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Chapter 101

Chapter 101. Anticancer Drugs I: Cytotoxic Agents. Cytotoxic Anticancer Drugs. Largest class of anticancer drugs Act directly on cancer cells and healthy cells to cause their death About 50% of cytotoxic anticancer drugs are phase-specific Subdivided into nine major groups.

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Chapter 101

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  1. Chapter 101 Anticancer Drugs I: Cytotoxic Agents

  2. Cytotoxic Anticancer Drugs • Largest class of anticancer drugs • Act directly on cancer cells and healthy cells to cause their death • About 50% of cytotoxic anticancer drugs are phase-specific • Subdivided into nine major groups

  3. Anticancer Drugs • Cytotoxic drugs • Alkylating agents • Platinum compounds • Antimetabolites • Hypomethylating agents • Antitumor antibiotics • Mitotic inhibitors • Topoisomerase inhibitors • Miscellaneous cytotoxic drugs

  4. Cell-Phase Specificity • Sequence of events that a cell goes through from one mitotic division to the next • Cell-cycle phase–specific drugs • Toxic only to cells that are in a particular phase • Must be in the in the blood continuously over a long time • Cell-cycle phase–nonspecific drugs • Can act during any phase of the cell cycle

  5. Toxicity • Many anticancer drugs are toxic to normal tissues – especially tissue with high growth fraction • Bone marrow • Hair follicles • GI epithelium • Germinal epithelium

  6. Dosage, Handling, and Administration • Antineoplastic drugs are often mutagenic, teratogenic, and carcinogenic • Direct contact can result in local injury • Extravasation of vesicants • Carmustine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, mechlorethamine, mitomycin, plicamycin, streptozocin, vinblastine, vincristine

  7. Alkylating Agents • Highly reactive compounds • Cells are killed by the alkalization of DNA • Cell-cycle phase–nonspecific agents • Drug resistance is common • Toxicities • Occur in tissues with high growth fraction • Bone marrow, hair follicles, GI mucosa, and germinal epithelium

  8. Fig. 101-1. Cross-linking of DNA by an alkylating agent. A, Reactions leading to cross-linkage between guanine moieties in DNA. B, Schematic representation of interstrand cross-linking within the DNA double helix. (A = adenine, C = cytosine, G = guanine, T = thymine.)

  9. Classes of Alkylating Agents • Nitrogen mustards • Cyclophosphamide (Cytoxan) • Nitrosoureas • Carmustine (BCNU) • Other • Temozolomide (Temodar) • Busulfan (Myleran)

  10. Platinum Compounds • Cell-cycle phase–nonspecific agents • Cisplatin (Platinol-AQ) • Carboplatin (Paraplatin) • Oxaliplatin (Eloxatin)

  11. Antimetabolites • Folic acid analog • Methotrexate (Rheumatrex) • Pemetrexed (ALIMTA) • Pyrimidine analogs • Cytarabine (Cytosar-U) • Fluorouracil (Adrucil) • Capecitabine (Xeloda) • Floxuridine (FUDR) • Gemcitabine (Gemzar)

  12. Antimetabolites • Purine analogs • Mercaptopurine (Purinethol) • Thioguanine (Tabloid) • Pentostatin (Nipent) • Fludarabine (Fludara) • Cladribine (Leustatin) • Nelarabine (Arranon)

  13. Fig. 101-2. Actions of methotrexate, leucovorin, and fluorouracil. (FdUMP = 5-fluoro-2'-deoxyuridine-5'-monophosphate, X = blockade of reaction.)

  14. Hypomethylating Agents • New class of anticancer drugs • Become incorporated into the DNA • Azacitidine (Vidaza) • Decitabine (Dacogen)

  15. Antitumor Antibiotics • Cytotoxic drugs originally isolated from cultures of Streptomyces • Used only to treat cancer – not infections • Injure cells through direct interaction with DNA • Poor GI absorption – IV administration • Two main groups • Anthracyclines and nonanthracyclines

  16. Anthracyclines • Doxorubicin (Adriamycin) • Doxorubicin liposomal (Doxil) • Daunorubicin (DaunoXome) • Epirubicin (Ellence) • Idarubicin (Idamycin) • Mitoxantrone (Novantrone)

  17. Nonanthracyclines • Dactinomycin (Actinomycin D) • Bleomycin (Blenoxane) • Mitomycin (Mutamycin)

  18. Mitotic Inhibitors • Vinca alkaloids • Vincristine (Oncovin) • Vinblastine (Velban) • Vinorelbine (Navelbine) • Taxanes • Paclitaxel (Taxol) • Docetaxel (Taxotere)

  19. Other Mitotic Inhibitors • Ixabepilone (Ixempra) • Estramustine (Emcyt)

  20. Topoisomerase Inhibitors • Nuclear enzymes that alter the shape of supercoiled DNA • Topotecan (Hycamtin) • Irinotecan (Camptosar) • Etoposide (VePesid) • Teniposide (Vumon)

  21. Miscellaneous Cytotoxic Drugs • Asparaginase (Elspar) • Pegaspargase (Oncaspar) • Hydroxyurea (Hydrea, Mylocel) • Mitotane (Lysodren) • Procarbazine (Matulane) • Dacarbazine (DTIC-Dome)

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