevent infections that can lead to cancer Not useful once a cancer is diagnosed (they prevent chronic infections that over time can go on and increase the risk for developing cancer) -*HBV vaccine*- HBV chronic hepatitis B cirrhosis hepatocellular carcinoma. -*HPV vaccine*- Reduce the risk of infection with oncogenic HPV cervical dysplasia invasive cancer.

cisplatin activation

these are very small molecules, they get hydrated in aqueous solution and you have 2 reactive species (hydroxyl groups) that interact with the DNA and cause intrastrand kinking and breaks

MOA of Alkylating Agents

they usually have 2 functional arms the arms get activated and they bind to the DNA and tangle it up, interfering with its function

anthracyclines MOA

they work by intercalating into DNA and disrupting the DNA helix. that's probably true for mitoxantrone which is a synthetic product. the natural products have a boat conformation and prob can't fit into the DNA. they prob to DNA, bind & chelate and Fe atom, the Fe atom forms an oxide that shears the DNA

Trastuzumab (Herceptin®) for Stage II and High-risk Stage I Breast Cancer

used in adjuvant setting for high risk patients

Proteosome inhibitors

used in myeloma, in particular Bortezomib

Therapeutic Vaccines

used to treat established cancer Adjuvant- used after primary cancer treatment and patient clinically free of cancer. Therapeutic- used after the cancer is established- Sipuleucel-T (Provenge®)- Hormone refractory prostate cancer.

toxicity of CPA and IFF

*Bone marrow suppression (days 8-14), cystitis, immunosuppression* *at high doses - cardiac toxicity*

toxicity of procarbazine

*MOA inhibitor* --> some of the old anti-depressant agents are also MOA inhibitors. you can't give both together because you can cause severe toxicity, particularly *hypertensive crisis* other - Myelosuppression, nausea, vomiting, leukemia, infertility (men)

5FU toxicity

*depends on dose/schedule* 1. *mucositis* 2. myelosuppression 3. hand-foot syndrome (neuropathic syndrome with flaming red hands, severe pain, can go on for months after and then dry skin with slough off)

Vincristine toxicity

*neurotoxic* - neuropathy including constipation (if used to treat ALL in children, they can develop life threatening constipation) a lot of neuron function is due to MT function

Most anticancer drugs have a disproportionately greater effect on what type of cells?

*rapidly proliferating cells* (cells in active DNA synthesis - cancer cells) normal cells in the human body that also rapidly proliferate (hair, G.I. tract cells, bone marrow cells) that leads to the side effects of chemo

Doxorubicin toxicity

-*Lifetime dose of 550 mg/m^2 due to cardiotoxicity* --> if you go above that level between 550-650, the incidence of clinical CHF is 10% (below that it's 3%). if you go above 650, it goes up almost asymptotically. monitor heart function with echo -myelosuppression, N/V, red urine, vesicant, alopecia, radiation recall, mucositis, diarrhea.

Cell Cycle-specific Chemo Agents

-Act at specific stages of the cell cycle especially those stages representing active DNA/cell proliferation -Not very effective in G0 cells (quiescent cells) -Cancer cells are quite quiescent so one of the theories why cancer is so hard to treat is is that you can kill off the actively dividing cancer cells but the stem cells remain there to repopulate the tumor

Antibody

-Complex multimeric glycoprotein molecules produced by B-cells that specifically bind to foreign and infectious agents in the body. -Large molecules- 150,000-700,000 Da compared to 854 Da (paclitaxel) or 580 Da (doxorubicin). -Different classes- IgG, IgM, IgA, etc.

