Phase B Pharmacology

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Methotrexate cell cycle specificity

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cell-cycle specific

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Methotrexate trade name

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-

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Methotrexate Drug class

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antimetabolite; antifolate (folate acid analogue)

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Methotrexate chemistry

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has same structure as folate except it has an amino group on C4 & a methyl group on N10

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Methotrexate MoA

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inhibits dihydrofolate reductase & directly inhibits folate-dependent enzymes of de novo purine & thymidylate synthesis; prevents conversion of FH2 ->FH4; FH2 builds up as toxic inhibitory substrate; reactions requiring FH4 cannot continue; interrupts synthesis of DNA & RNA; also blocks N5, N10-methylene tetrahydrofolate conversion back to FH2 & TMP (headed for DNA synthesis) b/c it is a preferred cofactor for thymidylate synthetase

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Methotrexate pharmacologic effects

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inhibition of DHFR results in block of reduction of FH2->FH4; also inhibits formation of thymidylate & purines and arrests DNA, RNA & protein synthesis in rapidly dividing cells (S phase)

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Methotrexate MoR

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impaired transport of methotrexate into cells; production of altered forms of DHFR with lowered affinity for the inhibitor; increased intracellular [DHFR] through gene amplification or altered gene regulation; lowered ability to synthesize methotrexate polyglutamates; increased expression of drug efflux transporter of MRP class; lowered folate transporter; mutated DHFR, excessive DHFR

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Methotrexate absorption

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polar; poorly cross blood-brain barrier; readily absorbed from GI tract @ doses <25mg/m^2 but larger doses are incompletely absorbed; routinely administered via IV

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Methotrexate distribution

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After IV administration, drug disappears from plasma in triphasic fashion; rapid distribution phase followed by renal clearance (2-3 hr half-life); 3rd phase has 8-10 hr half-life; if last phase is prolonged, it may cause toxic effects

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Methotrexate metabolism

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usually minimal; after high doses metabolites are readily detectable

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Methotrexate tox

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neutropenia; GI and oral mucostitis; myelosuppression; nephrotoxicity; hepatotoxicity; teratogenic effects (inhibits DNA synthesis & depletes FH4)

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Methotrexate interactions

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w/penicillin - may reduce renal clearance; w/NSAIDs - with high doses of methotrexate elevates and prolongs serum methotrexate levels

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Methotrexate therapeutic uses

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Treatment of stage I, stage II, or stage III non-metastatic or low risk metastatic gestational trophoblastic neoplasia-low-dose methotrexate as single agents, hysterectomy for stage II or stage III if future fertility is not a concern; treatment of stage II or stage III high-risk metastatic gestational trophoblastic neoplasia-high-dose methotrexate as single agents with leucovorin rescue; treatment of stage IV high-risk metastatic gestational trophoblastic neoplasia-surgery, radiation, high-dose methotrexate as single agent with leucovorin rescue; used with misoprostol to induce abortion; acute lymphoblastic leukemia in children; severe debilitating psoriasis; induction of remission in refractory rheumatoid arthritis

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Mechanism of leucovorin rescue when administered 24 hours after methotrexate

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Given 24 hours after methotrexate to reduce competition; bypasses FH 4 pathway and replenishes N5, N10 methylene tetrahydrofolate cofactor so that cells can make dTMP; normal cells are better at transporting leucovorin than tumor cells so this "rescues" normal cells will tumor cells are still being killed by methotrexate

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Cyclophosphamide cell cycle specificity

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cell-cycle nonspecific

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Treatment for retinoblastoma (small tumors)

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Surgery; radiation therapy cryotherapy; photocoagulation

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Treatment for retinoblastoma (any size tumor)

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Chemo/size reduction (so that one of the treatments for small tumors can be used, such as surgery); opthalmic arterial infusion; subtenon chemo; high does chemo w/stem cell transplant in severe cases

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What does the log kill hypothesis say?

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The sooner tumor cells are detected and the fewer tumor cells that are present, the less likely the patient is to die

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What is the definition of the log till hypothesis?

