Cancer Chemotherapy I, II, III
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| Mechanism of Nitrogen Mustards | alkylation of DNA primarily at the N-7 position of guanine causing lethal errors into the genetic code. This also causes depurination leading to single and double strand breaks
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| Melphalan | nitrogen mustard. phenylalanine derivative. enters cell by active transport.
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| Chlorambucil | similar to melphalan
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| Cyclophosphamide | a nitrogen mustard. must be activated by hepatic CYT p450 (2C9) to aldophosphamide. Aldophosphamide is activated (hydrolized) in target cells to active phosphamide mustard. LOW hepatotoxicity
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| Lomustine (CCNU) | a Chloroethyl Nitrosourea. Mech: Alkylation, DNA crosslinking, and carbamoylation of proteins. It's lipid soluble giving the drug a longer effective half-life. The metabolite readily enters CNS reaching effective chemotherapeutic levels. WAFER.
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| Carmustine (BCNU) | a Chloroethyl Nitrosourea. Mech: Alkylation, DNA crosslinking, and carbamoylation of proteins. It's lipid soluble giving the drug a longer effective half-life. The metabolite readily enters CNS reaching effective chemotherapeutic levels. WAFER.
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| Cisplatin | a platinum coordination complex. only cis-dichloro form is active. alkylating activity achieved when chloride ions dissociate leaving a positively charged complex. cleared rapidly in kidneys. plasma bound drug is inactive
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| Oxaliplatin | a cisplatin that is not cross-resistant.
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| Carboplatin | a cisplatin with substantially less renal toxicity.
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| Procarbazine | non-specific alkylator (DNA, RNA, protein). activated by hepatic enzymes.
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| Cyclophosphamide toxicities | immunosuppresion (duh), pulmonary fibrosis, cystitis, water retention, alopecia, carcinogenesis
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| carmustine and lomustine toxicities | delayed but severe hematopoietic depression, pulmonary fibrosis, renal insufficiency, alopecia, nausia/vomiting
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| cisplatin toxicities | nephrotoxicity, myelosuppression, ototoxocity, nephrotoxicity reduced by sulfhydryl containing free radical scavenger amifostine. dose-limiting toxicity: leukopenia and thrombocytopenia
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| Alkylating agent resistance: | 1. dec. permeability 2. inc. conjugation 3. inc. DNA repair 4. inc. metabolism
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| Vincristine (mech resistance and toxicity) | plant-derived. binds tubulin. inhibits polymerization. spindle fiber formation and mitosis inhibited. cytoskeletal movement disrupted.
resistance: MDR. Tox: neurotoxicity, ADH release,
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| Vinblastine (mech, resistance and toxicity) | plant-derived. binds tubulin. inhibits polymerization. spindle fiber formation and mitosis inhibited. cytoskeletal movement disrupted.
resistance: MDR. Tox: myelosuppression, mucositis. LESS neurotoxicity, dose-limiting toxicity: granulocytopen
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| Paclitaxel (mech and tox) | from yew tree. use when anthracycline or cisplatin have failed. promotes and stabilizes microtubule assembly. resistance: MDR. protein bound form has superior response and reduced tosxicity. Toxicity: neutropenia, mucositis. cardiac arrhythmias.
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| Docetaxel | semisynthetic analogue of paclitaxel
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| ixabepilone | binds B-tubulin and promotes polymerization and stabilizes microtubules. Arrests cell in G2/M. Use for taxane/anthracycline res. breast cancer. Dose limit side effects = neutropenia, cardiotoxicity and peripheral neuropathy.
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| etoposide (mech, res, and tox) | derived from mandrake plant. inhibits topoisomerase II. resistance: MDR. Tox: leukopenia, thrombocytopenia
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| teniposide (meh, res, and tox) | derived from mandrake plant. inhibits topoisomerase II. resistance: MDR. Tox: leukopenia, thrombocytopenia
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| irinotecan (mech, res, tox) | plant alkaloid. inhibits topoisomerase I. resistance: MDR. tox: neutropenia, diarrhea (esp. in pts w/ homozygous *28 allel of uridine diphosphate glucuronylsyltranferase 1A1 gene)
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| topotecan (mech, res) | plant alkaloid. inhibits topoisomerase I. resistance: MDR.
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| doxorubicin (mech, res) | an anthracycline. mechanism: DNA intercalation, and single strand breaks. Taken up rapidly in heart, kidney, liver, lung, spleen. Res: MDR
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| daunorubicin (mech, res) | an anthracycline. mechanism: DNA intercalation, and single strand breaks. Taken up rapidly in heart, kidney, liver, lung, spleen. Res: MDR
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| dexrazoxane (mech) | an iron chelator to inhibit free radical formation, and reduce cardiac damage from anthracyclines.
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| bleomycin (mech) | has DNA and iron binding regions. S peptide binds DNA, brings Fe conplex into a position in which it can depurinate and depyrimidate through OXYDATION. performs BOTH single and double stranded breaks. concentrates in skin, lung and tumor tissue.
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| Anthracycline toxicity | CARIOTOXIC! arrhythmias and CHF. Cardiac tissue lacks SOD, so it's super sensitive, and anthracyclines decrease glutathione.
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| bleomycin resistance and toxicity | Res: inc. bleomycin hydrolase expression, inc DNA repair enzymes, dec. cellular uptake. Tox: pneumonitis (it uses 02 to make radicals) and skin lesions
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| Methotrexate (the long names on the other side for 2 and 3 are purine ring things) | folic acid analogue. inhibits DHFR (no FH2 -> FH4). inhibit s phase: 1. dUMP ->dTMP 2. glycinamide ribonucleotide -> N-formyl glycinamide ribonucleotide 3. 5-aminoimidazole-4-carboxamide ribnucleotide -> 5-formaminoimidazole-4-carbozamide ribonucleotide
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| methotrexate - how is it administered? | oral and intravenous and intrathecal. intravenous leaves the urine 90% unmetabolzied. Binds plasma proteins. if other drugs that bind plasma proteins are present, they knock off MTX and inc. concentration of free drug.
