Anti-Cancer Drugs
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Created by:
codyswallows on March 6, 2012
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When you can't just take it out.
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83 terms
Terms | Definitions |
|---|---|
 T/F: Alkylating agents do not require activation (Also: Wise men know the exceptions.). | FALSE except for Busulfan. |
| What 3 alkylating agents methylate DNA? What do the other alkylating agents generally do to DNA? | Triazenes, hydrazines, busulfans. The others add alkyl chlorethyl function, cross-link using platinum or rearrange to cross-link DNA (mitomycin C). |
| How do alkylating agents work, generally speaking? | Cross-link DNA to prevent function. |
| Alkylating agents work by producing a double-or single-stranded modification to DNA. What site on DNA is most vulnerable to alkylating agents? | N7 guanine >> N1, N3 adenine, N3 cytosine, O6 guanine. |
| How does carmustine work? | Carbamoylation of other proteins, prevents DNA repair and prevents cross-resistance between alkylating agents. |
| What are 4 mechanisms of resistance to alkylating drugs? | Decreased metabolic activation; increased DNA repair decreased drug permeability; increased glutathione synthesis (conjugation and inactivation via glutathione-S-transferase). |
| What is a nasty-looking side effect of some alkylating agents if administered IV? How can this be avoided? | Vesicant action (painful blisters); avoid by administering orally. |
| Alkylating agents primarily affect what cells? What is the result? | Rapidly dividing cells in bone marrow (megakaryocytes, platelets, granulocytes) --> bone marrow suppression; GI tract; also alopecia (hair loss). |
| What are the long-term consequences of treatment with alkylating agents? | Ovarian failure, testicular failure, acute leukemia (rare). |
| What is the dose-limiting toxicity of alkylating agents? How is dosing altered to minimize toxicity? What alkylating agent has other dose-limiting toxicities, and what are they? | Myelosuppression; dose in 21-day intervals to give blood components time to recover. Cisplatin is limited by renal toxicity, ototoxicity and peripheral neuropathy. |
| Why are neoplastic cells susceptible to antimetabolite action? | They have increased metabolic requirements for folic acid, purines and pyrimidines. |
| What is an antimetabolite, and how does it work against cancer? What are the 3 classes of antimetabolites that treat cancer? | A chemical that inhibits the use of a metabolite, e.g., folic acid analogues, purine analogues and pyrimidine analogues are used to treat cancer. These drugs are incorporated into DNA and block chain elongation. |
| Where do folic acid analogues act? Name the prototypical folic acid analog. | Act at catalytic site of dihydrofolate reductase, e.g., methotrexate. |
| What are 4 mechanisms of resistance to folic acid analogues? | Decreased transport to cell (carrier-dependent uptake); lower-affinity dihydrofolate reductase enzyme; gene amplification of dihydrofolate reductase; decreased polyglutamate formation (drug not trapped as extensively - not as much bound to DHFR?) |
| What are the primary adverse effects of folic acid analogues? | Bone marrow suppression, dermatologic, GI mucosa. |
| What drug can be used to "rescue" adverse effects due to folic acid? How does this work? | Leucovorin (a folic acid analogue that allows for some purine and pyrimidine synthesis in the presence of methotrexate). |
| Name the pyrimidine analogues. | 5-Fluorouracil, capecitabine, cytarabine, gemcitabine. |
| What are the primary adverse effects of pyrimidine analogues? | Myelosuppression and mucositis. |
| Name 2 metabolic derivatives of 5-FC and discuss how they inhibit DNA synthesis / protein synthesis. | FdUMP inhibits thymidylate synthase --> inhibition of thymidine nucleotide synthesis. FUTP is incorporated into RNA and interferes with protein synthesis via uracil substitution. |
| How does leucovorin increase 5-FU-mediated cell kill? | Leucovorin provides precursor for purines and pyrimidines; the more nitrogen bases available, the more DNA synthesis and protein synthesis = more 5-FU action. |
| What pyrimidine analogue is administered as a pro-drug that is activated within the tumor? What is the route of administration, what is it converted to, and what is special about its adverse effects?*** | Capecitabine is an orally administered pro-drug that is converted to 5-FU within the tumor. It does not usually produce myelosuppression or alopecia. |
