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IOS6 exam 3
Pharmacology of Cancer Drugs (Agarwal)
| Question | Answer |
|---|---|
| Nitrogen Mustards (alkylating agents) | Mechlorethamine, Cyclophosphamide, Chlorambucil |
| Nitrosourea (alkylating agents) | Carmustine |
| Alkyl sulfonate (alkylating agents) | Busulfan |
| Triazenes (alkylating agents) | Dacarbazine |
| Platinum Compounds (Alkylating agents) | Cisplatin, Carboplatin, Oxaliplatin |
| Intrinsically reactive alkylating agents: | Mechlorethamine, Carmustine, Busulfan, Chlorambucil, Cisplatin, Carboplatin, Oxaliplatin |
| Alkylating agent requiring metabolic activation | Cyclophosphamide |
| MOA of alkylating agents | Crosslinking of DNA, & alkylation of DNA and/or protein. This leads to DNA damage and ultimately causes the cell to die by apoptosis.. |
| MOA of Carmustine | Spontaneous degradation to organic isocyanate (forms carbamoylated protein) and 2-chloroethyl carbonium ion (alkylation of Guanine of DNA). |
| Active metabolite of cyclophosphamide responsible for anti-cancer activity... | Phosphoramide mustard |
| Mechanism of resistance for methotrexate... | Impaired transport into cells, impaired polyglutamate formation, increased or altered dihydrofolate reductase (major mechanism), decreased thymidylate synthase |
| Unique toxicities of MTX... | toxic against rapidly growing cells of bone marrow and GI epithelium, hepatotoxicity, fibrosis, cirrhosis, nephrotoxicity (drug precipitation) |
| Pyrimidine Analogs | 5-fluorouracil, Capecitabine (5-FU analog) |
| MOA of 5-FU | Inhibits biosynthesis of pyrimidine nucleotides by irreversibly inhibiting thymidylate synthase after acting as a normal substrate (dUMP). |
| Active metabolite of 5-FU... | fluorodeoxyuridylate (F-dUMP) |
| Mechanism of resistance to 5-FU... | less enzymes to convert 5-FU to F-dUMP, increased or altered thymidylate synthase |
| Most important anti-metabolite used in therapy of acute myelocytic leukemia... | Cytarabine (cytosine arabinoside; AraC) |
| MOA of cytarabine... | Inhibits DNA polymerase & DNA elongation through incorporation of AraCMP/DP/TP in place of dCTP. |
| Mechanism of resistance of cytarabine... | degradation of AraC by cytidine deaminase, decreased deoxycytidine kinase that converts AraC to AraCMP, conversion of AraCMP to inactive AraUMP by dCMP deaminase |
| Toxicity of cytarabine... | myelosuppression & other GI disturbances |
| Anti-metabolite that is part of 1st line regimen for patients w/metastatic pancreatic and non-small cell lung cancers... | Gemcitabine (dFdC) |
| MOA and toxicity of gemcitabine... | Similar to cytarabine, however, efficacy is not confined to S-phase; it is equally effective against confluent and growing cells. Toxicity includes myelosuppression & flu-like syndrome. |
| MOA of mercaptopurine (6-MP) | Inhibition of multiple pathways in conversion of inosine monophosphate (IMP) to adenine & guanine. Must be activated by HGPRT. |
| Mechanisms of resistance of mercaptopurine... | decreased HGPRT (acquired resistance), decreased affinity of enzyme for substrate, decreased transport, increased degradation, increased activity of MDR protein. |
| Toxicities of mercaptopurine... | hyperuremia, bone marrow suppression, nausea, vomiting, jaundice |
| MOA of fludarabine... | Inhibition of DNA polymerase, and incorporation into DNA and RNA. Leads to DNA chain termination and induction of apoptosis. |
| MOA of hydroxyurea... | Inhibition of diphosphate reductase (enzyme that catalyzes reductive conversion of ribonulceotides to deoxyribonucleotides) thus inhibiting DNA synthesis. (S-phase specific) |
| Mechanism of resistance and toxicities of hydroxyurea... | Elevation in diphosphate reductase activity. Toxicity: hematopoietic depression, GI disturbance, and mild skin reactions. |
| Vinca alkaloid agents... | Vinblastin, Vincristine, Vinorelbine |
| MOA of vinca alkaloids | Binds to tubulin & block ability of protein to polymerize into microtubules, which blocks cell division from occurring. This ultimately leads to apoptosis. |
| Mechanism of resistance of vinca alkaloids... | MDR...tumor cells contain markedly increased P-glycoprotein, a membrane MDR efflux pump that transports drugs from cells. |
| Unique toxicities of vinca alkaloids... | Vinblastine: considerable bone marrow suppression, GI disturbance, neurologic manifestations Vincristine: little bone marrow suppression, severe constipation, neurologic manifestations Vinorelbine: granulocytopenia, less neurotoxicity |
| MOA of paclitaxel & docetaxel | Promotes polymerization of microtubules by binding to β-tubulin subunit, finally leading to aberrant structures. This causes arrest in mitosis and apoptotic death. |
| Mechanism of resistance and toxicities of paclitaxel and docetaxel... | MDR, β-tubulin mutations Toxicities: bone marrow toxicity, hypersensitivity reactions |
| Topoisomerase targeting agents... | Etoposide/Teniposide, Camptothecin and analogs (topotecan and irinotecan) |
| MOA of topoisomerase targeting agents | Ternary complex w/TOPO 1/II and DNA, resulting in permanent double stranded break. Inhibits DNA replication, transcription, & cause "abortive mitosis" eventually leading to cell death. |
| Cells most sensitive to etoposide & teniposide | Cells in S and G2 phases |
| Mechanism of resistance and toxicity to etoposide & teniposide | Amplified MDR-1 gene that encode P-gp, mutation/decreased expression of TOPO II Toxicity: Etoposide (leukopenia, nausea, vomiting, stomatitis, diarrhea, alopecia, hepatic toxicity) Teniposide (myelosuppression, nausea, vomiting) |
| Cells most sensitive to the camptothecin analogs, irinotecan & topotecan... | Cells in S phase |
| Topoisomerase bound by etoposide and teniposide | TOPO II |
| Topoisomerase bound by irinotecan & topotecan | TOPO I |
| Toxicities of irinotecan & topotecan | Irinotecan: hematological toxicity, neutropenia, thrombocytopenia, N/V Topotecan: delayed diarrhea, myelosuppression |
| MOA of actinomycin D (dactinomycin) | Binds to double-helical DNA resulting in a block in transcription of DNA by RNA polymerase. Also causes single-strand breaks in DNA possibly by free-radical or throught TOPO action. |
| Toxicity of dactinomycin | anorexia, N/V, hematopoietic suppression |
| MOA of Doxorubicin & analogs idarubicin | Intercalate w/DNA affecting DNA and RNA synthesis; single & double strand breaks; DNA damage via drug binding to DNA & TOPO II; free-radical generation (semiquinone radical reacts w/O2 producing oxygen radical) |
| Toxicity of doxorubicin | cardiotoxicity by reactive oxygen species |
| MOA of mitoxantrone | DNA strand breaks via TOPO II |
| Toxicity of mitoxantrone | Limited free-radical production, so less cardiotoxic than doxorubicin; acute myelosuppression & cardiac toxicity |
| MOA of bleomycins | Cytotoxic action via oxidative damage leading to single & double stranded breaks in DNA. |
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