Cancer Chemotherapeutics 
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TABLE OF CONTENTS 
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* ALKYLATING AGENTS 
* ANTIMETABOLITES 
* ANTIBIOTICS 
* MITOTIC INHIBITORS 
* CHROMATIN FUNCTION INHIBITORS 
* HORMONES AND HORMONE INHIBITORS 
* IMMUNOMODULATORS 
* MISCELLANEOUS 
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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) 
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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) 
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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) 
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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) 
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CHROMATIN FUNCTION INHIBITORS 
* I. CAMPTOTHECINS 
* topotecan (Camptosar) 
* irinotecan (Hycamtin) 
* II. EPIPODOPHYLLOTOXINS 
* etoposide (VP-16, VePesid, Toposar) 
* teniposide (VM-26, Vumon) 
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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) 
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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) 
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MISCELLANEOUS 
* l-aspariginase (Elspar, Kidrolase) 
* pegaspasgase (Oncaspar) 
* hydroxyurea (Hydrea, Doxia) 
* leucovorin (Wellcovorin) 
* mitotane (Lysodren) 
* porfimer (Photofrin) 
* tretinoin (Veasnoid) 
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MECHANISM OF ACTION 
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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 
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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 
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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 
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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 
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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 
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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 
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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 
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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 
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by Michael T. Milano, MD PhD
MTMilano@yahoo.com
www.geocities.com/MTMilano/palm/