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A given dose of the chemotherapeutic drug kills a constant proportion of a cell population rather than a constant number of cells. The log kill hypothesis proposes that the magnitude of tumor cells killed by anticancer drugs is a logarithmic function.

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Why is it effective to use chemotherapeutic drugs in combination?

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Prevents resistance; combination of cell cycle specific and cell cycle nonspecific allows growing and at rest cells to be targeted; additive and synergistic mechanisms of action; different toxicities = less myelosuppression

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Cell cycle specific versus cell cycle nonspecific

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Cell cycle specific inhibits DNA synthesis during the as phase. Cell cycle nonspecific alkaloids and damages DNA, pushes cells into apoptosis, works on replicating or non-replicating cells and thus works for slow gross tumors

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Cyclophosphamide trade names

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cytoxan, neosar

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Cyclophosphamide cell cycle specificity

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Cell cycle nonspecific but best on G1 or S-phase cells

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Cyclophosphamide drug class

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Alkylating agent

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Cyclophosphamide structure/chemistry

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bis-chloroethyl amine compound in a group of reactive compounds called nitrogen mustard; activated via CYP450 isoenzyme; it is hydroxylated to 4-hydroxycyclophospliamide in equilibrium with aldophosphamide; non-ends and I cleavage of aldophosphamide produces toxic metabolites: phosphoramide mustard and acrolein

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Cyclophosphamide mechanism of action

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Alkylating agents from strong electrophilic cyclic carbonium ions (carbocations) that form covalent linkages with the various nucleophilic moieties via alkylation; allow 2-chloroethylsidechains to alkylation separate guanines resulting in cross-linking the of nucleic acids sidechains; disrupts normal nucleic acid function; phosphoramide is an anti-neoplastic cytotoxic metabolite; acrolein causes hemorrhagic cystitis but conjugated by MESNA in urine

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Cyclophosphamide pharmacological effects

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Disturbs DNA synthesis; lethality of DNA operating agents depends on creation of DNA strand breaks by repair enzymes and in intact apoptotic response (p53 has to be working)

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Cyclophosphamide method of resistance

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Resistance develops quickly if administered as single agents; decreased permeation of dragons the cells; increased intracellular glutathione-glutathione is a nucleophile
scavenger and is better than DNA so it competes for alkylation by reacting with the drug; increased activity of DNA repair pathways; increase metabolism of the activated forms of cyclophosphamide

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Cyclophosphamide absorption

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Well absorbed orally; also given intravenously

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Cyclophosphamide elimination

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Eliminated by hepatic metabolism

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Cyclophosphamide metabolism

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Activated by CY2B forming 4-hydroxycyclophosphamide which is oxidized by aldehyde oxidase yielding inactive metabolites carboxyphosphamide and 4-ketocyclophosphamide which is reversibly converted to aldophosphamide which can spontaneously cleave and to generate phosphoramide mustard and acrolein

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Cyclophosphamide toxicity

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hemorrhatic cystitis (prevented by coadministration with MESNA and fluids); myelosuppression; nausea, vomiting, alopecia; neurotoxicity

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Cyclophosphamide drug interactions

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Caution when used in combination with other immunosuppressants

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Cyclophosphamide therapeutic uses

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Breast cancer; lymphomas; chronic lymphocytic leukemia in combination of for non-Hodgkin's lymphoma; ovarian cancers; solid tumors in children; can also be used to reduce organ rejection after transplantation

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Doxorubicin cell cycle specificity

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Cell cycle nonspecific

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Doxorubicin tradename

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adriamycin, doxil, valrubicin

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Doxorubicin drug class

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intercalating agents; anthracycline antibiotic

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Doxorubicin structure/chemistry

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Anthracycline antibiotics have the tetra cyclic ring structure attached to an unusual sugar, daunosamine; cytotoxic agents of this class all have quinone and hydroquinone moieties on adjacent rings that permit the gain and loss of electrons

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Doxorubicin mechanism of action

