Flashcards in Cytotoxic Drugs Deck (44):
Define mono-functional alkylation.
1 reactive group is involved, leading to protein miscoding and apoptosis
Define bi-functional alkylation.
It involves 2 reactive groups, leading to cross-linking of DNA making repair too difficult and resulting in apoptosis
Name the mono-functional alkylating agent discussed in lecture and its unique mechanism.
Streptozocin. It is taken up by GLUT2 transporter (linked to glucose)
Which alkylating agents are limited by renal toxicity?
Streptozocin, Cisplatin (irreversible damage to renal tubules), Oxaliplatin
Which alkylating agents are dose-limited by myelosuppression?
Cyclophosphamide and Carmustine
Name the adverse effect associated with all alkylating agents, though it is only dose-limiting for two.
Which alkylating agent is ototoxic, causing tinnitus and hearing loss?
Maybe they're really saying "this statin" but you can't tell because you can't hear jack
Which alkylating agent can cause hemorrhagic cystitis, and what do you give to prevent this complication?
Cyclophosphamide causes hemorrhagic cystitis. We can give mercaptoethan sulfonate (MESNA) to prevent.
Cyclops already lost an eye, he doesn't want to lose his bladder so he takes MESNA (he don't wanna deal with that mess, nah)
Discuss the pharmacokinetics of cyclophosphamide.
It is a prodrug metabolized in the liver by P450s (liver is protected from hepatotoxicity by enzymes however) and becomes phosphoramide mustard
Discuss the mechanisms of resistance that affect alkylating agents.
Increased capacity of tumor cells to repair DNA lesions (harder if bi-functional), decreased transfer of the drug into the cell, increased production of glutathione and glutathione-associated proteins that conjugate the drug, and increased glutathione S-transferase expression (catalyzes conjugation rxn)
Name the antimetabolites and their general mechanism of action.
Methotrexate, 5-Fluorouracil, Cytarabine, 6-Mercaptopurine, 6-Thioguanine
They all act as antagonists of biosynthetic pathways
What is the dose-limiting adverse effect for all of the antimetabolites?
What kinds of cancers are more susceptible to antimetabolites?
Cancers with a high growth fraction because they have a higher metabolism. These are CCS drugs.
Interaction of allopurinol with which antimetabolite can lead to life-threatening myelosuppression?
6-MP. Dosage of 6-MP should be decreased 50-75% when combined with allopurinol to prevent this response.
Describe the mechanism of action of methotrexate.
Antimetabolite; it is a folic acid analog that inhibits DHFR (dihydrofolate reductase) preventing purine and amino acid synthesis thus interrupting DNA, RNA, and protein synthesis
Describe the mechanism of action of 5-Fluorouracil.
Antimetabolite; analog of uracil that is converted to 5-FdUMP and incorporated into DNA inhibiting thymidylate synthetase (required for de novo pyrimide synthesis) thus slowing cancer cell replication
Describe the mechanism of action of Cytarabine.
It is converted to Ara-CTP and competitively inhibits DNA polymerase-a and DNA polymerase-b, blocking DNA replication and repair respectively
Describe the mechanism of action of 6-MP and 6-thioguanine.
They are purine analogs that convert to thio-dGTP, which is then incorporated into DNA of replicating cancer cells resulting in apoptosis
Discuss the mechanism of resistance against methotrexate.
Decreased drug transport via impaired expression of reduced folate carrier protein (aka MTX transporter), decreased polyglutamate addition to MTX, amplification of DHFR gene, mutant DHFR protein w/ reduced affinity for MTX, and increased MDR1 expression
What drugs interact with methotrexate?
PCN, cephalosporins, and NSAIDs
Name the plant alkaloids and the primary mechanism of resistance to these drugs.
IVVE P (think ivy plant)
Irinotecan, Vinblastine, Vincristine, Etoposide, and Paclitaxel.
Resistance develops from increased MDR1 gene expression
Describe the mechanism of action for Vinblastine and Vincristine.
