Cancer Chemotherapeutics ______________________________________ TABLE OF CONTENTS ______________________________________ * ALKYLATING AGENTS * ANTIMETABOLITES * ANTIBIOTICS * MITOTIC INHIBITORS * CHROMATIN FUNCTION INHIBITORS * HORMONES AND HORMONE INHIBITORS * IMMUNOMODULATORS * MISCELLANEOUS ______________________________________ ALKYLATING AGENTS * I. NITROGEN MUSTARDS * mechlorethamine (Mustargen) * cyclophosphamide (Cytoxan, Neosar) * ifosfamide (Ifex) * phenylalanine mustard; melphalen (Alkeran) * chlorambucol (Leukeran) * uracil mustard * estramustine (Emcyt) * II. ETHYLENIMINES * thiotepa (Thioplex) * III. ALKYL SULFONATES * busulfan (Myerlan) * IV. NITROSUREAS * lomustine (CeeNU) * carmustine (BiCNU, BCNU) * streptozocin (Zanosar) * V. TRIAZENES * dacarbazine (DTIC-Dome) * VI. PLATINUM COORDINATION COMPLEXES * cis-platinum, cisplatin (Platinol, Platinol AQ) * carboplatin (Paraplatin) * VII. OTHERS * altretamine (Hexalen) ______________________________________ ANTIMETABOLITES * I. FOLIC ACID ANALOGS * methotrexate (Amethopterin, Folex, Mexate, Rheumatrex) * II. PYRIMIDINE ANALOGS * 5-fluoruracil (Adrucil, Efudex, Fluoroplex) * floxuridine, 5-fluorodeoxyuridine (FUDR) * capecitabine (Xeloda) * fludarabine: (Fludara) * cytosine arabinoside (Cytaribine, Cytosar, ARA-C) * II. PURINE ANALOGS * 6-mercaptopurine (Purinethol) * 6-thioguanine (Thioguanine) * gemcitabine (Gemzar) * cladribine (Leustatin) * deoxycoformycin; pentostatin (Nipent) ______________________________________ ANTIBIOTICS * doxorubicin (Adriamycin, Rubex, Doxil, Daunoxome- liposomal preparation) * daunorubicin (Daunomycin, Cerubidine) * idarubicin (Idamycin) * valrubicin (Valstar) * mitoxantrone (Novantrone) * dactinomycin (Actinomycin D, Cosmegen) * mithramycin, plicamycin (Mithracin) * mitomycin C (Mutamycin) * bleomycin (Blenoxane) * procarbazine (Matulane) ______________________________________ MITOTIC INHIBITORS * I. TAXANES (DITERPENES) * paclitaxel (Taxol) * docetaxel (Taxotere) * II. VINCA ALKALOIDS * vinblatine sulfate (Velban, Velsar, VLB) * vincristine sulfate (Oncovin, Vincasar PFS, Vincrex) * vinorelbine sulfate (Navelbine) ______________________________________ CHROMATIN FUNCTION INHIBITORS * I. CAMPTOTHECINS * topotecan (Camptosar) * irinotecan (Hycamtin) * II. EPIPODOPHYLLOTOXINS * etoposide (VP-16, VePesid, Toposar) * teniposide (VM-26, Vumon) ______________________________________ HORMONES AND HORMONE INHIBITORS * I. ESTROGENS * diethylstilbesterol (Stilbesterol, Stilphostrol) * estradiol, estrogen (many brands) * esterified estrogens (Estratab, Menest) * estramustine (Emcyt) * II. ANTIESTROGENS * tamoxifen (Nolvadex) * toremifene (Fareston) * II. AROMATASE INHIBITORS * anastrozole (Arimidex) * letrozole (Femara) * III. PROGESTINS * 17-OH-progesterone (many brands) * medroxyprogesterone (many brands) * megestrol acetate (Megace) * IV. GnRH AGONISTS * goserelin (Zoladex) * leuprolide (Leupron) * V. ANDROGENS * testosteraone (many brands) * methyltestosterone (many brands) * fluoxmesterone (Android-F, Halotestin) * VI. ANTIANDROGENS * flutamide (Eulexin) * bicalutamide (Casodex) * nilutamide (Nilandron) * VII. INHIBITORS OF SYNTHESIS * aminoglutethimide (Cytadren) * ketoconazole (Nizoral) ______________________________________ IMMUNOMODULATORS * rituximab (Rituxan) * trastuzumab (Herceptin) * denileukin diftitox (Ontak) * levamisole (Ergamisol) * bacillus Calmette-Guerin, BCG (TheraCys, TICE BCG) * interferon alpha-2a, alpha 2b (Roferon-A, Intron A) * interleukin-2, aldesleukin (ProLeukin) ______________________________________ MISCELLANEOUS * l-aspariginase (Elspar, Kidrolase) * pegaspasgase (Oncaspar) * hydroxyurea (Hydrea, Doxia) * leucovorin (Wellcovorin) * mitotane (Lysodren) * porfimer (Photofrin) * tretinoin (Veasnoid) ______________________________________ MECHANISM OF ACTION ______________________________________ ALKYLATING AGENTS * cell cycle non-specific (greater effect in G1,S) * alkylation of DNA (through carbonimum ion intermediates); radiomimetic * covalent cross-linking of DNA, RNA and proteins * single-strand DNA breaks * abnormal DNA base-pairing * I. NITROGEN MUSTARDS * mechlorethamine: alkylation of G(N7) * cyclophosphamide: alkylation by hydroxylated metabolites. Also acts as an immuno-supressant * ifosfamide: activated by liver enzymes * phenylalanine mustard: cross-links DNA and RNA * chlorambucol: cross-links DNA and RNA * uracil mustard * estramustine: facilitated by ER mediated uptake * II. ETHYLENIMINES * thiotepa: cross-links DNA and RNA. * III. ALKYL SULFONATES * busulfan: cross-links DNA and RNA. * IV. NITROSUREAS * converted into a carbonium ion (alkylating agent) and isothiocyanate molecule (may interact with proteins) * more active in dividing cells * lomustine * carmustine * streptozocin * V. TRIAZENES * dacarbazine: alkylation; purine anti-metabolite; binds to protein sulfhydryl groups * VI. PLATINUM COORDINATION COMPLEXES * cross links DNA strands; affinity for alkylation at G(N7) and A(N7) * interstrand and intrastrand cross-linking; binds to protein SH groups * cis-platinum * carboplatin * VII. OTHERS * altretamine: active liver metabolites. exact mechanism unknown ______________________________________ ANTIMETABOLITES * S phase specific * structurally related to normal cellular components * interfere with nucleotide synthesis * compete with cellular nucleotides in DNA and RNA synthesis * I. FOLIC ACID ANALOGS * methotrexate: blocks folate reductase, and thus intereferes with transfer of one-carbon units, thereby inhibiting production of methionine, A, G, T. * II. PYRIMIDINE ANALOGS * 5-fluoruracil: converted to 5-Fd(UMP) inhibits dUMP - TMP conversion via binding to thymidylate synthetase * floxuridine, 5-fluorodeoxyuridine: prodrug of 5-FU; hydrolysis by thymidine phosphorylase to 5-FU * capecitabine: prodrug of 5-FU; hepatic metabolism to 5'-deoxy-5-fluorocytidine which is converted to 5'-deoxy-5-fluorouridine by cytidine deaminase; hydrolysis by thymidine phosphorylase to 5-FU * fludarabine: has modifications in both the base and sugar moieties; activated by phosphorylation; incorporates into DNA, inhibiting DNA polymerization, terminating chain elongation; inhibits DNA proof-reading exonuclease activity * cytosine arabinoside: analog of dC, with D-arabinose sugar group; activated by phosphorylation; antagonizes d(CTP), inhibiting DNA polymerase; incorpoarted into DNA - inhibition of DNA chain elongation and SS breaks; inhibits CDP - dCDP * II. PURINE ANALOGS * 6-mercaptopurine: analog of hopoxanthine; intracellular activation; competitive inhibitor of purine synthesis * 6-thioguanine: intracellular activation; competitive inhibitor of purine synthesis * gemcitabine: competes with dCTP for incorporation into DNA; masked from DNA repair enzymes; inhibits DNA synthesis * cladribine: phosphorylated by deoxycytidine kinase; metabolite impairs synthesis of new DNA, inhibits repair of existing DNA, disrupts cellular metabolism * pentostatin: inhibits adenosine deaminase, increasing intracellular dATP ______________________________________ ANTIBIOTICS * cell cycle non-specific, except: bleomycin: causes cells to accumulate in G2 procarbazine: acts in S phase * intercalation into double-stranded DNA and disruption of DNA; binding to DNA helix * agents inhibit DNA synthesis, nucleotide incorporation, DNA dependent RNA synthesis, DNA uncoiling and/or topoisomerase II (leading to strand breaks). * doxorubicin: intercalates in DNA, binding to S-P backbone; binds to cell membranses, blocking phosphatidyl-inositol activation; free radical mediated DNA single-strand breaks: reduced semiquinone free radical metabolites (via P450) - reduced O2 - superoxide and H2O2; also inhibits topoisomerase II * daunorubicin: same mechansism as doxorubicin * idarubicin: same mechansism as doxorubicin * valrubicin: metabolites are active; less tight DNA binding; tends to arrest cells in G2; also inhibits topoisomerase II * dactinomycin: intercalates in small groove of helix and binds to dG; tight binding of the dactinomycin prevents unwinding of the DNA; also inhibits topoisomerase II * mithramycin: intercalates into to DNA; binds to surface of DNA helix. also used for hyperCa++ * mitomycin C: activated metabolite cross links DNA (and RNA) * mitoxantrone: high-affinity intercalation; cells late in S phase more sensitive * bleomycin: Cu and Fe chelating glycopeptides; cause DNA stand breaks via oxidative processes (mediated by superoxide and H2O2); cleaved at G-C and G-T sequences; inhibits DNA ligase and DNA synthesis (RNA and protein synthesis are less affected). * procarbazine: directly damages DNA; depolymerizes DNA; inhibits DNA, RNA and protein synthesis ______________________________________ MITOTIC INHIBITORS * cell cycle specific (M phase) * disrupts the mitotic spindle, inhibiting chromosomal segregation and thereby blocking mitosis * I. TAXANES (DITERPENES) * derived from bark of Pacific Yew * prevents microtubular depolymerization thereby inhibiting reorganization of the microtubular network * microtubular stabilization also promotes the formation of abnormal bundles of microtubules * paclitaxel * docetaxel * II. VINCA ALKALOIDS * derived from the Madagascar periwinkle plant * binds to tubulin causing termination of microtubular assembly, arresting cells in metaphase * formation of paracrystalline aggregates of vinca:tubulin shifts the equilibrium further toward microtubule disassembly * inhibits DNA dependent RNA synthesis, purine synthesis and amino acid metabolism * vinblatine sulfate * vincristine sulfate * vinorelbine sulfate ______________________________________ CHROMATIN FUNCTION INHIBITORS * CAMPTOTHECINS * derived from the bark of Camptotheca acuminata * cell cycle specific (S phase) * binds to topoisomerase I-DNA complex, preventing religation of breaks * induces reversible single-strand breaks, relieving torsional strain of DNA * double strand breaks formed during DNA synthesis * topotecan * irinotecan * EPIPODOPHYLLOTOXINS * derived podophyllotoxin, which arise from the Mayapple root * cell cycle specific (S-G2 phase); arrests cells in metaphase * complexes with topoisomerase II, inhibiting its enzymatic function. * topoisomerase is needed to unwind DNA and allow transcription and replication * drug-enzyme complex also causes production of DNA double stranded breaks and DNA-protein cross linkages * possibly inhibits nucleotide transport * etoposide * teniposide ______________________________________ HORMONES AND HORMONE INHIBITORS * I. ESTROGENS * binds to estradiol