antineoplastics I – Flashcards
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| what is 5-flouro-uracil 5-FU used for? is it complexed w/anything? |
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| 5-FU is very commonly used in solid tumors. it is complexed with regimine (and other anti-neoplastic agents) |
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| what is cytarabine used for? what is it? |
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| leukemias, lymphomas - it is a purine analogue that is incorporated into DNA and disrupts synthesis |
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| what are alkylating agents used for? |
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| solid tumors and lymphomas |
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| what do platinum analogues do? |
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| form adducts w/DNA |
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| what is asparginase? how does it work? |
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| breaks down asparginase (cancer cells don't have asparagine synthetase and get it from the diet) |
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| what is placitaxel? when is it used, what does it do? |
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| an alkaloid that is used in solid tumors, it inhibits cell division in M phase |
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| what are protein tyrosine kinase inhibitors? |
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| protein tyrosine kinase inhibitors such as herceptin have a specific protein which can be targeted with an antibody |
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| what are topoisomerase inhibitors used for? what is an example of one? |
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| lymphomas. etoposide is an example of one used for lymphomas, doxorubicin forms free radicals to break DNA but has cardio toxicities |
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| what is methotrexate used for? what cells can it affect other than tumor cells? |
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| methotrexate is active against solid tumors by inhibiting dihydrofolate reductase (blocks folic acid production needed for DNA synthesis). other fast growing cells besides tumor cells such as bone marrow, hair, GI epithelium, and mucosal are also affected by methotrexate |
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| what is 6-mercaptopurine? what is it used for? |
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| this adosine analogue is incorporated as a mercaptoadosine adduct and confuses DNA polymerase. 6-mercaptopurine is used for lymphomas and & leukemias - NOT solid tumors |
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| what is the implication of the log-kill hypothesis? |
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| it takes several cycles to get the level of cancer cells down to zero (from 10^9 -> 10^8 is one log kill) so early prevention helps reduce this necessity, along with sx and radiation |
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| what is the primary treatment for hematologic and diffuse cancers (eg leukemias?) |
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| chemotherapy |
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| when is chemotherapy used? |
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| chemotherapy can be used as adjuvant therapy after surgery and radiation of solid tumors, initial therapy before surgery to downstage breast cancer, as chemoprotection in high risk individuals |
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| what is selective toxicity? |
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| aiming directly at cancer modality (though some normal cells will be affected), monoclonal antibodies can are better with this or working with tyrosine kinase |
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| what chemotherapy agents target the M (mitotic) phase? |
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| alkaloids such as vinicristine and vinblastine |
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| what antimetabolits inhibit the S phase? |
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| methotrexate and 5-FU |
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| what chemo drugs target the G2 phase? |
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| etoposide and bleomycin |
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| what drugs are non phase specific? |
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| alkylating drugs, nitrosources, antitumor antibx, procarbazine, cisplatin, and dacarbazine |
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| what are common toxicities of chemotherapy? |
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| anemia, bone marrow toxicity, immune suppression, GI tract damage b/c of fast epithelial overturn (ulceration/decreased absorption=nutritional strain), loss of hair, sores, sterility, nausea, vomiting, possibility of induced cancer |
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| how can drug resistance to chemotherapy occur? |
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| decreased permeation/increased drug efflux (ex P-glycoprotein in methotrexate and vinicristine), increased intracellular thiol conc., increased activity of DNA repair pathways, and increased rates of metabolism |
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| what is p-glycoprotein? |
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| a multidrug resistance gene expressed in lots of cancer cells |
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| what are the nitrogen mustards/DNA alkylating agents? how do they work? what are bifunctional alkylating agents? |
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| cyclophosphamide (prototype), mechlorethamine, ifosamide, chlorambucil. they attach a methyl modality to DNA molecules (guanine is the preference base) and keep it from replicating appropriately. bifunctional alkylating agents can also cause interstrand cross-linking. they are good for solid tumors b/c they are very harsh on DNA so when they do divide, they don't go anywhere |
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| when is meclorethamine used? ADRs? |
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| meclorethamine is used as a component of MOPP in tx of hodgkins disease, it causes injection site pain, is highly reactive with other drugs and can cause myelosuppression |
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| how is cyclophosphamide metabolized? |
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| cyclophosphamide is not toxic on its own, it is processed by cytochrome P450 to make toxic metabolites such as aldophosphamide. cancer cells dont have the enzymes to inactivate aldophosphamide, so aldophosphamide becomes acrolein which is cytotoxic (however, not the primary anti tumor species) and can cause hemorrhagic cystitis** and phosphoramide mustard which is the primary antitumor agent. |
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| when is cyclophosphamide used? |
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| is used for both lymphomas and solid tumors |
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| what kind of drug is cyclophosphamide considered? why is mesna disulfide/predrug hydration coadministered? |
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| a prodrug. disulfide/predrug hydration coadministered is given to lessen hemorrhagic cystitis from acrolein |
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| what is different about ifosfamide? |
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| ifosfamide is similar to cyclophosphamide but takes longer/need larger doses to get to ifosfamide mustard. |
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| what is significant about chlorambucil? |
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| chlorambucil is an alkylating agent that has good bioavailability, is well tolerated on a daily basis and has lower toxicity that can be more easily reversed |
