Carcinogenic Agents
.chemical carcinogens.physical carcinogens (radiant energy)
.oncogenic microbes (viruses, bacteria)
Chemical Carcinogens.general features -most chemical carcinogens require metabolic activation for conversion into ultimate carcinogens -carcinogenic potency of a chemical is determined by .reactivity of its derivative .balance between metabolic activation & inactivation reactions
-DNA is the primary target of chemical carcinogens .any gene may be the target, however, mutated oncogenes & tumor suppressors (RAS & p53), are particularly important ones
.steps in chemical carcinogenesis
• -initiation-induced by initiators, (altered cells)• .initiation alone is not sufficient for tumor formation
• .targets of initiators are DNA, RNA, & proteins .initiation causes mutation .mutated cell passes on DNA lesions to daughter cells
-promotion-induced by promoters, (tumor production) .induce tumors in initiated cells, steps, -proliferation of preneoplastic cells -malignant conversion (mutations) -tumor progression .no tumor if promoter is applied alone or before initiator .no tumor if time between multiple applications of promoter is extended .do not affect DNA directly & their effects are reversible
.types of initiators -direct-acting carcinogens (alkylating agents) .require no metabolic conversion to become carcinogenic .most of them are weak carcinogens .some are cancer chemotherapeutic drugs (may induce second cancer in patients treated by them)
-indirect-acting (procarcinogens)
.require metabolic conversion to ultimate carcinogen.examples
-polycyclic aromatic hydrocarbons
(fossil fuels, animal fat, smoked meat, fish-various cancers)
-benzopyrene (tobacco-lung cancer)
-aromatic amines & azo dyes (rubber & aniline dye industries- cancer of urinary bladder)
-naturally occurring (microbial products-aflatoxin B1-hepatocellular carcinoma) -food preservatives (nitrites & amides- carcinomas of GIT) -metals (nickel, chromium-lung cancer) -others (arsenic, vinyl chloride, pestesides, fungicides)
.types of promoters
• -exogenous, (cigarette smoke, alcohol, viruses)• -endogenous, (hormones, bile acids)
Radiation Carcinogenesis.types -UV lights (A, B, C) -ionizing radiations .electromagnetic (x-rays, Υ rays) .particulate (α particles, β particles, protons, neutrons).general features -contribution to human cancer is small -latency of effect -cumulative effect
Ultraviolet Rays
.skin cancer, degree of risk depends on• -type of UV rays (UVB is carcinogenic)
• -intensity of exposure
• -quantity of melanin pigment in skin
• .effects of UV rays on cells
• -inhibition of cell division
• -inactivation of enzymes
• -induction of mutation
• -death
Ionizing Radiation
• .types of cancers• -acute & chronic myeloid leukemias,
• thyroid cancer (most frequent)
• -cancers of breast, lung, & salivary glands (intermediate in frequency)
• -cancers of skin, bone, & GIT (resistant to radiation),
• but any cell can undergo cancerous changes with sufficient exposure to radiation
Microbial CarcinogenesisOncogenic Viruses.mechanisms of action -direct oncogenic effect (HPV, HBV, HCV, EBV-nasopharyngeal carcinoma) -sustained polyclonal B-cell proliferation>mutations>monoclonal neoplastic cell proliferation (EBV- Burkitt Lymphoma) -immune-mediated chronic inflammation >cell death>cell regeneration> mutations>cancer (HBV, HCV)
Oncogenic DNA Viruses
• .Human Papilloma Virus (HPV)• -lesions
• .squamous papilloma of skin (wart- types 1, 2, 4, 7)
• .genital warts (types 6, 11)
• .squamous cell carcinoma of cervix & anogenital region (types 16, 18)
• .oral & laryngeal carcinomas
• .nasopharyngeal carcinoma
• .Epstein-Barr virus (EBV)
• -non-Hodgkin lymphomas• .Burkitt
• .B-cell in immuno-suppressed
• -Hodgkin lymphoma
• -nasopharyngeal & gastric carcinomas
• .Hepatitis B Virus (HBV-liver cancer) -HBV & HCV cause 70% to 85% of hepatocellular carcinoma worldwide.Kaposi sarcoma herpes virus (Kaposi sarcoma)
• Oncogenic RNA Viruses.human T-cell leukemia virus type-1 (T-cell leukemia/lymphoma) -has tropism for CD4+ T cells -infection requires transmission of infected T cells via sexual route, blood products, or breast feeding -leukemia develops in 3%-5% of infected individuals after 40-60 yrs.HCV (liver cell carcinoma)
• Oncogenic Bacteria.helicobacter pylori, diseases -gastric carcinoma .chronic gastritis>gastric atrophy> intestinal metaplasia of lining cells> dysplasia>cancer .takes decades & occurs in 3% of infected individuals -gastric lymphoma .T-cell stimulation>polyclonal B cell proliferation>lymphoma by acquiring mutations