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Chapter 101Chapter 101

Anticancer Drugs I: Cytotoxic Anticancer Drugs I: Cytotoxic AgentsAgents

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Cytotoxic Anticancer DrugsCytotoxic Anticancer Drugs Largest class of anticancer drugsLargest class of anticancer drugs Act directly on cancer cells and healthy cells Act directly on cancer cells and healthy cells

to cause their death to cause their death About 50% of cytotoxic anticancer drugs are About 50% of cytotoxic anticancer drugs are

phase-specificphase-specific Subdivided into nine major groupsSubdivided into nine major groups

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Anticancer DrugsAnticancer Drugs Cytotoxic drugsCytotoxic drugs

Alkylating agentsAlkylating agents Platinum compoundsPlatinum compounds AntimetabolitesAntimetabolites Hypomethylating agentsHypomethylating agents Antitumor antibioticsAntitumor antibiotics Mitotic inhibitorsMitotic inhibitors Topoisomerase inhibitorsTopoisomerase inhibitors Miscellaneous cytotoxic drugsMiscellaneous cytotoxic drugs

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Cell-Phase SpecificityCell-Phase Specificity Sequence of events that a cell goes through Sequence of events that a cell goes through

from one mitotic division to the nextfrom one mitotic division to the next Cell-cycle phase–specific drugsCell-cycle phase–specific drugs

Toxic only to cells that are in a particular phaseToxic only to cells that are in a particular phase Must be in the in the blood continuously over a Must be in the in the blood continuously over a

long timelong time Cell-cycle phase–nonspecific drugsCell-cycle phase–nonspecific drugs

Can act during any phase of the cell cycleCan act during any phase of the cell cycle

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ToxicityToxicity Many anticancer drugs are toxic to normal Many anticancer drugs are toxic to normal

tissues – especially tissue with high growth tissues – especially tissue with high growth fractionfraction Bone marrowBone marrow Hair folliclesHair follicles GI epitheliumGI epithelium Germinal epitheliumGerminal epithelium

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Dosage, Handling, and Dosage, Handling, and AdministrationAdministration

Antineoplastic drugs are often mutagenic, Antineoplastic drugs are often mutagenic, teratogenic, and carcinogenicteratogenic, and carcinogenic

Direct contact can result in local injuryDirect contact can result in local injury Extravasation of vesicantsExtravasation of vesicants

Carmustine, dacarbazine, dactinomycin, Carmustine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, mechlorethamine, daunorubicin, doxorubicin, mechlorethamine, mitomycin, plicamycin, streptozocin, vinblastine, mitomycin, plicamycin, streptozocin, vinblastine, vincristinevincristine

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Alkylating AgentsAlkylating Agents Highly reactive compoundsHighly reactive compounds Cells are killed by the alkalization of DNACells are killed by the alkalization of DNA Cell-cycle phase–nonspecific agentsCell-cycle phase–nonspecific agents Drug resistance is commonDrug resistance is common ToxicitiesToxicities

Occur in tissues with high growth fractionOccur in tissues with high growth fraction• Bone marrow, hair follicles, GI mucosa, and germinal Bone marrow, hair follicles, GI mucosa, and germinal

epitheliumepithelium

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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.)

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Classes of Alkylating AgentsClasses of Alkylating Agents Nitrogen mustardsNitrogen mustards

Cyclophosphamide (Cytoxan)Cyclophosphamide (Cytoxan) NitrosoureasNitrosoureas

Carmustine (BCNU)Carmustine (BCNU) OtherOther

Temozolomide (Temodar)Temozolomide (Temodar) Busulfan (Myleran)Busulfan (Myleran)

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Platinum CompoundsPlatinum Compounds Cell-cycle phase–nonspecific agentsCell-cycle phase–nonspecific agents Cisplatin (Platinol-AQ)Cisplatin (Platinol-AQ) Carboplatin (Paraplatin)Carboplatin (Paraplatin) Oxaliplatin (Eloxatin)Oxaliplatin (Eloxatin)

