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New Roman(0(:A 0 @DWingdingsRoman(0(:A 0 PDArial Narrowan(0(:A 0 "`DSymbolarrowan(0(:A 0 pDArialarrowan(0(:A 0 G.i  @n?" dd@  @@`` --x(4j           c  G             '                l      / 2   [`abcdefghijkn $R$IsGOtv=$$$$$$$$$$$$$R$w 0.m6N, :0e0e    A A      ?1 d0u0@Ty2 NP'p<'pA)BCD|E|| f߈f@8nW <4ddddl # 0g4LdLd@:A 0ppp@ ʚ;Sk8ʚ;<4!d!dlT# 0X<4ddddlT# 0X0___PPT10 ___PPT9v/ 0Z? %O =r!Cancer and Detoxification Defects"" Cancer Suppressors and PromotersProto-oncogenes: functional genes actively involved in normal cell proliferation and differentiation Oncogenes: transformed genes that promote uncontrolled cell growth and proliferation Tumor Suppressor Genes Gatekeeper genes: prevent a cell s entry into the division cycle until conditions are appropriate Caretaker genes: maintain the integrity of the cell s genomePdPfU fKfQ-, V Double Hit TheoryFor cancer to develop, an oncogene must mutate so as to be jammed  on and a tumor suppressor gene must mutate so as to be jammed  off f<TP53:  Guardian of the Genome TP53 is a tumor suppressor gene that codes for the protein p53 which acts to begin the process of apoptosis, or cell suicide, in cells whose DNA has been irreparably damaged TP53 is the last line of defense against malignancy In more than half of all human cancers, TP53 is brokenRadiation and Chemotherapy.Doctors used to believe that radiation and chemotherapy acted by preferentially killing the most rapidly dividing cells But if this is the case why are many rapidly dividing cancers resistant to therapy, and more perplexing, why do tumors become resistant to the effects of radiation and chemotherapy /Z/Radiation and ChemotherapyRather than killing cancer cells directly, perhaps radiation and chemotherapy act by damaging cellular DNA sufficiently to cause TP53 to start producing p53 When tumors relapse after therapy, the change correlates closely with knockout mutations to TP53 The most intractable tumors  lung, bladder, melanoma, colorectal, and prostate  are ones in which TP53 is already mutatedzZzRadiation and ChemotherapyInstead of looking for agents that kill dividing cells, perhaps researchers should have been looking for agents that promote apoptosis This is not to say that chemotherapy has been wholly ineffective in treating cancer, only that its effectiveness has been largely accidental*TP53 and Evolution: The Kamikaze ConundrumGenes like TP53 that code for apoptosis by definition cannot be passed on to daughter cells since once engaged, the cell is dead Not all evolution, of course, happens at the level of individual genes Natural selection is still operating at the level of the whole individual organism DNA MethylationFolate deficiency induces DNA strand breaks and hypomethylation in the p53, tumor suppressor gene Folate deficiency appears to enhance carcinogenesis Even marginal dietary folic acid deficiency (<300mg/d) may alter DNA composition*0Health Risks and ExposureTwo critical components to evaluating health risks from exposure to environmental and occupational agents: 1. Hazard identification 2. 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Cancer therapy and p53. Curr Opin Oncol 1995 Nov;7(6):547-53. Wallace-Brodeur RR, Lowe SW. Clinical implications of p53 mutations. Cell Mol Life Sci 1999 Jan;55(1):64-75. `i!^b! EH $ 0޽h ? z33~v___PPT10V..&Z+[W_D' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D8' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*$%(D' =-g6B fade*<3<*$D' =%(D' =%(D8' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*$%(D' =-g6B fade*<3<*$+8+0+$ +  -K0 `((  (x ( c $lm`   m x ( c $\mP`  m p ( Tm?``d RLeGrand EK. An adaptationist view of apoptosis. Q Rev Biol 1997 Jun;72(2):135-47. @Si0 6 H ( 0޽h ? z33___PPT10i.w+D=' = @B +  -K0 p,8(  ,x , c $p;m`   m x , c $+B#style.visibility<*0%(D' =+4 8?RCBBCB#ppt_wB*Y3>B ppt_w<*0D' =+4 8?\CB#ppt_hBCB#ppt_hB*Y3>B ppt_h<*0+8+0+0 +  -K0 4:(  4x 4 c $m`   m x 4 c $mP` m  4 TЌm? H ~Taioli E, Zocchetti C, Garte S. Models of interaction between metabolic genes and environmental exposure in cancer susceptibility. 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