ONCOLOGY Cytotoxic Agents. ONCOLOGY Cytotoxic agents Selective toxicity based on characteristics that distinguish malignant cells from normal cells Antineoplastic

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


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.


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.


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.


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.


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.


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.


Vinca alkaloids (eg, vincristine, vinblastine, vinorelbine)

Taxanes

Spindle-tubule inhibitorsSpindle-tubule inhibitors

Agarwala SS. Current Cancer Therapeutics. 3rd ed. 1998;105-122.


Podophyllotoxin derivatives (eg, etoposide, teniposide)

Camptothecin derivatives (eg, topotecan, irinotecan)

Topoisomerase inhibitors: ClassesTopoisomerase inhibitors: Classes

Agarwala SS. Current Cancer Therapeutics. 3rd ed. 1998;105.


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.


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.


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.

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ONCOLOGY Cytotoxic Agents. ONCOLOGY Cytotoxic agents Selective toxicity based on characteristics that distinguish malignant cells from normal cells Antineoplastic