ONCOLOGY Cytotoxic Agents

ONCOLOGY Cytotoxic agents Selective toxicity based on characteristics that distinguish malignant cells from normal cells Antineoplastic effects –Cell death –Cell growth inhibited –Cell differentiation Effects of chemotherapy Haskell CM. Cancer Treatment. 4th ed. 1995;32.

ONCOLOGY Cytotoxic agents Cell cycle and cytotoxic opportunities CELL DIFFERENTIATION CELL LIFE CYCLE TIME CELL DIVISION G 2 PERIOD (CHROMOSOME REPLICATION) S-PHASE G 1 PERIOD

ONCOLOGY Cytotoxic agents Nitrogen mustards (eg, cyclophosphamide, melphalan) Aziridines (eg, thiotepa) Alkyl alkone sulfonates (eg, busulfan) Nitrosoureas (eg, carmustine) Nonclassic alkylating agents (eg, procarbazine) Platinum compounds (eg, carboplatin, cisplatin) Alkylating agents: Classes Gerson SL. Current Cancer Therapeutics. 3rd ed. 1998;1.

ONCOLOGY Cytotoxic agents Polyfunctional compounds Cytotoxicity results from alkylation of guanine and interference with DNA replication/transcription to RNA Cell-cycle–phase nonspecific Alkylating agents: Mechanism of action Gerson SL. Current Cancer Therapeutics. 3rd ed. 1998;1.

ONCOLOGY Cytotoxic agents Anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin) Anthracenedione (ie, mitoxantrone) Mitomycin C Bleomycin Dactinomycin Plicamycin Antitumor antibiotics Blum RH. Current Cancer Therapeutics. 3rd ed. 1998;37-40.

ONCOLOGY Cytotoxic agents Polyfunctional agents Principal mechanism: binding directly to DNA, causing uncoiling/breakage of helix, impairment of DNA and RNA synthesis Other mechanisms –Free-radical formation –Chelation of important metals –Inhibition of topoisomerase II Antitumor antibiotics: Mechanism of action Blum RH. Current Cancer Therapeutics. 3rd ed. 1998;35,37.

ONCOLOGY Cytotoxic agents Replacing metabolites in key DNA/RNA replication molecules, thereby impairing function Competing with metabolites at catalytic sites of key enzymes Competing with metabolites at regulatory sites of key enzymes Antimetabolites: Mechanism of action Haskell CM. Current Cancer Therapeutics. 3rd ed. 1998;36.

ONCOLOGY Cytotoxic agents Antifols (eg, methotrexate) Purine analogues (eg, thioguanine, pentostatin, cladribine) Pyrimidine analogues (eg, fluorouracil, cytarabine, gemcitabine) Antimetabolites: Classes Chiao J, et al. Current Cancer Therapetuics. 3rd ed. 1998;50-66.

ONCOLOGY Cytotoxic agents Vinca alkaloids (eg, vincristine, vinblastine, vinorelbine) Taxanes Spindle-tubule inhibitors Agarwala SS. Current Cancer Therapeutics. 3rd ed. 1998;

ONCOLOGY Cytotoxic agents Podophyllotoxin derivatives (eg, etoposide, teniposide) Camptothecin derivatives (eg, topotecan, irinotecan) Topoisomerase inhibitors: Classes Agarwala SS. Current Cancer Therapeutics. 3rd ed. 1998;105.

ONCOLOGY Cytotoxic agents Additive (eg, estrogen, progestins, androgens) Ablative (eg, ovariectomy, orchiectomy) Competitive (eg, antiestrogens, antiprogestins, antiandrogens) Inhibitive (eg, aromatase inhibitors, LH-RH analogues) Hormonal agents: Categories LH-RH=luteinizing hormone-releasing hormone Kiang DT. Current Cancer Therapeutics. 3rd ed. 1998;88-90.

ONCOLOGY Cytotoxic agents Modulate activity of hormones on nuclear or cytoplasmic receptors and subsequent induction of mRNA synthesis/protein synthesis/changes in cell functioning Hormonal agents: Mechanism of action Haskell CM. Cancer Treatment. 3rd ed. 1995;31-51.

Hormonal agents: Examples Kiang DT. Current Cancer Therapeutics. 3rd ed. 1999; Haskell CM. Cancer Treatment. 4th ed. 1995; ONCOLOGY Cytotoxic agents Megestrol acetate for advanced breast and endometrial cancers Tamoxifen for breast cancer and in combination for other cancers, such as melanoma LH-RH agonists in combination with flutamide for androgen blockade in prostate cancer Prednisone as part of combination therapy for Hodgkin’s disease, non-Hodgkin’s lymphoma, myeloma, and acute lymphoblastic leukemia; and as palliative therapy for breast and prostate cancer

ONCOLOGY Other agents Cytokines (eg, interleukin-2, interferon alpha, colony stimulating factors) Immunomodulating reagents (eg, bacillus Calmette-Guérin, levamisole) Octapeptide (eg, octreotide) Biologic agents Baar J, et al. Current Cancer Therapeutics. 3rd ed. 1998;67-76.

ONCOLOGY Other agents Produced normally by mononuclear phagocytes, endothelial cells, fibroblasts, neutrophils Acts to control number of circulating blood neutrophils Improves neutropenia and reduces infection in solid-tumor patients receiving myelosuppressive therapy Granulocyte-colony stimulating factor (G-CSF): Mechanism of action Baar J, et al. Current Cancer Therapeutics. 1998;71-72.