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intercalates between nucleoside bases of DNA and inhibits template utilization, directly affecting transcription and replication; forms free oxygen radicals that damage DNA when reduced; most importantly forms of tripartite complex with topoisomerase II into DNA-this complex allows for the double-stranded breaks but inhibits ligase activity and replication leading to apoptosis

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Doxorubicin mechanism of resistance

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Overexpression of transition linked DNA repair may contribute to resistance; multidrug resistance of P-glycoprotein-try to overcome with calcium channel blockers; increased efflux via MRP transporter family; increased glutathione activity into decreased activity or mutation of topoisomerase II or enhanced abilities to repair breaks

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Doxorubicin absorption

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Administered intravenously

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Doxorubicin distribution

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Does not cross the blood-brain barrier; taken up by heart, kidneys, lungs, liver and spleen

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Doxorubicin elimination

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Elimination half-lives of three hours and 30 hours-eliminated by conversion to aglycones and other interactive products

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Doxorubicin metabolism

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Cleared by complex pattern of hepatic metabolism and binary excretion; all are converted to active alcoholic intermediate that plays role in therapeutic activity

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Doxorubicin toxicity

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Myelosuppression; leukopenia; sometimes anemia; thrombocytopenia; alopecia, stomatitis, and G.I. problems; erythmatous streaking (allergic reaction);* cardiomyopathy-free radicals contribute to cardiac toxicity, give iron chelator to eliminate formation of Fe so free radicals don't form

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Doxorubicin drug interactions

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Used in combination with cyclophosphamide and vinca alkaloids for lymphoma treatment

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Doxorubicin therapeutic uses

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Treatment of AIDS-related Kaposi's sarcoma, malignant lymphomas and in solid tumors (breast cancer); small cell carcinoma of long; pediatrics/adult sarcomas (osteogenic, Ewing's, soft tissue)

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Oxaliplatin cell cycle specificity

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Cell cycle nonspecific

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Oxaliplatin drug class

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Alkylating agent

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Oxaliplatin structure/chemistry

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tetravalent, inorganic, water-soluble, planning-containing complex; oxalate (leaving group) and diaminocyclohexane (DACH-bulky, contributes to greater toxicity)

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Oxaliplatin mechanism of action

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Enter cell by diffusion and active cut transporters, reacts with DNA forming intra-and inter-strand cross-links particularly at N7 of guanine nucleotides which forms cross-links by inducing DNA adducts and inhibits replication and transcription; formation of breaks and miss coding if recognized by P 53 and other checkpoint proteins leading to apoptosis; plan and activated by water; covalently binds to nucleophilic sites on DNA; invented to be less cytotoxic than cisplatin

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Oxaliplatin mechanism of resistance

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Does not display across resistance with other drugs in class; resistance is not mediated through loss of function of MMR proteins; repair of cross-link DNA adducts of by methods such as nucleotide excision repair; less resistance than cisplatin

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Oxaliplatin absorption

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Very brief half-life in plasma due to rapid uptake and its reactivity

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Oxaliplatin distribution

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Rapidly taken up by tissues

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Oxaliplatin elimination

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Renal excretion at rate dependence on creatinine clearance

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Oxaliplatin metabolism

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Metabolism within tissues rapidly converts it into non-toxic metabolites so renal function doesn't have to be taken into account

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Oxaliplatin toxicity

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Peripheral neuropathy with large doses; mild to moderate hematologic toxicity unstable in chloride or alkaline solutions

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Oxaliplatin interactions

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Does not display cross resistance with cisplatin or carboplatin

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Oxaliplatin therapeutic uses

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Antitumor activity in gastric and colon cancer due to MMR independent effects; suppresses expression of thymidylate synthase (target of 5-fluorouracil)and ferments synergy of the two drugs

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5 -fluorouracil cell cycle specificity

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Cell cycle specific

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5 -fluorouracil tradename

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adrucil, efudex (topical)

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5-fluorouracil drug class

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Anti-metabolite

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5-fluorouracil mechanism of action