Alkylating Agents

-oldest of the chemotherapy agents -*inactive until metabolized by the microsomal P450 system* to form highly reactive electrophils that react with nucleophilic (amino-, carboxyl-, phosphate, or sulfhydryl-) groups cross-linking DNA and interfering with its function. -May also act through the covalent bonding of alkyl groups to other cellular molecules including proteins and cell membrane lipids (but DNA is the major mechanism)

Differentiating agents

1. *Baroxitene* - retinoid, used to treat cutaneous T-cell lymphoma in early stages 2. *Arsenic trioxide* - APL 3. *All-trans-retinoic acid (ATRA)* - APL -*APL Differentiation Syndrome- dyspnea, fever, weight gain, hypotension and pulmonary infiltrates* (start chemo to lower WBC & then begin these agents once WBC has dropped down, reduces risk of APL Differentiation Syndrome)

Approaches to Overcome Drug Resistance (4)

1. *Increase dose or dose intensity/density* -Autologous bone marrow transplant 2. *Inhibit MDR p-glycoprotein pump activity* -verapamil 3. *Inhibit glutathione production* 4. *Modulate drug-enzyme complexes* -5-FU-leucovorin-thymidylate synthase ternary complex

Non-classical Alkylating Agents - Platinum coordination complexes (2)

1. *carboplastin* 2. *cisplatin* 3. oxaliplatin

3 examples of classical alkylating agents

1. Carmustine (BCNU®) 2. Cyclophosphamide (Cytoxan®) --> one of the oldest 3. Mechlorethamine (nitrogen mustard, Mustargen®)

Principles of Chemotherapy (5)

1. Combinations of anticancer drugs should be used to avoid the emergence of tumor resistance 2. Each drug should be active against the tumor as a single agent. 3. The drugs should have non-overlapping toxicities. 4. The optimal (usually maximal tolerated) dose of each agent should be used (at max dose you get max log kill) 5. *Treatment should be scheduled at regular intervals and not delayed* --> delaying treatment stimulates the emergence of resistance and decreases the efficacy of treatment

Chemotherapy Resistance Mechanisms (7)

1. Increased gene expression -Increased expression of DNA repair enzymes (ERCC1- cisplatin resistance in lung cancer --> enzyme that repairs DNA strand breaks) -Gene amplification- increased target (DHFR) 2. Increased membrane transporters (ABCG2). 3. Target protein mutations. -T790M+ mutation in erlotinib resistance 4. Enhanced drug metabolism -Increased glutathione-S-transferase expression 5. p53 mutations/deletions- resistance to drug-induced apoptosis 6. Mutation of cellular drug import transporter proteins 7. Kinetic resistance- low proliferation with many cells in G0.

How to Treat MTX Intoxication

1. Leucovorin rescue 2. Hemodialysis/hemofiltration - doesn't work that well 3. Thymidine infusion - experimental 4. Glucarpidase infusion (recombinant bacterial carboxypeptidase G2)

2 groups of MT inhibitors + examples

1. Taxanes -Carbazitaxel (Jevatana®) -*Docetaxel (Taxotere®)* -*Paclitaxel (Taxol®)* 2. Vinca alkaloids -*Vincristine (Oncovin®)* -*Vinblastine (Velban®)* -Vinorelbine (Navelbine®)

antimetabolites - 4 important ones

1. antifolates - *methotrexate* 2. fluoropyrimidines - *5-FU* 3. deoxycitadine analogs - *cytarabine* 4. purine antagonists - *fludarabine*

monoclonal antibodies MOA (5)

1. can block a stimulatory ligand by binding to the receptor or the ligand 2. can cross link receptors and send an apoptotic signal to the cancer cell causing it to die 3. receptor down modulation - herceptin (when you cross link the receptor it gets withdrawn into the cell, taking it off the surface, decreasing the stimulation for tumor growth) 4. antibody dependent cellular toxicity - tumor cell is opsonized and macrophages recognize the tumor cell, attack it, ingest it and destroy it 5. complement dependent cytoxicity: the antibody Alamtuzumab is known to activate complement and punch holes in target cells

Non-classical Alkylating Agents - 4 examples (without platinum coordination complexes)

1. procarbazine - oral agent 2. dacarbazine 3. temazolamide 4. bendamustine

Modulation of 5-FU Cytotoxicity by Leucovorin

5FU and leucovorin bind to thymidylate synthetase, that complex has a long 1/2 life and that shunts FU into the DNA synthesis pathway away from the RNA synthesis and increases cytotoxicity

BCR-Abl

9;22 translocation that brings the BCR-Abl gene together & you get constitutive expression of TK stimulating growth

Monoclonal antibody

A single antibody derived from a single B-cell clone that recognizes a single specific antigenic determinant.