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| what is is chronic myeloid leukemia (CML), and what drugs are used for it? |
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| CML is a BCR-ABL translocation (phila chr) causing unregulated tyrosine kinase -> unregualted WBCs. busulfan (sulfonate alkylator) was used, not imatinib mesylate is used, which as less side effects and has a higher CML selectivity by inhibiting a portion of the defective enzyme (allows pts to live more comfortably) |
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| what is carmustine? what is it used in? what is an ADR? |
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| carmustine is a nitrosourea alkylating agent that is highly lipid soluble, and is used in treating hodgkins/non-hodgkins lymphomas, brain cancers, and *meningial leukemias* by causing cross-linking, usually on guanine. it can cause cancer eventually |
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| how do platinum salts such as cisplatin work? ADRs? when are they used? |
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| platinum salts form covalent intrastrand cross linking of dsDNA (alkylation), keeping it from necessary separation in replication via DNA polymerase. ADRs include nephrotoxicity (monitor creatinine clearance). they are used in solid tumors. ototoxicity/peripheral neuropathy. |
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| what is FOLFOX? |
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| FOLFOX is a combination of 5-flourouracil and leukovorin (leukovorin is essentially folic acid. this will supplement body with some folate so you do not have as much bone marrow suppression) |
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| what are anthracyclines? |
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| tetracycline antibx including doxorubicin (most important), daunorubicin, mitoanrone, idarubicin |
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| what is doxorubicin used for? ADRs? |
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| doxorubicin is widely used for lymphomas, leukemias, and solid tumors. it inhibits topoisomerase II and produces free radicals and is used in a high dose initially with synergistic agents to minimize the # cycles, due to high toxicity, esp w/potential irreverible CHF (blood markers should be monitored) |
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| what is dexrazoxane? |
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| an agent coadministered with doxorubicin that chelates Fe to prevent iron-mediated free radical generation - reduces cardiotoxicity. this shows how good doxorubicin is for killing cancer if there are drugs being developed to keep its toxicity down |
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| what does bleomycin do? when is it used? ADR? |
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| bleomycin is an antibiotic that causes DNA strand breaks (formes Fe free radicals) and is used in hodgkins as well as certain testicular/lung CAs. it is associated with dose-related pulmonary fibrosis. |
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| what are examples of antimetabolites? |
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| methotrexate, 5-FU, mercaptopurine, and cytarabine |
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| what is the M/A for methotrexate (MTX)? |
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| methotrexate inhibits dihydrofolate reductase (and thymidylate synthase) b/c is is very close to folic acid in structure and competes with it. it exists in a *polyglutamated* form in cells which is too bulky to leave, and has to be eliminated in 2 phases by the renal system. |
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| what is MTX used for? |
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| MTX is indicated for ALL, NHL, solid tumors as well as RA and psoriasis |
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| what is leucovorin? |
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| activated folate administered with high dose methotrexate (like w/choriocarcinoma) to avoid severe bone marrow depression |
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| what is significant about methotrexate being a weak acid? |
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| if MTX levels remain high, nephrotoxicity can result, this can be avoided by alkalinizing urine to ionize and eliminate MTX |
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| what are ADRs for MTX? |
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| bone marrow suppression, ulcers, and pulmonary fibrosis (not as bad as bleomycin) |
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| what are some drug-drug interactions w/MTX? |
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| antibx such as sulfonamides/tetracyclines can cause increased toxicity (or other highly plasma protein bound drugs). drugs that compete for tubular secretion such as PCN/cephs, or reduce renal flow (NSAIDs) and keep MTX levels too high. high MTX levels can be adjusted with leukovorin. |
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| what drugs can inhibit both thymidylate synthase? |
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| methotrexate and 5-FU |
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| what does 5-flourouracil do? when is it used? ADRs? |
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| 5-FU is activated to FdUMP which complexes with tetrahydrofolate to inhibit thymidine synthetase, stopping DNA synthesis. FdUMP also causes miscoding of RNA, making protein translation difficult. is used in solid tumors esp the colon. it can cause bone marrow suppression. |
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| what is mercaptopurine? |
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| a purine antimetabolite that mimics adenine and causes misreading in DNA, leading to miscoding and faulty translation. |
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| what is cytarabine? |
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| a pyrimidine that is incorporated and activated into CTP which inhibits DNA polymerase - it is an S phase specific metabolite. |
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| why are purines and pyrimidines analogues good for leukemias and lymphomas? |
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| because they have rapidly dividing cells |
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| are alkylating agents cell cycle specific agents? |
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| no |
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| are antimetabolites cell specific agents? |
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| yes, for S phase |
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| what kind of DNA do alkylators damage? |
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| preformed DNA via interstrand crosslinks |
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| what kind of DNA do antimetabolites damage? |
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| new DNA (why they are good for leukemias and lymphomas) |
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| what level of proliferation do alkylators target? |
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| rapid and slow G0 proliferating cells |
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| what level of proliferation do antimetabolites target? |
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| just rapidly proliferating cells |
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| of alkylators and antimetabolites, which is more likely to kill BM cells or cause secondary lymphomas/leukemias? |
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| antimetabolites |
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| of alkylators and antimetabolites, which is more likely to have larger carcinogenic, tetragenic and mutagenic properties? |
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| alkylators |