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| methotrexate resistance and toxicity | inc. DHFR activity and reduced transport. tox: Low dose - myelosuppresion and mucositis. High dose - fatal myelosuppression, renal tox, hepatotox, neurotox, teratogen. LEUKOENCEPHALOPATHY if intrathecal.
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| Leukovorin (mech, and what does it potentiate) | MTX rescue - aborts MTX toxicity by supplying reduced folate to cells. Potentiates activity of 5-FU
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| 5-FU - mech, res and tox | pyrimidine analogue, metabolized to 5-FdUMP (dTMP analogue). POTENT suicide inhibitor of thymidylate synthase. 5-FUTP incorp into RNA = defective transcripts. Res: inc TS expression. Tox: myelosuppression, GI distress, conjunctivitis
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| 5-FU pharmacology | short half life. metabolism in liver and extrahepatic tissue. intracellular phosphorylation - longer half life. Additional effectiveness when used with allopurinol or AFTER MTX
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| Capecitabine | a 5-FU prodrug. Final step of activation by Thymidine Phosphorylase (elevated enzyme in some tumors).
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| Cytosine Arabinoside (Ara C, or cytarabine) - mech: | ribose replaced with arabinose (pyrimidine analogue). Ara C physphorylated to Ara CTP by deoxycytidine kinase. Potent inhibitor of DNA polymerase. causes defective ligation in DNA synth and premature chain termination.
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| Gemcitabine (mech and tox) | pyrimidine analogue- good for breast cancer, non-small-cell lung cancer, pancreatic carcinoma and ovarian carcinoma.
Tox: GI ulcers, seizures, myelosuppression, nausea, vomiting
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| Cytosine Arabinoside (Ara C, or cytarabine) resistance and tox | RES: dec. cytosine kinase, inc. cytosine deaminase. Deaminase inhibitors increase half life.
Tox: GI ulcers, seizures, myelosuppression, nausea, vomiting
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| Azaciticdine (mech) | inhibits DNA methyltransferases - hypomethylation. Also converted to 5-aza CTP (incorp into RNA) - treats myelodysplastic syndrome.
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| 6-mercaptopurine (mech and res) | purine analogue. converted by HPRT to nucleoside monophosphates. FEEDBACK inhibition of de novo purine synth. Competitively inhibits biosynthetic reactions. Converted to triphosphate, incorp into DNA AND RNA. RES: HPRT mutation, inc TPMT expression
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| 6-thioguanine (mech and res) | purine analogue. converted by HPRT to nucleoside monophosphates. FEEDBACK inhibition of de novo purine synth. Competitively inhibits biosynthetic reactions. Converted to triphosphate, incorp into DNA AND RNA. RES: HPRT mutation, inc TPMT expression
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| 6-MP and 6-TG metabolism and Toxicity | 6-MP: s-methylation by TPMT and oxidation by XO.
6-TP: s-methylation.
Tox: myelosuppresion and hepatotoxicity
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| Asparaginase. mech, tox | converts asparagine to aspartate. Deprives cells of asparagine, inhibits protein syth. Tox: reduction in concentration of secreted proteins (clotting factors, insulin, albumin, etc), HYPERSENSITIVITY REACTION (anaphylaxis) and hepatotox.
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| imatinib mesylate. mech, tox | competitively blocks ATP binding site of c-able tyrosine kinase in CML (remember, CML has bcr-abl translocation). Treats CML and ph+ ALL. It also inhibits c-kit and PDGF-assoc. tyrosine kinases (GI tumors). Tox: CHF!!, and myelosuppression
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| erlotinib. mech, tox | inhibits EGF receptor-associated tyrosine kinase (non-small cell lung cancer, and pancreatic cancer). Tox: CHF risk
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| gefitinib. mech, tox | inhibits EGF receptor-associated tyrosine kinase (non-small cell lung cancer, and pancreatic cancer). Tox: CHF risk
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| vemurafenib. mech | inhibits BRAF serine-threonine kinase, especially when it contains the V600E mutation (50% of malignant melanomas)
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| cetuximab. mech | monoclonal antibody against EGF receptor (head, neck, and metastatic colon cancer)
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| trastuzumab. mech, tox | monoclonal antibody that induces an antibody-dependent cell-mediated cytotoxicity in HER2 breast cancer. Tox: cardiotoxidity esp. when used after anthracyclines
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| bevacizumab. mech, tox | humanized monoclonal antibody against VEGF, designed to inhibit angiogenesis (lung, colon and kidney cancer). Tox: inc. risk of thrombolytic events.
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| rituximab. mech, tox | mouse/human anti-CD20 monoclonal antibody promotes complement-mediated lysis of malignant B-cells in CD20 positive NH B-cell lymphoma and CLL. Tox: HBV reactivation
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| gemtuzumab ozogamicin. mech | monoclonal antibody against myeloid cell surface antigen CD33. The antibody conjegates to the DNA-cleaving antibiotic calicheamicin. Whatever that means.
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| vorinostat. use? | "biological response modifier" - for cutaneous t-cell lymphoma
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| bortezomib. mech and use? | proteasome inhibitor, treats multiple myeloma and mantle cell lymphoma
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| all-trans-retinoic acid | vitamin A. first line therapy in AML (promyelocytic leukemia).
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