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• • • • • • • • CARCINOGENIC AGENTS AND THEIR CELLULAR INTERACTIONS LEARNING OBJECTIVES By the end of lecture the student should be able to know: Different types of carcinogens Mechanism of action of carcinogens Therapeutic agents that also act as carcinogens Skin cancer and radiation Viral carcinogens and types CARCINOGEN A carcinogen is any substance or agent that, because of the way it affects cell DNA, can cause cancer Carcinogens may be chemical substances; physical agents, such as asbestos dust; or biological agents, such as certain viruses and bacteria In the workplace, carcinogenic substances may be inhaled, absorbed through the skin or even ingested in some cases MECHANISM OF ACTION initiator — mutagenic agent that damages DNA permanently. Mechanism is rapid and irreversible promoters — encouraging cell proliferation. Augmenting agent not carcinogen by themselves. They do not affect the DNA directly and so mechanism is reversible TYPES OF CARCINOGENS Three main types: – Chemical • Direct acting • Indirect acting – – Physical (radiation) Biological (especially virus) CHEMICAL CARCINOGENS Direct-acting • Weak carcinogens • Require no chemical transformation • Alkylating agents – Cyclophosphamide, chlorambucil, nitrosoureas • Second malignancy decades later • Acylating agents - Acetyl-imidazole, Dimethylcarbamyl chloride CHEMICAL CARCINOGENS Indirect-acting • Require metabolic conversion before they become active. • Aromatic amines and azo dyes • Beta-naphthylamine: Bladder CA in rubber factories • Azo dyes used in food color • Nitrosamines and amides • Formed endogenously in acid environment of stomach: GI cancer • Aflatoxin B • Aspergillus in grains: Hepatocellular cancer • Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA CHEMICAL CARCINOGENS • • • • • • • • • • DRUGS THAT ARE ALSO CARCINOGENS Adriamycin (doxorubicin) Androgenic steroids Chlorambucil Cisplatin Cyclophosphamide Cyclosporin A Diethylstilbestrol Ethylene oxide Melphalan Tamoxifen • • • IONIZING RADIATION Death of pioneer radiation researchers from neoplasms High incidence of leukemia among radiologists recognized in 1940s Osteosarcoma incidence in radium dial painters MOLECULAR PROGRESSION MUTATION ACCUMULATION • • • • SKIN CANCER One of the most common human cancer and one of the most preventable ~106 cases of BCC and SCC are diagnosed per year This is more than all other types of cancer combined Most of these will be caused by exposure to ultraviolet (UV) irradiation • • • • • • • • • • • • ASBESTOS Widely used in construction, insulation, and manufacturing Family of related fibrous silicates: Chrysotile Crocidolite Causes malignant mesothelioma Mainly occurs in pleural and peritoneal cavities Rare in general population RADIATION CARCINOGENESIS Ionizing radiation: chromosome breakage, translocations and point mutations 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 VIRAL CARCINOGENESIS Viral infections account for an estimated one in seven human cancers worldwide Retroviral carcinogens: – Only cancer causing RNA viruses Prototype retrovirus: – GAG (core proteins) – POL (reverse transcriptase) – ENV (envelope proteins) • • • • • • HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 Common in Japan and Caribbean basin Transmission: sexual, blood product, breastfeeding CD4 T cell target for neoplastic transformation TAX gene essential for cell proliferation The proliferating T cells are at increased risk of mutations and genomic instability induced also by TAX Leukemia develops in infected person after latent period of 40-60 yrs HTLV-1 and ATL • • • • • • • • 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 HUMAN PAPILLOMA VIRUS (HPV) Over 70 subtypes DNA virus with small double-stranded circular genome Sexual transmission leading to cervical cancer Co-factors include cigarette smoking, coexisting microbial infection, hormonal changes Subtypes possess varying degrees of low risk and high risk • • • • • • • • • • • • MECHANISM OF ACTION Oncogenic potential related to two viral genes E6 and E7 Enhance p53 degradation causing block of apoptosis and decreased activity of p21 cell cycle inhibitor Also activates cyclins E and A Thus restraints to cell proliferation is removed LOW AND HIGH RISK HPV HPV subtypes classified as low risk or high risk based on whether the associated genital tract lesions are at significant risk for malignant progression High risk : HPV 16 and 18, cause squamous cell carcinoma of cervix and anogenital region Low risk: HPV 6 and 11, cause benign squamous papillomas warts EPSTEIN BARR VIRUS (EBV) Infects B cells and possibly epithelial cells of oropharynx LMP1 acts as oncogene promotes B- cell survival and proliferation Prevents apoptosis by activating BCL2 EBNA-2: activates cyclin D and src genes Cytokine vIL-10 prevent macrophages and monocytes from activating T cells and thus is required for EBV dependent transformation of B cells EPSTEIN-BARR VIRUS (EBV) • Four cancers – Burkitt’s lymphoma – B-cell lymphoma in immunosupressed – Nasopharyngeal carcinoma – Hodgkin’s disease • Association with Burkitt’s – High antibody titer – DNA clonally present in tumor cells – EBV transforms cultured lymphocytes • • • • HELICOBACTER PYLORI Increased epithelial cell proliferation in a background of chronic inflammation Gastric infection linked to gastric lymphomas and adenocarcinomas Detection of H pylori in majority of cases of gastric lymphomas Antibiotic treatment results in gastric lymphoma regression in most cases • • HEPATITIS B AND C VIRUS Cause hepatocellular carcinoma HBV & HCV genomes do not encode any viral oncoproteins Chronic heptaocellular injury leads to compensatory proliferation of hepatocytes Mediators such as reactive oxygen species are released which are genotoxic and mutagenic NF-kB pathway blocks apoptosis Chromosome rearrangement and deletion occurs • • • • • REFERENCES Pathologic basis of disease Robbins & Cotran 8th edition Ch. 7, Neoplasia Pgs. # 309-316 • • • • --------------THE END------------------