carcinogénesis química etapas

Species susceptibilities to chemical carcinogenes: a critical appraisal of the roles of genetic and viral agents. Mol Cell Biol 19: 1673-1685. Curr Cancer Drug Targets 5: 249-266. BUTTERWORTH BE, POPP JA, CONOLLY RB AND GOLDSWORTHY TL. Genotoxic carcinogens are complete carcinogens and qualitatively and quantitatively change a cell's genetic information (Trosko 2001). Todo el contenido de iLive se revisa médicamente o se verifica para asegurar la mayor precisión posible. The tumour suppressor proteins p53; p21 and pRb play crucial roles in cellular protection, because they encourage the blocking of cells at G1 (Khan et al. p53R2 is induced by p53 and p73, while R2 synthesis occurs during S phase. Charlotte Auerbach and chemical mutagenesis. Oncol Rep 6: 925-932. BARRET JC AND WISEMAN RW. 2000. LUCH A. 2003, Dixon and Kopras 2004). The constituent cells of a malign neoplasia show yet more changes in cell biology (Fig. Genetic errors, cell proliferation, and carcinogenesis. The previously described metabolic methods are equally important for both humans and animals, although there exist qualitative and quantitative differences between them. These can stretch from 5 to 7 years if we take into account the posterior analysis of the results obtained via the different methods (Tennant et al. Chronic inflammation and cancer. Neste último caso pode pensar-se num efeito indirecto do No entanto, as células em proliferação têm Mol Aspects Med 21: 167-223. primeira e na última etapa deste processo, ou seja, na iniciação e na progressão, ocorrem A iniciação favorece a divisão celular simétrica, Mol Carcinog 30: 131-137. Q Carcinogenesis 21: 1611-1618. Animal models deficient in p53 protein and ras genes are more sensitive to the identification of genotoxic carcinogens (Sills et al. Carcinogenesis 21: 345-351. Apoptose Relative potency of chemical carcinogens in rodents. Environ Health Perspect 61: 69-96. %�� Environ Health Perspect 104S: 1101-1104. A angiogénese, como acontecimento epigenético, é fundamental durante a IARC Sci Publ 147: 15-32. VOGELSTEIN B AND KINZLER KW. La alteración de cualquiera de estos tres procesos puede iniciar el proceso de la carcinogénesis. J Nutr 29: 552S-555S. This classification is based on their involvement in maintaining genome integrity and DNA repair, respectively (Lai and Shields 1999). Os estudos realizados em modelos animais, em ensaios in vitro e em estudos a dose aumenta a incidência, a multiplicidade das neoplasias e diminui o período de The acquisition of the capacity to survive and grow independently from other cells represents a crucial event in the mechanism of cancer development. Nat Rev Mol Cell Biol 1: 233-236. Chemical carcinogenesis is a multistage and multicausal process in which normal cells become first initiated, then malignant and invasive. The loss of p53 function activates proto-oncogenes and inactivates tumour suppressor genes therefore performing an exceptional role in chemical carcinogenesis (Luch 2005). 1992, Lutz 1998, Camargo et al. La respuesta tóxica del tejido sanguíneo. Bras. 1992, Cohen and Lawson 1995). Cancer chemoprevention and apoptosis mechanisms induced by dietary polyphenolics. Thus it is best to think of mutated cancer genes as contributing to, rather than causing, cancer (Vogelstein and Kinzler 2004). ¿Qué estudia la carcinogénesis? HAYSES JD AND PULFORD DJ. 1998. La última de estas etapas, progresión, es exclusiva de la transformación maligna e implica la capacidad de invadir tejidos vecinos o a distancia. They do not react directly with DNA, do not raise adducts and show negative on mutagenicity tests carried out in vivo and in vitro (Butterworth et al. Carcinogenesis is a complex multistep process. 