Common Toxicities of Chemotherapy (4)

Affects rapidly dividing normal cells 1. *Bone marrow cells*: -Granulocytopenia (Decreased neutrophils) -Thrombocytopenia (Low platelets) -Anemia (Decreased erythrocytes) 2. *G.I. tract*: mucositis (inflammation of oral caivty), diarrhea, nausea, vomiting 3. *Hair follicles*: alopecia 4. *Reproductive cells*: loss of fertility. --> Especially spermatogonia. --> Ova are in "suspended animation" until fertilization, so tend to be less affected. young woman are more protected, that tends to change as women get older. once a woman hits 40 y/o, risk becomes much higher

Acquired Resistance to chemo drugs

After initial sensitivity, following therapy, surviving cancer cells are selected for resistance to that drug. -*Specific Resistance*: Cells are resistant to a single drug or class of similar agents (i.e. methotrexate). -*General Resistance*: Multidrug resistance (MDR)- Broad resistance across a number of drug classes (gp160, ABCG2) --> pumps out lipophilic compounds out of the cell, very primitive. a lot of chemo drugs are lipophilic bc they are derived from alkaloids so they are pumped out of the cell. major mechanism of broad resistance

Vincristine indications- non malignant

Also used for ITP (non malignant conditions)

verapamil

Ca2+ channel blocker --> used to Inhibit MDR p-glycoprotein pump activity

Erlotinib toxicities

Diarrhea, acneform rash, gastric perforation (rare), interstitial pneumonitis (incidence 1%; 0.5% fatal), hemorrhage.

DHFR & MTX resistance

Dihydrofolate reductase mechanism of methotrexate resistance comes in 2 forms: stable and unstable 1. *stable* = gene amplification on the chromosome of the cancer cell 2. *unstable* = you form a special type of chromosome called double minute. double minutes do not have centromeres so they're assortment is random. if you remove MTX, the resistance disappears so the cells become sensitive again

Cyclophosphamide MOA

MOA: these drugs have 2 functional arms, they get activated, bind to DNA and they can intrastrand or inter strand binding and kinking

temazolamide toxicity

Myelosuppression, N/V, headache

bendamustine toxicity

Myelosuppression, N/V, hypersensitivity reactions, fever, fatigue.

major toxicity of carmustine

Myelosuppression, delayed nadir (days 21-28) --> watch with all alkylating agents *Administer every 6-8 weeks!!* --> most chemo agents are given 3-4 weeks, with this class of drugs you need to delay the treatment to every 6-8 weeks)

Cytarabine toxicity

Myelosuppression, fevers, arthralgia, cerebellar neurotoxicity (HDAC, irreversible), ocular toxicity (HDAC, irreversible) May be given intrathecally for leukemic meningitis

Irinotecan toxicities

Myelosuppression, hepatitis, transaminitis, fever, acute and delayed diarrhea -Acute diarrhea: treat with *atropine* 0.25-1.0 mg IVP -Delayed: early treatment with loperamide (4 mg p.o., then 2 mg q 2 hr. until diarrhea free for 12 hrs. dose dependent toxicity: *neutropenia* (myelosuppression)

toxicity of dacarbazine

Myelosuppression, nausea, vomiting, vesicant

Imatinib toxicities

Nausea, vomiting, diarrhea, edema, rash, hepatotoxicity, arthralgia, myalgia, hemorrhage, myelosuppression.

5FU is often used in combination with what?

Often used in combination with leucovorin to increase activity (modulation)

temazolamide is a prodrug of what?

Prodrug of dacarbazine

Docetaxel MOA

Stabilizes microtubules

Receptor Tyrosine Kinases (RTK)

TKs work in 2 parts as 2 homodimers (although some are heterodimers): when the ligand binds, they come together and transphosphorylate sending a signal to the nucleus of the cell & stimulates cell growth which stimulates resistance to radiation and chemo)

Rituximab target

Targets CD20 that is broadly expressed on B-cells.