| What 2 pyrimidine analogues are S-phase-specific, and how do they work? Why is gemcitabine a superior inhibitor? | Gemcitabine and cytarabine are ineffective in non-dividing cells. They are activated within the cell and incorporated into DNA, inhibiting template function and terminating chain elongation. After gemcitabine derivative is incorporated, an additional base is added before DNA polymerase stops, making it harder for repair mechanisms to excise the base ("masked termination"). Thus, gemcitabine inhibits both DNA replication and repair. |
| Name the 5 purine analogues. | Mercaptopurine, thioguanine, cladribine, fludarabine, pentostatin. |
| What are the 3 mechanisms of action for mercaptopurine and thioguanine? | Metabolite meTIMP inhibits PPAT --> decreased de novo purine synthesis; metabolite TGTP is incorporated into RNA --> cytotoxicity; metabolites dTGTP is incorporated into DNA --> cytotoxicity. TGTP and gTGTP are products of the purine salvage pathway. |
| What enzyme inactivates mercaptopurine? | Xanthine oxidase. |
| What are the 5 mechanisms of resistance to mercaptopurine? | Decreased expression of HGPRT (converts mercaptopurine for purine salvage pathway), increased alkaline phosphatase activity, decreased drug uptake, increased drug efflux, altered enzyme structures, altered recognition of DNA breaks. |
| What enzyme in mercaptopurine metabolism may exhibit variation among individuals, requiring dosage modification? | TPMT (inactivation of purine salvage pathway product). |
| What is the mechanism of action for purine analogues cladribine, fludarabine and pentostain? | ATP depletion: conversion to triphosphate form by dCK --> incorporation into DNA --> 3'-termination --> DNA strand-breaks accumulate --> poly-ADP-ribose-polymerase synthesis increases --> NAD consumed (needed for ATP synthesis) --> ATP depletion. (In short: incorporation into DNA depletes ATP) |
| What are 6 mechanisms of resistance to cladribine, fludarabine and pentostatin? | Dereased nucleoside transport, decreased/deficient dCK activity, altered intracellular pools of competing nucleotides, altered regulation of ribonucleotide reductase, increased drug inactivation by 5'-nucleotidase, defective induction of apoptosis. |
| What are the 3 classes of drugs that inhibit mitotic spindle production? What do they do, basically? | Vinca alkaloids, taxanes and a drug used to treat gout. These drugs interfere with microtubule function. |
| What is the drug used to treat gout? | Colchicine. |
| How do vinca alkaloids work, basically? | Prevent microtubule assembly. |
| How do taxanes work, basically? | Prevent microtubule disassembly. |
| What are the vinca alkyloids? | Vincristine, vinblastine, vinorelbine (the cousins vini). |
| What is the primary toxicity associated with mitotic spindle inhibitors? Why is this the case? What is another toxicity? | Peripheral neuropathy due to impaired neurotransmitter trafficking in axons. Can also depress bone marrow --> neutropenia, thrombocytopenia. |
| What are 3 mechanisms of resistance to mitotic spindle inhibitors? | Decreased uptake, increased efflux, mutation of tubulin binding sites. |
| What are the 4 classes of topoisomerase inhibitors? What topoisomerases do they inhibit? | Campothecins inhibit topoisomerase-I. Podophyllotoxins, anthracyclines and actinomycins inhibit topo-isomerase-II. |
| What are the 2 drugs that belong to the camptothecin class of topoisomerase inhibitors? | Topotecan, irinotecan. |
| What are the 2 drugs that belong to the podophyllotoxin class of topoisomerase inhibitors? | Etoposide, teniposide. |
| What are the 5 drugs that belong to the anthracycline class of topoisomerase inhibitors? | Doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone. |
| How do camptothecins, podophyllotoxins and actinomycins work? | Inhibition of topoisomerases: Bind topoisomerase-DNA complex; when replication enzymes interact with this complex, double-stranded DNA breaks occur and the cleavage/relegation reaction is inhibited. |
| What are the 3 mechanisms of resistance to camptothecins? | Increased efflux, mutation/increased expression of topoisomerase-I, increased expression of topoisomerase-II. |
| What are the 3 mechanisms of resistance to podophyllotoxins and actinomycins? | Increased efflux, mutation/ decrease expression, p53 mutation (no sensing DNA damage). |
| What are the 3 mechanisms of action for anthracyclines? | Stabilizes initial DNA-TOPO-II enzyme complex --> dsDNA breaks; intercalates between DNA base pairs --> helix changes shape --> DNA pol inhibited; reduces to semiquinone and hydroxyl radicals --> lipid peroxidation, DNA scission, direct oxidation of purines, pyrimidines, thiols, amines. |
| What are the 4 mechanisms of resistance to anthracyclines? | Increased efflux, increased glutathione peroxidase, decreased expression/mutation, increased repair efficiency. |
| What are the 3 primary toxicities of anthracyclines? | Extravasational necrosis, acute cardiotoxicity, CHF. |
| What drug binds directly to DNA via electrostatic interactions involving an iron complex? | Bleomycin. |