2000. Several experiments have proved that chemical compounds, which create ROS in excess, encourage initiation, promotion and neoplasic progression through genotoxicity (Galati et al 2000, Shacter and Weitzman 2002). Several studies have been developed in order toevaluate the differences between several exogenous and endogenous factors on individual susceptibility to carcinogenesis (Table I) (Barrett 1993, Bartsch and Hietanen 1996, Maronpot 1996, Lutz 1998, 1999, Ishikawa et al. Only in some cases, such as with tobacco smoke, does the epidemiological evidence of cause and effect be held beyond any doubt (Gutiérrez and Salsamendi 2001). Bolt et al. Methods, and the apparent persistence of initiated cells. Drug Metab Rev 30: 339-357. Mol Cell Biol 19: 12-20. Mechanisms for the initiation and promotion of carcinogenesis: a review and a new concept. 2000, Williams 2001). A true threshold dose in chemical carcinogenesis cannot be defined for a population, irrespective of the mode of action. Mutat Res 405: 117-124. Role of urinary physiology and chemistry in bladder carcinogenesis. The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development (King et al. GOLKA K, KOPPS S AND MYSLAK ZW. 2000). 2001. Gutiérrez e Salsamendi, 2001; Pitot, 2001). La transformación es el resultado de la interacción de una célula normal con un agente transformante (carcinógeno). percorrido pelas células seja sempre o mesmo (Lutz, 2000; Guttiérrez e Salsamendi, Quuíímmiiccooss. Epidemiological techniques have been useful for identifying exposure to high carcinogenic concentrations. 1998, Mostafa et al. 2001. ANZ J Surg 73: 680-686. In addition, mutated genes can influence the nature of neoplasia that is developed, increasing the difficulty of measuring the response in humans (Pritchard et al. Br J Cancer 38: 1-23. Is there a causal connection? It can be done via the excision of bases, or nucleotides, recombined repair or mismatch repair (Farmer 1994, Moustacchi 1998, Miller et al. Errors in DNA replication are also associated with initiation. De hecho, representa más del 80% de los casos diagnosticados. Mutagenesis 13: 405-408. tecidos (Potter, 1978; Simons, 1999; Williams, 2001; Player et al., 2004). 1992, Butterworth and Bogdanffy 1999). The initiated cell is not a neoplasic cell but has taken its first step towards this state, after successive genotypical and phenotypical changes have occurred (Trosko 2003). (1996) states that exposure to these compounds favours the synthesis of other substances responsible for neoplasic development. 1984 The detection of environmental mutagens and potential carcinogens. Melnick et al. MOSTAFA MH, SHEWEITA SA AND O'CONNOR PJ. 2005. 2003. FOULDS L. 1954. Demethylation of promoter regions at the CpG sequences can lead to an over-expression of proto-oncogenes, and silencing ofgene expression can occur as a result of hypermethylation, sometimes leading to chromosome condensation (Klaunig et al. A expansão clonal das células HARTWING A, ASMUSS M, EHLEBEN I, HERZER U, KOSTELAC D, PELZER A, SCHWERDTLE T AND BURKLE A. 2000, Oesch et al. En términos generales, la carcinogénesis se considera hasta la fecha como resultado de la interrupción de la homeostasis celular, que se expresa en una pérdida de control sobre la reproducción y para mejorar los mecanismos de defensa celular de la acción de las señales de apoptosis, es decir, la muerte celular programada. TOTH B. 1992; Weisburger, 1999; Williams, 2001). YANG M AND SCHLUETER R. 2005. At first, these occurrences were associated with epigenetic mechanisms, but nowadays it is widely agreed that promotion also involves genetic changes (Simons 1995, Hanahan and Weinberg 2000). Regul Toxicol Pharmacol 29: 23-36. Mutat Res 424: 237-247. Se conocen tres fases de la carcinogénesis: iniciación, promoción y progresión. Each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. DIXON K AND KOPRAS E. 2004. The role of interindividual variation in human carcinogenesis. 2000). tem de possuir potencial proliferativo e sofrer mutações nos genes que regulam a sua 2013 carcinogénesis 1. The extrapolation of results obtained via experimental work with rodents is contested by the following arguments (Gaylor and Chen 1986, Huff 1992, Tennant et al. Cancer Lett 93: 9-16. 