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USU Pharm lec 70-72

Cancer Chemotherapy I, II, III

QuestionAnswer
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
Melphalan nitrogen mustard. phenylalanine derivative. enters cell by active transport.
Chlorambucil similar to melphalan
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
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.
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.
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
Oxaliplatin a cisplatin that is not cross-resistant.
Carboplatin a cisplatin with substantially less renal toxicity.
Procarbazine non-specific alkylator (DNA, RNA, protein). activated by hepatic enzymes.
Cyclophosphamide toxicities immunosuppresion (duh), pulmonary fibrosis, cystitis, water retention, alopecia, carcinogenesis
carmustine and lomustine toxicities delayed but severe hematopoietic depression, pulmonary fibrosis, renal insufficiency, alopecia, nausia/vomiting
cisplatin toxicities nephrotoxicity, myelosuppression, ototoxocity, nephrotoxicity reduced by sulfhydryl containing free radical scavenger amifostine. dose-limiting toxicity: leukopenia and thrombocytopenia
Alkylating agent resistance: 1. dec. permeability 2. inc. conjugation 3. inc. DNA repair 4. inc. metabolism
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,
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
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.
Docetaxel semisynthetic analogue of paclitaxel
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.
etoposide (mech, res, and tox) derived from mandrake plant. inhibits topoisomerase II. resistance: MDR. Tox: leukopenia, thrombocytopenia
teniposide (meh, res, and tox) derived from mandrake plant. inhibits topoisomerase II. resistance: MDR. Tox: leukopenia, thrombocytopenia
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)
topotecan (mech, res) plant alkaloid. inhibits topoisomerase I. resistance: MDR.
doxorubicin (mech, res) an anthracycline. mechanism: DNA intercalation, and single strand breaks. Taken up rapidly in heart, kidney, liver, lung, spleen. Res: MDR
daunorubicin (mech, res) an anthracycline. mechanism: DNA intercalation, and single strand breaks. Taken up rapidly in heart, kidney, liver, lung, spleen. Res: MDR
dexrazoxane (mech) an iron chelator to inhibit free radical formation, and reduce cardiac damage from anthracyclines.
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.
Anthracycline toxicity CARIOTOXIC! arrhythmias and CHF. Cardiac tissue lacks SOD, so it's super sensitive, and anthracyclines decrease glutathione.
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
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
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.
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.
Leukovorin (mech, and what does it potentiate) MTX rescue - aborts MTX toxicity by supplying reduced folate to cells. Potentiates activity of 5-FU
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
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
Capecitabine a 5-FU prodrug. Final step of activation by Thymidine Phosphorylase (elevated enzyme in some tumors).
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.
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
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
Azaciticdine (mech) inhibits DNA methyltransferases - hypomethylation. Also converted to 5-aza CTP (incorp into RNA) - treats myelodysplastic syndrome.
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
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
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
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.
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
erlotinib. mech, tox inhibits EGF receptor-associated tyrosine kinase (non-small cell lung cancer, and pancreatic cancer). Tox: CHF risk
gefitinib. mech, tox inhibits EGF receptor-associated tyrosine kinase (non-small cell lung cancer, and pancreatic cancer). Tox: CHF risk
vemurafenib. mech inhibits BRAF serine-threonine kinase, especially when it contains the V600E mutation (50% of malignant melanomas)
cetuximab. mech monoclonal antibody against EGF receptor (head, neck, and metastatic colon cancer)
trastuzumab. mech, tox monoclonal antibody that induces an antibody-dependent cell-mediated cytotoxicity in HER2 breast cancer. Tox: cardiotoxidity esp. when used after anthracyclines
bevacizumab. mech, tox humanized monoclonal antibody against VEGF, designed to inhibit angiogenesis (lung, colon and kidney cancer). Tox: inc. risk of thrombolytic events.
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
gemtuzumab ozogamicin. mech monoclonal antibody against myeloid cell surface antigen CD33. The antibody conjegates to the DNA-cleaving antibiotic calicheamicin. Whatever that means.
vorinostat. use? "biological response modifier" - for cutaneous t-cell lymphoma
bortezomib. mech and use? proteasome inhibitor, treats multiple myeloma and mantle cell lymphoma
all-trans-retinoic acid vitamin A. first line therapy in AML (promyelocytic leukemia).
Created by: iplayguitar on 2012-04-25



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