 cause damage to chromosomes by introducing changes to DNA

 More than 200 years ago, the London surgeon Sir Percival Pott correctly attributed scrotal skin cancer in chimney sweeps to chronic exposure to soot

 require no metabolic conversion to become carcinogenic  in general weak carcinogens  cancer chemotherapeutic drugs (e.g., alkylating agents )  evoke later a second form of cancer, usually leukemia

 The problem with base “alkylation” is that pairing between the modified base and its normal counterpart is disrupted, leading to a mutation

 require metabolic conversion to become carcinogenic  polycyclic hydrocarbons -are present in fossil fuels  benzo [a] pyrene and other carcinogens are formed in the high-temperature combustion of 1- tobacco in cigarette smoking ( most common ) 2- broiling meats smoked fish

 The principal active products in many hydrocarbons are epoxides, which form covalent adducts (addition products) with molecules in the cell, principally DNA, but also with RNA and proteins.  The aromatic amines and azo dyes are another class of indirect-acting carcinogens  β-naphthylamine was responsible for a 50-fold increased incidence of bladder cancers in heavily exposed workers in the aniline dye(woodworking) and rubber industries.

 for their conversion to DNA-damaging agents, much interest is focused on the enzymatic pathways that are involved, such as the cytochrome P-450-dependent monooxygenases  The genes that encode these enzymes are polymorphic,>> and enzyme activity varies among different individuals  It is widely believed that the susceptibility to chemical carcinogenesis depends at least in part on the specific allelic form of the enzyme inherited

it is a naturally occurring agent produced by some strains of Aspergillus, a mold that grows on improperly stored grains and nuts

 most chemical carcinogens are mutagenic  all direct and ultimate carcinogens contain highly reactive electrophile groups that form chemical adducts with DNA, as well as with proteins and RNA  Contain electron-deficient atoms that react with electron-rich atoms in DNA.  the commonly mutated oncogenes and tumor suppressors, such as RAS and p53  aflatoxin B 1, produce characteristic mutations in the p53 gene, such that detection of the " signature mutation " within the p53 gene

 Initiators › Carcinogens that interact with and cause mutations in DNA  Promoters ( drugs,hormones) › Interact with cells to promote growth, block differentiation › Leads to additional permanent changes after initiator damage › Does not cause cancer by itself › It seems most likely that while the application of an initiator may cause the mutational activation of an oncogene such as RAS, subsequent application of promoters leads to clonal expansion of initiated (mutated) cells › cause pathologic hyperplasias of liver, endometrium

 Sequence of chemical carcinogenesis › Initiation  Irreversible mutation › Promotion  Promoters (e.g., estrogen) stimulate mutated cells to enter the cell cycle. › Progression  Development of tumor heterogeneity  Examples-production of cells that invade or metastasize

 Unprotected miners of radioactive elements have a 10-fold increased incidence of lung cancers!  survivors of the atomic bombs dropped on Hiroshima and Nagasaki disclosed a markedly increased incidence of leukemia after an average latent period of about 7 years, as well as an increased mortality rate from thyroid, breast, colon, and lung carcinomas.

 Therapeutic irradiation of the head and neck can give rise to papillary thyroid cancers years later

causing atoms to lose electrons and become ions Generally by hydroxyl free radicals

 Natural UV radiation derived from the sun can cause skin cancers (melanomas, squamous cell carcinomas, and basal cell carcinomas).  At greatest risk are fair-skinned people who live in locales such as Australia and New Zealand that receive a great deal of sunlight

 Nonmelanoma skin cancers are associated with total cumulative exposure to UV radiation, whereas melanomas are associated with intense intermittent exposure -as occurs with sunbathing  ability to damage DNA by forming pyrimidine dimers

 Glycosylase recognizes the damaged base, and removes the damaged base.  AP endonuclease cleaves the abasic sugar-phosphate backbone.  Exonuclease, DNA polymerase, and ligase work sequentially to complete the repair event.

 human T-cell leukemia virus-1 (HTLV-1) is the only retrovirus that has been demonstrated to cause cancer in humans  T-cell leukemia/lymphoma  endemic  endemic in certain parts of Japan and the Caribbean  HTLV-1 has tropism for CD4+ T cells, and this subset of T cells is the major target for neoplastic transformation  Human infection requires transmission of infected T cells via sexual intercourse, blood products, or breastfeeding.  Leukemia develops only in about 3% to 5% of infected individuals after a long latent period of 20 to 50 years!!!

 can transactivate the expression of genes that encode cytokines, cytokine receptors, and costimulatory molecules  This inappropriate gene expression leads to autocrine signaling loops and increased activation of pro-mitogenic signaling cascades  directly binding to and activating cyclins  TAX can repress the function of several tumor suppressor genes that control the cell cycle, including CDKN2A/p16 and p53

infection with HPV itself is not sufficient for carcinogenesis with a mutated RAS gene results in full malignant transformation

 t(8 ; 14), leading to activation of the MYC gene, is a major feature of this viruse. > emerge of lymphoma cells  Activation of MYC lead to down –regulation of LMP- 1 > evasion occurs.  Especially in non-endemic areas ( 80%)> no EBV genome but occur through this mechanism.  the B lymphoblasts in immunosuppressed patients do express viral antigens, such as LMP-1, that are recognized by T cells ( contrast to burkitt )  Nasopharyngeal carcinoma the EBV genome is found in all tumors. LMP-1 is expressed in epithelial cells as well

 Between 70% and 85% of hepatocellular carcinomas worldwide are due to infection with HBV or HCV  The oncogenic effects of HBV and HCV are multifactorial, but the dominant effect seems to be immunologically mediated chronic inflammation, hepatocellular injury, stimulation of hepatocyte proliferation, and production of reactive oxygen species that can damage DNA( by activated immune cells)  The HBx protein of HBV and the HCV core protein can activate a variety of signal transduction pathways that may also contribute to carcinogenesis. May act directly or indirectly.

 H. pylori infection has been implicated in both gastric adenocarcinoma and MALT lymphoma.  The mechanism of H. pylori-induced gastric cancers is multifactorial, including immunologically mediated chronic inflammation, stimulation of gastric cell proliferation, and production of reactive oxygen species that damage DNA.  H. pylori pathogenicity genes, such as CagA, may also contribute by stimulating growth factor pathways.  It is thought that H. pylori infection leads to polyclonal B-cell proliferations and that eventually a monoclonal B-cell tumor (MALT lymphoma) emerges as a result of accumulation of mutations.

 Parasites › Schistosoma hematobium  Squamous cell carcinoma of the urinary bladder