Paclitaxel toxicity

Toxicity: *anaphylactic reactions*, hypersensitivity reactions (unclear if the drug is causing it, it's a natural product but it's very insoluble in aqueous solution and is dissolved in this solution called Cremaphor which is a synthetic alcohol) -Pre-medicate with H-1 antagonist, H-2 antagonist, and steroids. Also cardiotoxic, myelosuppressive, mild NV, alopecia

how are cyclophosphamide and ifosfamide (conjugate of cyclophosphamide) activated?

activated similarly to phosphoramide mustard CPA and IFF are activated to phosphoramide mustards by the microsomal P450 enzyme system.

Comparison of Cisplatin with Carboplatin

although they have the same active moiety, they have very different toxicities (unclear if one is better than the other, choose based on what you're worried about) cisplatin = older drug, highly nephrotoxic (can cause irreversible kidney failure), carboplatin = mildly nephrotoxic cisplatin causes severe N/V, uncommon for carboplatin to cause N/V cisplatin causes neuropathy (often irreversible), carboplatin causes very mild neuropathy carboplatin is more potent in suppressing bone marrow

Antitumor Antibiotics

anthracyclines: *Doxorubicin* (mitoxantrone is a synthetic compound, the others are natural) others: *Bleomycin* these drugs are heterocyclic polyaromatic compounds - they will absorb UV light and reflect

anti-angiogenic agents block what?

block blood vessel growth into tumors

Bleomycin toxicity

but most important = *Pulmonary toxicity* (indiosyncratic but most are *dose related* - the higher the dose, the higher the risk of pulmonary fibrosis) hyper-sensitivity reactions, fever, chills, mucositis

Acrolein

byproduct of activation of CPA and IFF, can *hemorrhagic cystitis* *cytotoxic to the urinary bladder*. when patients are given very high doses of CPA and IFF, we often give it with a scavenger drug called *MESNA* (this scavenges acrolein because it can cause a severe burn of the bladder with severe bleeding)

T790M+ mutation

causes resistance to TK inhibitors. mutation it the ATP kinase domain of the epidermal growth factor receptor

overview of cell cycle

cells enter in G1, start synthesizing cellular constituents except the chromosome in S phase, the chromosomes are duplicated they then have a brief quiescent period and then go on to mitosis and cell division some cells go into a dead end phase (neuron --> becomes terminally differentiated and can never divide again) some cells can go on and undergo apoptosis (cells between fingers that form the hand)

Gliadel® wafers

cellular pads soaked in carmustine used for brain implantation they cut out a tumor and then pad the pocket that the tumor was in with gliadel wafers to give locally high levels of chemotherapy

Glucarpidase

cleaves MTX, standard of care treatment for MTX toxicity $50,000 a dose

Mitoxantrone

developed to be less toxic than Doxorubicin & Daunorubicin but it is less active on a mg/mg basis, you can go up to a higher level but you will see the toxicity at a higher level. it's tumor response rate is also lower

survival of CML with Imatinib

dramatic improvement in survival with targeted therapy

Log-Kill Hypothesis

each cycle of chemotherapy reduces the tumor by the same log amount multiple cycles of chemo are required to reduce the tumor below the level of detection. that does not mean the tumor is completely eradicated the hypothesis is that once you reduce the tumor below a certain finite level (b/t 10,000-100,000 tumor cells), the the immune system of the organism can then eradicate the remaining tumor cells

L-asparginase

enzyme used in childhood acute lymphocytic leukemia. Sourced from E. coli, Erwinia spps. one of the most common side effects = anaphylaxis (if they have anaphylaxis to the E. coli one, you can switch to Erwinia and they won't have anaphylaxis)

Gleevac (Imatinib)

first targeted drug that inhibits TK activity standard of care for CML (only treatments prior to Imatinib were bone marrow transplant or alpha interferon which didn't work that well)