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Prodrug; activated by addition of a ribose and a phosphate group; active form is FdUMP; directly inhibits thymidylate synthase so tumors can't make dTMP, inhibiting DNA replication; also inhibits RNA processing by incorporating into DNA; almost always give us leucovorin in order to increase thymidylate synthase production

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5-fluorouracil pharmacologic effects

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Inhibition of thymidylate synthase which blocks DNA synthesis

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5-fluorouracil mechanism of resistance

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Decreased enzymes involved in the activation of 5-fluorouracil; amplification/overexpression of thymidylate synthase by and autoregulatory feedback mechanism; mutant forms of thymidylate synthase don't bind FdUMP well

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5-fluorouracil absorption

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Administered parenterally (any medication route other than alimentary canal, such as intravenous, subcutaneous, intramuscular, or mucosal) because absorption after ingestion is unpredictable and incomplete

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5-fluorouracil distribution

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Rapid IV administration produces plasma concentration of .1 to 1 mM

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5-fluorouracil elimination

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Plasma clearance is rapid, half-life is 10 to 20 min.

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5-fluorouracil metabolism

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Metabolic degradation occurs in many tissues, especially liver; 5-fluorouracil is inactivated by reduction of pyrimidine ring which is carried out by dihydropyrimidine dehydrogenase

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5-fluorouracil toxicity

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Myelosuppression; nausea vomiting and other gastrointestinal effects; alopecia; mucocutaneous effects

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5-fluorouracil drug interactions

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With leucovorin-provides cofactor so FdUMP can bind and enhanced thymidylate synthase inhibition; with methotrexate given 24 hours prior-enhanced 5-fluorouracil activation/anabolism and RNA incorporation; with irinotecan, oxaliplatin-overcome resistance, decreased synthesis of thymidylate synthase

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5-fluorouracil therapeutic uses

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Produces partial responses in 10 to 20% of patients with metastatic colon carcinomas, upper gastrointestinal carcinomas, and breast carcinomas

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6-mercaptopurine cell cycle specificity

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Cell cycle specific

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6-mercaptopurine trade name

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purinethol

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6-mercaptopurine drug class

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antipurine (purine analogue)

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6-mercaptopurine structure/chemistry

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has the structure of purine, adenine, w/exception of an -SH attached at C6 instead of -NH2; readily converted to nucleotides in normal and malignant cells; nucleotides formed from 6-MP inhibit de novo purine synthesis and become incorporated into nucleic acids

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6-mercaptopurine mechanism of action

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6-MP must be activated by conversion to 6-thionosine-5'-monophosphate (T-IMP) by hypoxanthine guanine phosphoribosyl transferase (HGPRT) - a purine salvage enzyme; T-IMP inhibits 1st step in purine synthesis, PRPP amidotransferase inhibits conversion of IMP to AMP in purine metabolism; T-IMP is converted to T-GMP and incorporated into DNA and RNA

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6-mercaptopurine pharmacologic effects

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inhibits purine ring synthesis; inhibits nucleotide interconversion

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6-mercaptopurine mechanism of resistance

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primarily due to lack of activating enzyme - HGPRT; decreased drug transport into cell; increased drug efflux out of cell

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6-mercaptopurine absorption

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drug is normally administered PO w/o damage to intestinal mucosa

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6-mercaptopurine distribution

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6-MP has serum half-life of <2 hrs.; active metabolite is concentrated in cells resulting in a prolonged half-life of days

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6-mercaptopurine metabolism

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HGPRT-catalyzed anabolism; methylation of the sulfhydryl group & subsequent oxidation of the methylated derivatives; 6-MP is also oxidized by zanthine oxidase to 6-thiouric acid, an inactive metabolite

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6-mercaptopurine toxicity

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myelosuppression that develops more gradually that with folic acid antagonists; jaundice and hepatic enzyme elevations, anorexia, nausea or vomiting, may lead to leukemia

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6-mercaptopurine drug interactions

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synergistic with methotrexate - methotrexate increases the intracellular concentration of PRPP which Is required for 6-MP activation; allopurinol markedly reduces metabolism of purine analogues leading to severe leukopenia (abnormal decrease of white blood cells)

