Anticancer Agents

jmanderson's version from 2016-02-14 23:55

Anticancer Agents I (Principles)


Question Answer
Myelosuppression from chemotherapyPMNs in bone marrow are proliferating and often killed off by CTX → anemia, leukopenia, thrombocytopenia
Frequent chemo importanceis important for rapidly-growing tumors to prevent the cancer cells from proliferating back up to a symptomatic state (e.g., so tumor cell kill exceeds regrowth for a possible cure)
Log-Kill Hypothesisproposes a model for the effect of cytotoxic chemotherapy on tumor size. It states that a given dose of chemotherapy kills the same fraction of tumor cells regardless of the size of the tumor at the time of treatment.
Describe two things to consider when choosing chemotherapy combinations.most cancers are HETEROGENOUS, cancer cells may develop acquired/primary RESISTANCE
p-glycoprotein role in drug resistance has two binding sites for ATP and one binding site involved in drug transport. This efflux pump allows cells to expel drugs and thus contributes to multidrug resistance of cancer cells. This proteins comes from MDR1 gene.
Give the two classes of anti-cancer drugs that are susceptible to multidrug resistance protein (MRP).Anthracyclines, vinca alkaloids

Anticancer Agents II


Question Answer
Explain why antimetabolite agents suppress blood cell development.Antimetabolites inhibit DNA synthesis (S-phase inhibitors). Bone marrow cell replication inhibition → suppress blood cell development.
MTX moaacts on dihydrofolate reductase → blocks DNA synthesis and proliferation
5-FU moaacts on thymidylate synthase → blocks DNA synthesis and proliferation
Hydroxyurea moaacts on ribonucleotide reductase → blocks DNA synthesis and proliferation
Taxanes (palcitaxel, docetaxel) actioninterfere with M-phase (mitosis) by binding to microtubules to INHIBIT DEPOLYMERIZATION (molecular disassembly) into tubulin
Colchicine actionblock mitosis by KEEPING SPINDLES FROM BEING FORMED in the first place
Describe the mechanism of vinca alkaloid action and its effects on mitosis.binds to TUBULIN which prevents cells from forming spindles needed to move its chromosome during metaphase. Both Vinca Alkaloids and colchicine ARREST IN METAPHASE.
Give two ways in which alkylating agents affect mitosis.1) DNA-DNA strand break and DNA-protein CROSS-LINKS break (esp. with 7-nitrogen of guanine); 2)Misreading of GENETIC CODE (e.g., alkylation of guanine may shift electron configuration to form GT pairs rather than GC.
Explain why alkylating agents are carcinogenic.Alkylating agents (cyclophosphamide) acts on the cytochrome P-450 system by stimulating enzymes phosphatase and phosphamidase to activate aldophosphamide which breaks down into phosphoramide mustard and ACROLEIN (which is CARCINOGENIC)
Give three mechanisms of doxorubicin’s action.1) DNA TOPOISOMERASE II inhibitor (crucial for replication and transcription); 2) INTERCELATES btw base pairs of DNA (inhibits DNA-dependent RNA synthesis); 3) Generates FREE RADICALS (causing membrane damage and DNA strand breaks)
Give two mechanisms of action for cisplatin.1) C1-moieties react with N7 of guanine and other nucleophiles; 2) Crosslinks DNA intrastrand (fast) and interstrand (slow); 3) DNA-protein crosslinks

Anticancer Agents III (Hematologic Cancer and Lymphomas)


Question Answer
Describe the MOA of the metabolite of 6-mercaptopurine.Purine antagonist, metabolized to active form to inhibit enzymes for de novo purine nucleotide synthesis. 6-thioguanine inhibits glycoprotein synthesis, interferes with DNA/RNA formation, and incorporates thiopurine nucleotides into both DNA/RNA
Describe the MOA of asparaginase.Tumor cells lack asparagine synthetase so they require exogenous L-asparagine; asparaginase breaks it down → starving only tumor cells.
Give the MOA for imatinibInhibits the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents phosphorylation of the kinase substrate by ATP.
imatinib for which it is a first-line agent.for CML during blast crisis
Give the MOA of bortozemib and how it may act.Inhibits 26S proteasome, may inhibit NF-kappaB signaling pathway. Used in combo with melphalan and prednisone for previously untreated multiple myeloma.
Give a previously undescribed MOA for thalidomide.Anticancer activity may be due to inhibition of angiogenesis
Give a disadvantage of procarbazine over other alkylating agents.Incidence of SECONDARY CANCERS higher than for other alkylating agents.
Give the dose-limiting toxicity for BLEOMYCIN.pulmonary toxicity


