ONCOLOGY Cytotoxic Agents. ONCOLOGY Cytotoxic agents Selective toxicity based on characteristics...
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Transcript of ONCOLOGY Cytotoxic Agents. ONCOLOGY Cytotoxic agents Selective toxicity based on characteristics...
ONCOLOGYONCOLOGYCytotoxic AgentsCytotoxic Agents
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic agents
Selective toxicity based on characteristics that distinguish malignant cells from normal cells
Antineoplastic effects
– Cell death
– Cell growth inhibited
– Cell differentiation
Effects of chemotherapyEffects of chemotherapy
Haskell CM. Cancer Treatment. 4th ed. 1995;32.
ONCOLOGYONCOLOGYCytotoxic Cytotoxic agentsagentsCell cycle and Cell cycle and cytotoxic cytotoxic opportunitiesopportunities
CELLCELLDIFFERENTIATIONDIFFERENTIATION
CELLCELLLIFE CYCLELIFE CYCLE
TIMETIME
CELLCELLDIVISIONDIVISION
GG22 PERIOD PERIOD
(CHROMOSOME REPLICATION) (CHROMOSOME REPLICATION) S-PHASES-PHASE
GG11 PERIOD PERIOD
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic 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: ClassesAlkylating agents: Classes
Gerson SL. Current Cancer Therapeutics. 3rd ed. 1998;1.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic 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 actionAlkylating agents: Mechanism of action
Gerson SL. Current Cancer Therapeutics. 3rd ed. 1998;1.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic agents
Anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin)
Anthracenedione (ie, mitoxantrone)
Mitomycin C
Bleomycin
Dactinomycin
Plicamycin
Antitumor antibioticsAntitumor antibiotics
Blum RH. Current Cancer Therapeutics. 3rd ed. 1998;37-40.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic 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 actionAntitumor antibiotics: Mechanism of action
Blum RH. Current Cancer Therapeutics. 3rd ed. 1998;35,37.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic 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 actionAntimetabolites: Mechanism of action
Haskell CM. Current Cancer Therapeutics. 3rd ed. 1998;36.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic agents
Antifols (eg, methotrexate)
Purine analogues (eg, thioguanine, pentostatin, cladribine)
Pyrimidine analogues (eg, fluorouracil, cytarabine, gemcitabine)
Antimetabolites: ClassesAntimetabolites: Classes
Chiao J, et al. Current Cancer Therapetuics. 3rd ed. 1998;50-66.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic agents
Vinca alkaloids (eg, vincristine, vinblastine, vinorelbine)
Taxanes
Spindle-tubule inhibitorsSpindle-tubule inhibitors
Agarwala SS. Current Cancer Therapeutics. 3rd ed. 1998;105-122.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic agents
Podophyllotoxin derivatives (eg, etoposide, teniposide)
Camptothecin derivatives (eg, topotecan, irinotecan)
Topoisomerase inhibitors: ClassesTopoisomerase inhibitors: Classes
Agarwala SS. Current Cancer Therapeutics. 3rd ed. 1998;105.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic agents
Additive (eg, estrogen, progestins, androgens)
Ablative (eg, ovariectomy, orchiectomy)
Competitive (eg, antiestrogens, antiprogestins, antiandrogens)
Inhibitive (eg, aromatase inhibitors, LH-RH analogues)
Hormonal agents: CategoriesHormonal agents: Categories
LH-RH=luteinizing hormone-releasing hormone Kiang DT. Current Cancer Therapeutics. 3rd ed. 1998;88-90.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic 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 actionHormonal agents: Mechanism of action
Haskell CM. Cancer Treatment. 3rd ed. 1995;31-51.
Hormonal agents: ExamplesHormonal agents: Examples
Kiang DT. Current Cancer Therapeutics. 3rd ed. 1999;88-104.Haskell CM. Cancer Treatment. 4th ed. 1995;88-165.
ONCOLOGYONCOLOGYCytotoxic agentsCytotoxic 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
ONCOLOGYONCOLOGYOther agentsOther agents
Cytokines (eg, interleukin-2, interferon alpha, colony stimulating factors)
Immunomodulating reagents (eg, bacillus Calmette-Guérin, levamisole)
Octapeptide (eg, octreotide)
Biologic agentsBiologic agents
Baar J, et al. Current Cancer Therapeutics. 3rd ed. 1998;67-76.
ONCOLOGYONCOLOGYOther agentsOther 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 actionGranulocyte-colony stimulating factor (G-CSF): Mechanism of action
Baar J, et al. Current Cancer Therapeutics. 1998;71-72.