| What are the 3 primary mechanisms of resistance to bleomycin? | Decreased uptake, increased repair, increased inactivation via thiols or thiol-rich proteins. |
| How does asparaginase work? | Decreases levels of asparagine available to tumor. |
| What is the primary toxicity associated with asparaginase? | Hypersensitivity reactions. |
| How does hydroxyurea work? | Inhibits the iron complex of ribonucleotide reductase, the rate-limiting enzyme of DNA synthesis. |
| What is the primary toxicity associated with hydroxyurea? | Bone marrow suppression (pancytopenia, leukopenia, neutropenia, thrombocytopenia); mutagenic (secondary malignancies). |
| How does thalidomide work? | Inhibits tumor cell proliferation, adhesion to stroma, angiogenesis, NK cell activity. |
| What is the primary toxicity associated with thalidomide? | Emergent peripheral sensory neuropathy. |
| What condition does tretinoin treat? | Acute promyelocytic leukemia (gene fusion disease that results in inhibition of apoptotic pathways and myeloid differentiation). |
| How does tretinoin work? | Converts fusion protein inhibitory activity into pro-differentiation stimulatory activity --> APL cells differentiate. |
| What are the 6 main toxicities associated with tretinoin? | 25% will develop retinoic acid-APL syndrome; fever, dyspnea, weight gain; peripheral edema, pulmonary infiltrates; pleural or pericardial effusion; impaired myocardial contractility; occasional episodic decreased blood pressure. |
| All monoclonal antibody names end in ______. | "Mab." |
| Name the monoclonal antibodies that target EGFR. | Gemtuzumab, trastuzumab, cetuximab, panitumumab. |
| Name the monoclonal antibodies that bind CD20. | Rituximab, ofatumumab. |
| Name the monoclonal antibody that binds CD52. | Alemtuzumab. |
| Name the monoclonal antibody that binds VEGF. | Bevacizumab. |
| What is the primary advantage of antibody therapy? | Target-specific treatment. |
| What are the disadvantages of antibody therapy? | Poor tumor penetration (large mass), insufficient antigen expression common, expression on normal cells, anti-(animal) antibody induction by human host. |
| What are 3 ways monoclonal antibodies directly result in tumor cell death? | Complement-dependent cytotoxicity, antibody-dependent cellular toxicity, apoptosis (CD20). |
| What are the 2 possible toxicities of monoclonal antibody therapy? | Infusion reactions, cardiomyopathy (possible result of "off-target" action). |
| All tyrosine kinase inhibitors end in _____. | "nib." |
| Where to tyrosine kinase inhibitors bind the kinases? | Highly conserved ATP binding sites. |
| What are the 6 mechanisms of resistance to tyroskine kinas receptor inhibitors? | Decreased intracellular drug levels, increased plasma protein binding p-gp efflux, kinase gene amplification, clonal evolution of kinase-independent mechanism, mutations of ATP-binding sites. |
| What are the major toxicities associated with tyrosine kinase receptor inhibitors? | Fever, rash, nausea, anorexia, diarrhea, cardiotoxicity, reduced left ventricular ejection fraction and cardiac arrhythmias. |
| Name the EGFR tyrosine kinase inhibitors. | Gefitinib, erlotinib, lapatinib. |
| Name the BCR-ABL tyrosine kinase inhibitors. | Imatinib, dasatinib, nilotinib. |
| Name the VEGF, PDGFR, KIT and FLT tyrosine kinase inhibitors | Sunitlinib, sorafenib, pazopanib. |
| What are the mTOR inhibitors? | Sirolimus, everolimus, temsirolimus. |
| What 2 mTOR inhibitors are approved for treatment of advanced renal cell cancer? | Temsirolimus and everolimus. |
| What drugs might not be working properly if a cell is not sensitive to rapamycins? | mTOR inhibitors. |
| What is the VEGF antagonist? | Bevacizumab. |
| What are the primary toxicities associated with bevacizumab? | Hypertension, small incidence of GI bowel proliferation. |
| Name a proteasome inhibitor. What proteasome does it inhibit? | Bortezomib (inhibits 26S proteasome). |
| How does bortezamib work? | Stabilizes inhibitor protein IKB (blocks NFKB) --> continued presence of cell cycle proteins, oncogenes and apoptosis genes --> sensitizes cancer cells > normal cells to apoptosis. |
| What are the primary toxicities associated with proteasome inhibitors? | Thrombocytopenia, peripheral neuropathy, headache, paresthesias, dyesthesia, dizziness, N/V, diarrhea, anorexia, constipation, fever, insomnia, arthralgia. |
| How are old toxic anticancer drugs being made more effective in the modern era? | Antibody drug conjugation deliver to tumor. |
| Why is antibody drug conjugation delivery superior? (In other words, how were these drugs delivered before, and how are they delivered now?) | ADCs are internalized, preventing endothelial cell damage and intraluminal blood coagulation (localized targeting). |
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