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CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY

CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY. DAVID LEWIN MD. OVERVIEW. Three Classes of Carcinogens Chemical Radiation Viral Tumor Immunology Tumor Antigens Antitumor Effector Mechanisms Immunosurveillance Immunotherapy. CHEMICAL CARCINOGENS. Natural and Synthetic Agents

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CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY

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  1. CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY • DAVID LEWIN MD

  2. OVERVIEW • Three Classes of Carcinogens • Chemical • Radiation • Viral • Tumor Immunology • Tumor Antigens • Antitumor Effector Mechanisms • Immunosurveillance • Immunotherapy

  3. CHEMICAL CARCINOGENS • Natural and Synthetic Agents • Highly reactive electrophiles (electron deficient) • React with RNA, DNA or cellular proteins • Direct –Acting • Indirect-Acting

  4. CHEMICAL CARCINOGENS Kumar et al. Basic Pathology 6th ed. Table 6-7

  5. Direct Acting Agents • Weak carcinogens • Require no chemical transformation • Chemotherapeutic drugs • Alkylating agents • Cyclophosphamide, chlorambucil, nitrosoureas • Second malignancy decades later • Acylating agents • 1-Acetyl-imidazole, Dimethylcarbamyl chloride

  6. Indirect Agents • Require metabolic conversion before they become active. • Procarcinogen- initial chemical • Ultimate carcinogen: active end product • Examples • Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA • Benz[a]anthracene: skin cancer • Benzo[a]pyrene: cigarette smoke- lung cancer

  7. Indirect Agents Continued • Examples • Aromatic amines and azo dyes • Converted in liver by P-450 • Beta-naphthylamine: Bladder ca in rubber factories • Azo dyes: developed for food color • Nitrosamines and amides • Formed endogenously in acid environment of stomach • GI cancers? • Aflatoxin B • Aspergillus in grains • Hepatocellular cancer

  8. Mechanism of Action of Chemical Carcinogens • Mutagenic • Ras mutations in rodents • Promoter • Augmenting agents by themselves not carcinogenic • Produce cell proliferation • Must follow mutagenic chemical “initiator” • Tetra-decanoylphorbol-acetate (TPA) • Activate protein kinase C • Patients at High risk • Genetic disorders i.e.. HNPCC

  9. Radiation Carcinogenesis • Types of radiation • Ultraviolet rays of sunlight • Melanoma, Squamous cell carcinoma, basal cell carcinoma • X-rays • Early developers: skin cancer • ENT ca with irradiation: thyroid cancer • Nuclear fission • Survivors of nuclear bomb: leukemia • Radionuclides • Miners: lung cancer • Ionizing radiation: chromosome breakage, translocations and point mutations

  10. MECHANISMS OF VIRAL CARCINOGENESIS • ONCOGENES • Carry oncogenes in viral DNA • INSERTIONAL MUTAGENESIS • Altering structure and/or function of host genome.

  11. TUMOR VIRUSES • RNA VIRUSES (RETROVIRUSES) • DNA VIRUSES • Important for both types of viruses is that the infection not kill the cell

  12. RNA TUMOR VIRUSES • RETROVIRUSES • ONLY CANCER CAUSING RNA VIRUSES • PROTOTYPE RETROVIRUS: • GAG (CORE PROTEINS) • POL (REVERSE TRANSCRIPTASE) • ENV (ENVELOPE PROTEINS)

  13. MECHANISMS OF RETROVIRAL TRANSFORMATION • ACUTE TRANSFORMING RETROVIRUS • CONTAINS ACTIVE ONCOGENE • SLOW TRANSFORMING RETROVIRUS • INSERTIONAL MUTAGENESIS • DOES NOT CARRY AN ONCOGENE ITSELF • OTHER MECHANISMS (HTLV-I)

  14. HTLV AND ADULT T-CELL LEUKEMIA • GEOGRAPHIC DISTRIBUTION • ALL ATL PATIENTS ARE INFECTED • VIRUS FOUND IN TUMOR CELLS • VIRUS TRANSFORMS T CELLS IN CULTURE

  15. HTLV-1 and ATL Proliferation Malignancy Kumar et al. Basic Pathology 6th ed. Figure 6-31

  16. DNA TUMOR VIRUSES • EARLY GENES • DNA REPLICATION / GENE EXPRESSION • LATE GENES • CAPSID, PACKAGING TO PRODUCE VIRAL PARTICLES • EARLY GENES = CANCER CAUSING