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6-mercaptopurine therapeutic uses

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acute lymphocytic and juvenile chronic granulocytic (myelogenus) leukemias

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Vinblastine/Vincristine cell cycle specificity

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cell cycle specific

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vinblastine trade name

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velban

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Vinblastine/Vincristine Drug class

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anti-mitotic, vinca alkaloid

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Vinblastine/Vincristine structure/chemistry

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asymmetric dimeric compound capable of binding beta-tubulin monomers and preventing their joining with alpha-tubulin to form microtubules

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Vinblastine/Vincristine mechanism of action

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blocks cells in mitosis by binding specifically to beta-tubulin, blocking its ability to polymerize w/alpha-tubulin to form microtubules; cell division is arrested in metaphase, dissolution of mitotic spindle --> cell death

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Vinblastine/Vincristine pharmacologic effects

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cell cycle specific; blocks cells in mitosis; cell division is arrested in Mphase due to inability to form mitotic spindles & chromosomes, unable to alighn along metaphase plate, disperse randomly throughout cytoplasm exploded mitosis) or clup irregularly into balls or stars; undergo changes characteristic of apoptosis

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Vinblastine/Vincristine mechanism of resistance

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chromosomal abnormalities consistent with amplification of genes corresponding to the P-glycoprotein, a membrane efflux pump that transports drugs from cells - this amplification found in tumor cells after administration of single drug is responsible for cross resistance - calcium channel blockers can reverse this; other membrane transporters - MRP/multidrug resistance associated protein; mutations in beta-tubulin or in relative expression of beta-tubulin isoferms leads to less effective binding

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Vinblastine absorption

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administered IV and absorbed in blood stream; shouldn't be injected in extremity with poor circulation

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Vinblastine elimination

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half-life of 3-23 hours

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Vinblastine metabolism

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extensively metabolized in liver with conjugates and metabolites excreted in bile

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Vinblastine toxicity

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severe myelosuppression; alopecia and local cellulitis; nausea, vomiting, anorexia, diarrhea, stomatitis and dermatitis (but less gastrointestinal effects than Vincristine)

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Vinblastine therapeutic uses

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in combination with bleomycin and cisplatin - treat metastatic testicular tumors; Hodgkins disease and choriocarcinoma

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Vincristine trade names

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oncovin, vincasar PFS

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Vincristine absorption

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administered IV with glucocorticoids like prednisone

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Vincristine elimination

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half-life of 1-20 hours with majority of conjugates and metabolites (produced in liver) excreted in bile

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Vincristine metabolism

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metabolized in liver

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Vincristine toxicity

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less myelosuppression than Vinblastine; neurotoxicity - paresthesia (numbness and tingling of extremities) and loss of deep tendon reflexes followed by motor weakness; inadvertent intrathecal administration produces devastating and fatal neurotoxicity; gastrointestinal toxicty

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Vincristine therapeutic uses

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with glucocorticoids - treatment of choice to induce remission in childhood leukemias - tolerated better in children than adults

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2 factors that contribute to MDR

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P-glycoprotein pump acquired resistance and drug efflux; mutations/loss of p53 which confers loss of apoptosis and defects in the mismatch repair enzyme family

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3 drugs that require an active p53 in order to work

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cyclophosphamide, cisplatin, oxaloplatin; in Li Fraumeni you must be careful with giving chemotherapy because you may deactivate p52 in normal cells and promote another tumor

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Treatment for basal cell carcinoma

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surgery, topical chemotherapy (5-FU); laser therapy

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Treatment for squamous cell carcinoma

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surgery; topical chemotherapy (5-FU); laser therapy, regional lymph removal or irradation, cisplatin used for stage III SCC

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Treatment for melanoma, based on stage

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Stage I - surgery; Stage II - surgery + immunotherapy; Stage III - surgery + lymph dissection + maybe chemotherapy; Stage IV - no treatment is available

Front 109

Letrozole trade name

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femara

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Letrozole drug class

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aromatase inhibitor

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Letrozole mechanism of action