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AntimetabolitesAntimetabolites Folic acid analog Folic acid analog

Methotrexate (Rheumatrex) Methotrexate (Rheumatrex) Pemetrexed (ALIMTA)Pemetrexed (ALIMTA)

Pyrimidine analogsPyrimidine analogs Cytarabine (Cytosar-U)Cytarabine (Cytosar-U) Fluorouracil (Adrucil)Fluorouracil (Adrucil) Capecitabine (Xeloda)Capecitabine (Xeloda) Floxuridine (FUDR)Floxuridine (FUDR) Gemcitabine (Gemzar)Gemcitabine (Gemzar)

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AntimetabolitesAntimetabolites Purine analogsPurine analogs

Mercaptopurine (Purinethol) Mercaptopurine (Purinethol) Thioguanine (Tabloid)Thioguanine (Tabloid) Pentostatin (Nipent)Pentostatin (Nipent) Fludarabine (Fludara)Fludarabine (Fludara) Cladribine (Leustatin)Cladribine (Leustatin) Nelarabine (Arranon)Nelarabine (Arranon)

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

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Hypomethylating AgentsHypomethylating Agents New class of anticancer drugsNew class of anticancer drugs Become incorporated into the DNABecome incorporated into the DNA Azacitidine (Vidaza)Azacitidine (Vidaza) Decitabine (Dacogen)Decitabine (Dacogen)

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Antitumor AntibioticsAntitumor Antibiotics Cytotoxic drugs originally isolated from Cytotoxic drugs originally isolated from

cultures of cultures of StreptomycesStreptomyces Used only to treat cancer – not infectionsUsed only to treat cancer – not infections Injure cells through direct interaction with Injure cells through direct interaction with

DNADNA Poor GI absorption – IV administrationPoor GI absorption – IV administration Two main groupsTwo main groups

Anthracyclines and nonanthracyclinesAnthracyclines and nonanthracyclines

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AnthracyclinesAnthracyclines Doxorubicin (Adriamycin)Doxorubicin (Adriamycin) Doxorubicin liposomal (Doxil)Doxorubicin liposomal (Doxil) Daunorubicin (DaunoXome)Daunorubicin (DaunoXome) Epirubicin (Ellence)Epirubicin (Ellence) Idarubicin (Idamycin)Idarubicin (Idamycin) Mitoxantrone (Novantrone)Mitoxantrone (Novantrone)

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NonanthracyclinesNonanthracyclines Dactinomycin (Actinomycin D)Dactinomycin (Actinomycin D) Bleomycin (Blenoxane)Bleomycin (Blenoxane) Mitomycin (Mutamycin)Mitomycin (Mutamycin)

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Mitotic InhibitorsMitotic Inhibitors Vinca alkaloids Vinca alkaloids

Vincristine (Oncovin)Vincristine (Oncovin) Vinblastine (Velban)Vinblastine (Velban) Vinorelbine (Navelbine)Vinorelbine (Navelbine)

TaxanesTaxanes Paclitaxel (Taxol)Paclitaxel (Taxol) Docetaxel (Taxotere)Docetaxel (Taxotere)

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Other Mitotic InhibitorsOther Mitotic Inhibitors Ixabepilone (Ixempra)Ixabepilone (Ixempra) Estramustine (Emcyt)Estramustine (Emcyt)

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Topoisomerase InhibitorsTopoisomerase Inhibitors Nuclear enzymes that alter the shape of Nuclear enzymes that alter the shape of

supercoiled DNAsupercoiled DNA Topotecan (Hycamtin)Topotecan (Hycamtin) Irinotecan (Camptosar)Irinotecan (Camptosar) Etoposide (VePesid)Etoposide (VePesid) Teniposide (Vumon)Teniposide (Vumon)

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