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ONCOLOGY Cytotoxic Agents

ONCOLOGY Cytotoxic Agents. ONCOLOGY Cytotoxic agents. Effects of chemotherapy. Selective toxicity based on characteristics that distinguish malignant cells from normal cells Antineoplastic effects Cell death Cell growth inhibited Cell differentiation.

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ONCOLOGY Cytotoxic Agents

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  1. ONCOLOGYCytotoxic Agents

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

  3. CELLDIFFERENTIATION ONCOLOGYCytotoxic agents CELLDIVISION Cell cycle and cytotoxic opportunities G1 PERIOD CELLLIFE CYCLE G2 PERIOD TIME (CHROMOSOME REPLICATION) S-PHASE

  4. ONCOLOGYCytotoxic agents Alkylating agents: Classes • 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) Gerson SL. Current Cancer Therapeutics. 3rd ed. 1998;1.

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

  6. ONCOLOGYCytotoxic agents Antitumor antibiotics • Anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin) • Anthracenedione (ie, mitoxantrone) • Mitomycin C • Bleomycin • Dactinomycin • Plicamycin Blum RH. Current Cancer Therapeutics. 3rded. 1998;37-40.

  7. ONCOLOGYCytotoxic agents Antitumor antibiotics: Mechanism of action • 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 Blum RH. Current Cancer Therapeutics. 3rded. 1998;35,37.

  8. ONCOLOGYCytotoxic agents Antimetabolites: Mechanism of action • 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 Haskell CM. Current Cancer Therapeutics. 3rd ed. 1998;36.

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

  10. ONCOLOGYCytotoxic agents Spindle-tubule inhibitors • Vinca alkaloids (eg, vincristine, vinblastine, vinorelbine) • Taxanes Agarwala SS. Current Cancer Therapeutics. 3rd ed. 1998;105-122.

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

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

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

  14. ONCOLOGYCytotoxic agents Hormonal agents: Examples • 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 • Kiang DT. Current Cancer Therapeutics. 3rd ed. 1999;88-104. • Haskell CM. Cancer Treatment. 4th ed. 1995;88-165.

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

  16. ONCOLOGYOther agents Granulocyte-colony stimulating factor (G-CSF): Mechanism of action • 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 Baar J, et al. Current Cancer Therapeutics. 1998;71-72.

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