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decreases estrogen biosynthesis by selective inhibition of aromatase (estrogen synthase) (nonsteroidal competitive inhibitor) in peripheral tissues

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Letrozole pharmacologic effects

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3rd generation type 2 inhibitor - nonsteroidal and binds reversibly to the heme group of aromatase enzymes by way of a basic nitrogen atom; blocks estradiol synthesis from androstendione and testosterone

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Lerozole mechanism of resistance

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tumor may progress and become hormone insensitive (no longer requires hormone for growth)

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Letrozole absorption

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given orally

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Letrozole distribution

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rapidly absorbed after administration with maximum plasma levels reached ~1 hour after ingestion; 99.9% bioavailability

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Letrozole elimination

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after metabolism, eliminated as an inactive carbinol metabolite via kidneys; half-life ~40-42 hours

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Letrozole metabolism

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metabolized by CYP2A6 and CYP 3A4

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Letrozol toxicity

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associated with 100% incidence of osteoporosis (estradiol synthesis in bones causes breakage); mild nausea, headache, fatigue, hot flashes, joint pain

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Letrozole therapeutic uses

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25 mg administered PO i qd - efficacy in treatment of postmenopausal women with early stage/advanced hormone-receptor positive breast cancer

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Irinotecan cell cycle specificity

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cell cycle specific

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irinotecan trade name

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camptosar

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Irinotecan drug class

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antineoplastic

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Irinotecan structure/chemistry

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5-ring structure called camptotneun; the piperidine side chain is cleaved by carboxylesterase - converting enzyme to form SN-38 which is 1000-fold more biologically active than the patent prodrug; lactone ring must be intact for cytotoxic activity

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Irinotecan mechanism of action

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inhibits topoisomerase I in tumor cells by binding to and stabilizing DNA-topoisomerase I cleavable complex; inhibits religation of DNA during topoisomerase I induced relaxation step of DNA replication and causes single stranded breaks in DNA of tumor cells; collision of DNA replication fork with broken DNA strand causes irreversible double-stranded DNA breakd and cell death, making Irinotecan an S-phase specific agent

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Irinotecan pharmacologic effects

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by inhibiting DNA replication in rapidly dividing cells, it slows the growth of susceptible tumors

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Irinotecan mechanism of resistance

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lack of carboxylesterase-converting enzyme so prodrug activation to SN-38 cannot occur; P-glycoprotein pumps drug out of tumor cell (MDR); decreased expression of topoisomerase I in tumor cells or mutation in topoisomerase I that makes it unable to bind SN-38; tumor cells shift from topoisomerase I to topoisomerase II expression

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Irinotecan absorption

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IV administration every 3 weeks or in repeating cycles of every week for 4 of 6 weeks

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Irinotecan distribution

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43% bound to plasma proteins; active form, SN-38 is 90-96% protein bound in plasma; decreased penetration into CSF

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Irinotecan elimination

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50% recovered in urine and feces either unchanged or 1/4 metabolites; terminal half-life is 10 hours

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Irinotecan metabolism

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initial activation by carboxylesterase to SN-38; also a pH dependent equilibrium between active, closed ring lactone and inactive, open-ring carboxylate forms of irinotecan and SN-38; cytochrome P450 enzyme CYP3A is responsible for convertine irinotecan to 2 major inactive metabolites; extensive glucoronidation in liver of SN-38% is inversely related to toxicity and influenced by polymorphism of UGT1A1 enzyme

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Irinotecan toxicity

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delayed diarrhea (severe); myelosuppression with severe neutropenia; cholinergic syndrome resulting from inhibition of acetylcholinesterase (responds well to atropine)

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Irinotecan drug interactions

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many other drugs either inhibit activity or induce expression of cytochroe P450 enzyme, CYP3A which effects the metabolism; these include antibiotics, erythromycin (inhibits CYP3A) and rifampin (inducer)

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Irinotecan therapeutic uses

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primarily used for colorectal cancer treatment; can be used in combination with 5-FU to treat advanced colon cancer; can also treat lung, cervical, ovarian and gastric tumors

