Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chapter 101 Anticancer Drugs I: Cytotoxic Agents

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.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

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.3 Anticancer Drugs  Cytotoxic drugs  Alkylating agents  Platinum compounds  Antimetabolites  Hypomethylating agents  Antitumor antibiotics  Mitotic inhibitors  Topoisomerase inhibitors  Miscellaneous cytotoxic drugs

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.4

5 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

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.6 Toxicity  Many anticancer drugs are toxic to normal tissues – especially tissue with high growth fraction  Bone marrow  Hair follicles  GI epithelium  Germinal epithelium

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.7 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

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.8 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 Bone marrow, hair follicles, GI mucosa, and germinal epithelium

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.9 Fig 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.)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.10 Classes of Alkylating Agents  Nitrogen mustards  Cyclophosphamide (Cytoxan)  Nitrosoureas  Carmustine (BCNU)  Other  Temozolomide (Temodar)  Busulfan (Myleran)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.11 Platinum Compounds  Cell-cycle phase–nonspecific agents  Cisplatin (Platinol-AQ)  Carboplatin (Paraplatin)  Oxaliplatin (Eloxatin)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.12 Antimetabolites  Folic acid analog  Methotrexate (Rheumatrex)  Pemetrexed (ALIMTA)  Pyrimidine analogs  Cytarabine (Cytosar-U)  Fluorouracil (Adrucil)  Capecitabine (Xeloda)  Floxuridine (FUDR)  Gemcitabine (Gemzar)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.13 Antimetabolites  Purine analogs  Mercaptopurine (Purinethol)  Thioguanine (Tabloid)  Pentostatin (Nipent)  Fludarabine (Fludara)  Cladribine (Leustatin)  Nelarabine (Arranon)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.14 Fig Actions of methotrexate, leucovorin, and fluorouracil. (FdUMP = 5-fluoro-2'-deoxyuridine-5'-monophosphate, X = blockade of reaction.)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.15 Hypomethylating Agents  New class of anticancer drugs  Become incorporated into the DNA  Azacitidine (Vidaza)  Decitabine (Dacogen)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.16 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

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.17 Anthracyclines  Doxorubicin (Adriamycin)  Doxorubicin liposomal (Doxil)  Daunorubicin (DaunoXome)  Epirubicin (Ellence)  Idarubicin (Idamycin)  Mitoxantrone (Novantrone)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.18 Nonanthracyclines  Dactinomycin (Actinomycin D)  Bleomycin (Blenoxane)  Mitomycin (Mutamycin)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.19 Mitotic Inhibitors  Vinca alkaloids  Vincristine (Oncovin)  Vinblastine (Velban)  Vinorelbine (Navelbine)  Taxanes  Paclitaxel (Taxol)  Docetaxel (Taxotere)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.20 Other Mitotic Inhibitors  Ixabepilone (Ixempra)  Estramustine (Emcyt)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.21 Topoisomerase Inhibitors  Nuclear enzymes that alter the shape of supercoiled DNA  Topotecan (Hycamtin)  Irinotecan (Camptosar)  Etoposide (VePesid)  Teniposide (Vumon)

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.22 Miscellaneous Cytotoxic Drugs  Asparaginase (Elspar)  Pegaspargase (Oncaspar)  Hydroxyurea (Hydrea, Mylocel)  Mitotane (Lysodren)  Procarbazine (Matulane)  Dacarbazine (DTIC-Dome)