Autologous bone marrow transplant

harvest bone marrow out of patient, preserve it, put in the freezer and give the patient industrial strength doses of chemotherapy which overcomes resistance of the tumor and kills the tumor after the chemotherapy is metabolized or excreted, we give back the bone marrow and it repopulates the patient

Antineoplastic and Ancillary Drugs used in oncology

hematopoietic growth factors-filgrastim (G-CSF), erythropoietin prevent the low blood counts after treatment & can protect the patient from serious infection analgesics - pain is v common in cancer patients Antiemetics - many chemo drugs cause nausea & vomiting anti-microbials - many chemo drugs cause neutropenia, inc risk of life threatening infection (neutropenic infection) antiseizure/psychotropics/sedatives bone stabilizing agents - stabilizing bone against metastasis and reduce risk of pathologic fractures which are a major cause of morbidity

problem with using mouse/rat/rabbit monoclonal antibodies

human immune systems will recognize them as foreign and they will develop their own immune response to the antibody in a series of steps they converted most of the antibody to the human framework (FDA requires human mAb)

Docetaxel toxicity

hypersensitivity, myelosuppression, fluid retention (leg edema)

methotrexate MOA

inhibits DHFR you need reduced folates to synthesize thymidine giving MTX blocks that enzyme and the cell loses its pool of reduced folates, cannot generate thymidine, and it stops DNA synthesis

Hydroxyurea

inhibits ribonucleotide reductase used for 1. acute myelocytic leukemia to lower white counts 2. also usd in sickle cell to increased FHb prevent crises

cancer stem cell

just like stem cells in the liver, other organs, or bone marrow, it's felt that not all cancer cells are equal and the stem cells resupply the cancer cells this model of cancer stem cells fits many but not all cancers

most common cancers in males vs. females

males = prostate cancer young males = testicular cancer females = breast cancer most *lethal cancer* in males & females = lung cancer

Vincristine MOA

mitotic spindle inhibitor --> they destabilize mitotic spindles rather than stabilize them

is Bleomycin a single drug?

not a single drug, it is a mixture of fungal peptides

Dexrazoxane

reduces the toxicity & efficacy of anthracyclines

rheumatologic indications of CPA

rhematologic diseases like lupus, particularly of there is kidney involvement to suppress the immunity (*lupus nephritis*)

Paclitaxel MOA

stabilizes MT MTs are being assembled on one end, broken down on the other --> involved in many functions of the cell such as mobility, secretion, cell division. anything that interrupts on either end is often lethal to the cell

indications for temazolamide

standard for treating high grade brain tumors like *glioblastoma* --> easy to administer (capsule). patient takes oral doses with radiation therapy then continues oral temazolamide for 6 mo after

Cell Kill Hypothesis

states that a constant fraction of tumor cells will be killed with each chemotherapy cycle. Thus, cell killing is a *log-function* and the tumor burden will (in theory) never reach absolute zero.

Cytarabine MOA

taken into the DNA synthesis pathway and because it's lacking the 3'OH group it acts as a chain terminator in DNA synthesis

temazolomide vs. procarbazine in the tx of glioblastoma multiforme

temazolamide - survival was significantly better, also better tolerated than procarbazine

Tumor Growth Curve

tumors exhibit *Gompertzian growth* 1. early on you have an increasing growth rate (slow growth) 2. then you reach the log phase which is the accelerated phase of growth in tumor 3. as you lose nutrients & blood flow to the tumor it gets larger an larger, you have a slowing and then plate phase 4. by the time you reach the plateau phase the tumor is often lethal to the organism

how is carmustine administered?

very hydrophobic; administered in alcohol and results in burning at injection site.

Cancer cells are most sensitive to chemotherapy when?

when *tumor is small* & their *growth fraction is high* treat aggressively and early in the course of disease this is the theory behind adjuvant chemo (given after a person has surgery). if a woman w/ breast cancer has a lumpectomy done but there is a high risk that microscopic disease has spread, we come in with chemo because when we have small volume disease you are much less likely to have resistance and more likely to have the tumor sensitive to chemo