  17. DNA VIRUS LIFE CYCLE • PRODUCTIVE CYCLE • EARLY AND LATE GENES • CELL DEATH • NON-PRODUCTIVE CYCLE (LYSOGENIC) • ONLY EARLY GENES • CELL SURVIVES • MOST IMPORTANT FOR CARCINOGENESIS

  18. DNA TUMOR VIRUSES ASSOCIATED WITH HUMAN CANCER • HUMAN PAPILLOMA VIRUS (HPV) AND CERVICAL CANCER • HEPATITIS B (HBV) AND LIVER CANCER (HEPATOMA) • EPSTEIN-BARR VIRUS (EBV) AND BURKITT’S LYMPHOMA

  19. HPV AND CERVICAL CANCER • EPIDEMIOLOGY • CO-EXISTING INFECTIONS • SPECIFIC TYPES (16, 18) • HPV INTEGRATED DNA IN SOME CELLS • CAN TRANSFORM CELLS IN CULTURE

  20. University of Utah Web Site THE “GRADUAL” DEVELOPMENT OF MALIGNANCY • CARCINOMA OF THE UTERINE CERVIX • HPV INFECTION (KOILOCYTOSIS) • CONDYLOMA • DYSPLASIA (CIN) • CARCINOMA IN SITU • INVASIVE CARCINOMA

  21. University of Kansas Web site Epstein-Barr Virus (EBV) • Four cancers • Burkitt’s lymphoma • B-cell lymphoma in immunosupressed • Nasopharyngeal carcinoma • Hodgkin’s disease • Mechanism • LMP-1: cell growth and survival ( bcl-2) • EBNA-2: activates cyclin D and src genes • Association with Burkitt’s • High antibody titer • DNA clonally present in tumor cells • EBV transforms cultured lymphocytes

  22. HBV AND HEPATOMA • GEOGRAPHIC DISTRIBUTION (EPIDEMIOLOGY) • CHRONIC INFECTION- RR 200X • WOODCHUCKS (ANIMAL MODEL) • INTEGRATED VIRAL DNA

  23. Tumor Immunity • General Principles • Tumors not entirely self • Express non-self proteins • Immune-mediated recognition of tumor cells may be “positive mechanism of eliminating transformed cells • Immune surveillance

  24. Tumor Antigens • Tumor Specific Antigens • Present only on Tumor cells • Recognized by cytotoxic T cells • Bound by class I MHC • Several antigens in humans found that are not unique for tumor, however are generally not expressed by normal tissue • Melanoma-associated antigen-1 (MAGE-1): • Embryonal protein normally expressed in testis • Melanomas, breast ca, lung ca

  25. Tumor Antigens • Tumor Associated Antigens • Not unique to tumors, shared by normal cells • Differentiation- specific antigens • CALLA (CD10) in early B cells • Prostate specific antigen PSA

  26. Antitumor Effector Mechanisms • Cytotoxic T-cells • MHC restricted CD-8 cells (viruses) • NK cells • Destroying tumor cells without prior sensitization • Macrophages • Ifn-gamma • Humoral Mechanisms • Via complement and NK cells

  27. Antitumor Effector Mechanisms NK cell Cytotoxic T-cell Macrophage Humoral Mechanisms Kumar et al. Basic Pathology 6th ed. Figure 6-32

  28. IMMUNOSURVAILLANCE • Argument for: • Increased cancer in immunodeficient hosts • 200x increase in immunodeficiencies (lymphoma) • X-linked lymphoproliferative disorder (XLP • EBV related • Escape Mechanism Theories • Selective outgrowth of antigen-negative variants • Loss or reduction of HLA (escape T-cells) • Immunosuppression (Tumors secrete factors TGF-b)

  29. IMMUNOTHERAPY • Replace suppressed components of immune system or stimulate endogenous responses • Adoptive Cellular Therapy • Incubation of lymphocytes with IL-2 to generate lymphokine activated killer (LAK) cells with potent antitumor activity • Enriched tumor specific cytotoxic T cells • Tumor infiltrating lymphocytes (TIL)

  30. Cytokine Therapy • Activate specific and nonspecific (inflammatory) host defenses. • Interferon-a, TNF-a, Il-2, IFN-g • IFN-a activates NK cells, increase MHC expression on tumor cells • Used for hairy cell leukemia

  31. Antibody-Based Therapy • Antibodies as targeting agents for delivery of cell toxins “magic bullet” • Direct use of antibodies to activate host immune system • Her-2/neu in advance breast cancer

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