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Bleomycin cell cycle specificity

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cell cycle specific

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Bleomycin trade name

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blenoxane

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Bleomycin drug class

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peptide antibiotics

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Bleomycin structure/chemistry

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water-soluble, basic glycopeptide - the core is a complex metal-binding structure containing a pyrimidien chromophore linked to propionamide, an amide side chain, and 2 sugars; a terminal bithiazole carboxylic acid binds DNA

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Bleomycin mechanism of action

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causes oxidative damage to the deoxyribose of thymidylate and other nucleotides leading to singe/double stranded breaks in DNA; causes accumulation of cells in G2 phase because Fe interacts with oxygen causing senescence

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Bleomycin pharmacologic effects

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Cells senesce and are trapped in G2 phase

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Bleomycin mechanism of resistance

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increased hydrolase activity cleaves it to inactive form (but this is decreased in skin and lungs, contributing to toxicity in these sites)

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Bleomycin absorption

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administered parenterally - either IV or intramuscularly or directly into bladder

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Bleomycin distribution

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increased concentrations are found in skin and lungs; poorly crosses blood-brain barrier

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Bleomycin elimination

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half-life is ~3 hours; 2.3 of drug is excreted in urine

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Bleomycin toxicity

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pulmonary toxicity (pulmonary fibrosis because lungs lack hydrolase); little myelosuppression, so synergistic when used in combination therapy; cutaneous side effects; patients that hve been on bleomycin have to have more oxygen when under anaesthetic

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Bleomycin drug interactions

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used in combination therapy for neoplasias because of minimal toxicities

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Bleomycin therapeutic uses

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highly effective agains germ cell tumors of testis and ovary - especially with cisplatin and vinblastine or etoposide; also pleural effusions, hodgkin's disease, and squamous cell carcinomas of cervix

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Cisplatin cell cycle specificity

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cell cycle nonspecific

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cisplatin trade name

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platinol-A9

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Cisplatin drug class

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platinum alkylator

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Cisplatin structure/chemistry

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divalent, inorganic, water-soluble, Pt-containing complexes

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Cisplatin mechanism of action

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enters cells by diffusion and active copper transporter - chloride is replaced by water yielding positive charged molecule - the aquated species then reacts with nucleophilic sites on DNA and proteins (favored at low choloride levels in cell); platinum reacts with DNA forming intra/interstrand cross-links (especially at N7 of guanine) - may induce apoptosis; inhibits replication and transcription - most pronounced in S phase

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Cisplatin pharmacologic effects

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alkynator - causes cross linking

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Cisplatin mechanism of resistance

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shares cross-reisitance with carboplatin; other drug interactions inactivate cisplatin; overexpression of nucleotide excision repair; loss of function in mismatch repair proteins (MMR) that would normally initiate apoptosis; *requires active p53, can't use with Li Fraumeni patients

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Cisplatin absorption

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IV administration; initial half-life of 25-50 minutes, then 24 hours or longer

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Cisplatin distribution

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increased concentrations found in kidneys, liver, intestine and testes; 90% of Pt in blood covalently bound to plasma proteins

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Cisplatin elimination

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only small portion excreted by kidneys in 1st 6 hours - after 5 days up to 43% is recovered in urine bound to proteins and peptides

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Cisplatin toxicity

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nephrotoxicity (to prevent this, establish a chloride diuresis prior to treatment with saline) - don't use aluminum needles or infusion equpiment - given with a cytoprotective agent, amifostine; ototoxicity; severe nausea and vomiting, moderate myelosuppression; at high doses, can cause neuropathy; mutagenic, teratogenic, carcinogenic

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Cisplatin drug interaactions

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drug accumulations with glutathione and other sulfhydryls bind to and inactivate cisplatin

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Cisplatin therapeutic uses

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given only IV; used in combination with bleomycin, vinblastine for testicular cancer; ovarian carcinoma, cancers of bladder, head, neck, cervix, endometrium, lung, rectum, childhood neoplasms; also sensitizes cells to radiation therapy