hormone receptors, inhibitng tumor growth in estrogen sensitive tumors * diethylstilbesterol * estradiol, estrogen * esterified estrogens * estramustine: see alkylating agents above * II. ANTIESTROGENS * blocks estradiol hormone receptors, possibly inhibitng DNA synthesis and thus tumor growth in estrogen sensitive tumors * tamoxifen * toremifene * II. AROMATASE INHIBITORS * inhbits aromatase (primarily in fatty tissue) which converts adrenal hormones into estrogen * decreased serum estrogen levels inhibit tumor growth in estrogen sensitive tumors * anastrozole * letrozole * III. PROGESTINS * blocks progesterone hormone receptors, inhibitng tumor growth by unknown mechanism * 17-OH-progesterone * medroxyprogesterone * megestrol acetate * IV. GnRH AGONISTS * synthetic analog of luteinizing hormone-releasing hormone * overstimulation of of the LHRH-gonadotropin axis leads to inhibition of gonadotropin release, thereby diminishing estrogen and androgen formation * hormone sensitive tumors are therefore inhibited * goserelin * leuprolide * V. ANDROGENS * binds to androgen hormone receptors, inhibitng tumor growth via an anti-estrogenic effect in estrogen sensitive tumors * testosteraone * methyltestosterone * fluoxmesterone * VI. ANTIANDROGENS * binds to androgen hormone receptors, inhibiting androgen uptake and thus inhibitng tumor growth in androgen sensitive tumors * flutamide * bicalutamide * nilutamide * VII. INHIBITORS OF SYNTHESIS * aminoglutethimide: interferes with adrenal steroid hormone synthesis; specically inhibits conversion of cholesterol to delta-5-pregnenolone (inhibiting corticosteroids, androgens, estrogens) * ketoconazole: interferes with adrenal steroid hormone synthesis ______________________________________ IMMUNOMODULATORS * rituximab: a humanized mouse antibody, targeting, CD20, a B-lymphocyte marker; possibly induces apoptosis, but exact mechanism unclear * trastuzumab: monoclonal antibody against HER2/NEU; inhibits stimulation from growth factors * denileukin diftitox: fusion protein which adheres to interleukin-2 receptors, causing cell death * levamisole: used in conjunction with 5-FU; restores immune function and stimulates antibody formation, enhances T-cell responses, potentiates macrophage and monocyte formation and function, increases PMN mobility, adherence and chemotaxis, inhibits alkaline phosphatase * BCG: exact mechanism unknown; enhances inflammatory response * interferon: complex immuno-mediator. direct antiproliferative effect against tumor cells; stimulates natural killer cells and macrophages * interleukin-2: stimulates B and T cell lymphocytes ______________________________________ MISCELLANEOUS * l-aspariginase: cell cycle specific (G1 phase); catalyzes deamination of asparigine to aspartic acid and ammonia; asparagine is inactivated, inhibiting protein synthesis * pegaspasgase: modified version of l-aspariginase * hydroxyurea: cell cycle specific (S phase); inhibits ribonucleotide reductase, thereby inhibiting DNA synthesis * leucovorin: active reduced form of folic acid. enhances 5-FU binding to thymidylate synthetase * mitotane: exact mechanism unknown; may bind mitochondrial proteins of adrenal cortical; also inhibits corticosteroid production * porfimer: photosensitizing agent - propagation of free radicals; required light and O2 * tretinoin: promotes cellular maturation from pro-myelocytic AML - AML ______________________________________ by Michael T. Milano, MD PhD MTMilano@yahoo.com www.geocities.com/MTMilano/palm/