They bind B-tubulin, preventing polymerization of microtubules which blocks mitotic spindle formation during M phase resulting in mitotic arrest and thus apoptosis.
Describe the mechanism of action of Paclitaxel.
Binds with high affinity to B-tubulin and stabilizes microtubule formation, preventing polymerization of microtubules so cells can't form mitotic spindle apparatus
Describe the mechanism of action of Etoposide.
It inhibits topoisomerase II (this enzyme uncoils DNA by cutting both strands; its inhibition results in DNA strand breakage)
Describe the mechanism of action of Irinotecan.
It inhibits topoisomerase I (this enzyme uncoils DNA by cutting 1 strand; its inhibition results in DNA strand breakage)
Are plant alkaloids CCS or CCNS drugs?
*Except for Ironectan, which becomes CCNS at higher concentrations!
What is the dose-limiting adverse effect for plant alkaloids?
*With the exception of Vincristine, which is marrow sparing
(think Christ spared us)
Which plant alkaloid is marrow sparing, and what is its dose-limiting adverse effect?
Vincristine. Limited by peripheral neuritis/neuropathy with paresthesias.
Which cytotoxic agent can be given PO?
Name the antibiotics used for their cytotoxic effects, and their general mechanism of action.
DDDB (antibiotics are ddd-best)
Doxorubicin, Daunorubicin, Dactinomycin, and Bleomycin.
They act by inserting themselves between base pairs of DNA (i.e. intercalation) leading to strand breakage and/or interfering with replication enzymes
Are antibiotics CCS or CCNS drugs?
*With the exception of bleomycin, which is CCS
Describe the mechanism of action of Doxorubicin, Daunorubicin, and Dactinomycin.
DNA intercalation interferes w/ DNA & RNA synthesis, inhibition of topoisomerase II, and free radical formation leading to DNA scission
Describe the mechanism of action of bleomycin.
Intercalation, scission, and fragmentation of DNA d/t oxidation rxn mediated by DNA-bleomycin-Fe(II) complex
Describe the mechanism of resistance for Doxorubicin, Daunorubicin, and Dactinomycin.
Increased MDR1 gene expression, increased glutathione peroxidase activity, and resistance-rendering mutations to topoisomerase II
Describe the mechanism of resistance for bleomycin.
Increased levels of bleomycin hydrolase and DNA repair activity
What adverse effects are associated with Doxorubicin?
Cardiotoxicites 2/2 free radicals the drug generates, including acute arrhythmias, conduction abnormalities, and dose-limiting irreversible chronic cardiomyopathies.
Describe the adverse effects associated with Dactinomycin.
Dose-limiting BM suppression, GI disturbances, oral ulcers, and alopecia
Describe the adverse effects associated with bleomycin.
Dose-limiting pulmonary fibrosis
Describe the mechanism of action of L-Asparaginase.
Treats childhood ALL. ALL cells must rely on exogenous L-asparagine (healthy cells can synthesize it themselves). L-Asparaginase reduces L-asparagine levels
Describe the mechanism of action of hydroxyurea.
It is a CCS antimetabolite that inhibits ribonucleotide reductase during the S phase, preventing reduction of ribonucleotides to deoxyribonucleotides
Describe the mechanism of action of Mercaptoethan Sulfonate (MESNA).
It is coadministered with cyclophosphamide, b/c that drug causes acrolein accumulation leading to hemorrhagic cystitis so MESNA neutralizes acrolein at acidic pH in the urine
Discuss the clinical use for mannitol with cytotoxic drugs.
It is used to prevent nephrotoxicity of cisplatin and oxaliplatin via diuresis
Describe the mechanism of action of allopurinol.
A purine analog given to prevent hyperuricemia during 6-MP tx, however it also inhibits 6-MP metabolism by xanthine oxidase and can lead to toxic myelosuppression. Thus reduce 6-MP dose by 50-75% when coadministering