5-7 Anticancer Agents Handout Objectives


Question Answer
Give three advantages to giving combinations of anti-cancer drugs.1) It provides MAXIMUM CELL KILL within the range of toxicity tolerated by the host for each drug; 2) It offers a BROADER RANGE of coverage of resistant cell lines in a heterogeneous tumor proliferation; 3) It prevents new drug-resistant cell lines.
Give three general anti-cancer dosing principles.More effective in combination (may be synergistic).; More effective if they do not share common mechanisms of resistance.; More beneficial if they do not overlap in major toxicities.; Drugs should be administered as frequently as possible – to maximize dose intensity (dose per unit time) limiting tumor re-growth.; Desirable outcome is to achieve maximum cell kill with each treatment cycle, using the highest dose possible, repeating doses as frequently as tolerable.
Primary Resistanceabsence of response on first exposure
Acquired Resistanceabsence of response after previous exposures that had a response.
Give four categories or specific drugs that are susceptible to multi-drug resistance.Anthracyclines, Vinca alkaloids, Paclitaxel (Taxol), Etoposide, Mitomycin (Mutamycin), Plicamycin (Mithramycin)
Thrombocytopenia sxeasy bruising, prolonged bleeding, ecchymoses, petechia, bleeding gums, nosebleeds, internal bleeding
Anemia sxfatigue, dizziness, HA, irritability, SOB, tachycardia
Leukemia sxinfection, fever, sore throat, cough, SOB, nasal congestion, burning with urination, shaking chills, redness/swelling/warmth at site of injury
three dose-limiting toxicities for methotrexatemyelosuppression, GI toxicity, nephrotoxicity
Describe the rationale of “leucovorin therapy”.The malignant cells are killed selectively, while the normal cells are “rescued” by folinic acid. Thus, you can add this with otherwise lethal doses of methotrexate.
a problem with prolonged usage of 5-Fluorouracilmegaloblastic anemia
Compare an unusual and potentially dangerous adverse effect of cisplatin to its chief dose-limiting adverse effect.Neurotoxicity is a dangerous side effect. Nephrotoxicity is a dose-limiting AE.
Give the two main indications for paclitaxel.Ovarian carcinomas and advanced breast cancer
Give the cancer that etoposide is a first-line agent for.Small Cell Lung Cancer
Explain a way to minimize the necrotizing hemorrhagic cystitis that results from the breakdown of cyclophosphamide to acrolein.High Water Intake
Give the five “take-home messages” about alkylating agents.They directly damage DNA.; They have a broad spectrum of antitumor activity and immunosuppression.; They are active against both proliferating and nonproliferating cells; Their dose-limiting adverse effect is myelosuppression.; There are genotoxic and associated with an increased risk of leukomogenesis.
Give two mechanisms for resistance to cisplatin.Inhibition of drug uptake, block formation of DNA adducts, change concentration of regulatory proteins, increase in repair of cisplatin DNA adducts
Give two indications for L-asparaginase.ALL, lymphoma
the specific kind of cancer that tamoxifen is used forEstrogen-sensitive mammary gland cancer
what sort of agent FLUTAMIDE is along with one indicationAn androgen receptor antagonist used in prostatic carcinoma.
Explain what Category 1 of the National Comprehensive Cancer Network (NCCN) guidelines means for an anti-cancer agent and what this involves.Based on high-level evidence (e.g. randomized controlled trials) and there is uniform NCCN consensus.
Give the three typical stages of cancer treatment.1) Primary induction (short-term, 1-2 wks); 2) Maintenance; 3) Salvage
Give 4 symptoms of multiple myeloma.Involves bone marrow (pain), lytic lesions, bone fractures, and anemia. Pts. susceptible to infections.
Interpret why alkylating agents or nitrosureas should not be used in multiple myeloma patients who are candidates for stem-cell avoid compromising the stem-cell reserve
level 1 treatment in the maintenance phase of multiple myelomaTHALIDOMIDE (1) ± prednisone (2B); Lenalidomide (1)
the dose-limiting A.E. for vincristineNEUROTOXICITY is the dose-limiting factor (contraindicated in people with neuromuscular disorders)
Compare two mechanisms of fludarabine action.1) It is a triphosphate metabolite that interferes with DNA SYNTHESIS by inhibiting DNA polymerase-α and β. 2) It also induces APOPTOSIS
Explain how inhibition of adenosine deaminase by pentostatin results in cell death for tumor cells.Inhibits adenosine deaminase -> incr dATP -> inhibits ribonucleotide reductase -> blocks DNA synthesis