2000). Implications for risk assessment of suggested non-genotoxic mechanisms of chemical carcinogenesis. The discovery of the ability of oncogenes to induce neoplasic transformation when transfected into immortalized mouse cell lines, initially seemed to answer many basic molecular questions about the molecular origins of cancer. 2004. It then converts it into a powerful electrophilic product capable of establishing adducts with DNA (Straub and Burlingame 1981, Lai and Shields 1999, Galati et al. Afectan el estado de las membranas celulares que tienen receptores específicos para promotores, en particular, activan la proteína quinasa de membrana, afectan la diferenciación celular y bloquean los enlaces célula-célula. The role of DNA adducts in chemical carcinogenesis. Genotoxicity in the rodent urinary bladder. BONDY M. 2004. Other authors classify chemical carcinogens in function of their mechanisms of action as being genotoxic and non-genotoxic (mitogenic and cytogenic)(Cohen and Ellwein 1991, Butterworth et al. SCOTT RE, WILLE Jr JJ AND WIER ML. HWANG BJ, FORD JM, HANAWALT PC AND CHU G. 1999. Palavras-chave: etapas da carcinogênese, avaliação de carcinogeneicidade, carcinogênicos químicos, carcinogênese química. Arch Biochem Biophys 417: 3-11. Initiation and promotion at different ages and doses in 2200 mice. WANG TC, CHIOU CM AND CHANG YL. celular menos controlado e com maior potencial metastático. The detection of chemical carcinogens in an alternative medium-term bioassay. DEWHIRST MW, LORA-MICHIELS M, VIGLIANTI BL, DEWEY WC AND REPACHOLI M. 2003. Proc Natl Acad Sci USA 99: 12985-12990. (Santala et al., 2005). Carcinogenicity of azo colorants: influence of solubility and bioavailability. 2000. Ahora se ha establecido que el cáncer o el cáncer - una enfermedad del aparato genético de la célula, que se caracteriza por procesos patológicos crónicos a largo plazo, o más simplemente, la carcinogénesis, que se desarrollan en el cuerpo durante décadas. 1991, Barrett and Anderson 1993, Huff 1994, Koivusalo et al. Environmental risk factors for gastric cancer: the toxicologist's standpoint. histopatologia por lesões pré-neoplásicas e/ou neoplasias benignas (Gutiérrez e Genetic alterations and DNA repair in human carcinogenesis. Environ Health Perspect 76: 65-70. Mutat Res 33: 25-26. 1984. La pirólisis es un caso especial de termólisis. Nem todas as células expostas a agentes Toxicol Pathol 28: 382-387. Mutat Res 402: 67-75. In 1890, a high incidence of bladder cancer in chemical and rubber industry workers was observed across Europe. ROJAS M, CASCORBI I, ALEXANDROV K, KRIEK E, AUBURTIN G, MAYER L, KOOP-SCHNEIDER A, ROOTS I AND BARTSCH H. 2000. proliferação, mas não a diferenciação (Trosko, 2001). Environ Health Perspect 104: 123-134. Studies conducted using animal models, "in vitro" studies and epidemiologic assays enabled investigators to conclude that neoplasic pathogenesis is a complex process which can be divided into three distinct stages, from an operational point of view. NGUYEN-BA G AND VASSEUR P. 1999. Those carcinogenic compounds classified as direct act directly on DNA, but most require enzymatic conversion and are thus labelled as indirect or procarcinogens (Sarasin and Meunier-Rotival 1976, Hayes 1995, Lai and Shields 1999, Klaunig et al. La respuesta tóxica del riñon. Durante la fase de iniciación, el carcinógeno o su metabolito activo interactúa con los ácidos nucleicos (ADN y ARN) y las proteínas. The computational prediction of toxicity. If the damage reaches a gene responsible for neoplasic development then the probability of developing cancer will be greater (Cohen 1995). alterações na estrutura do genoma (Simons, 1995; Pitot, 2001). 2005). XU J AND MORRIS GF. Results obtained from these studies permit the identification of the harmful carcinogenic compounds in the absence of real and credible human references and protect the public health (Huff 1992). Neoplasias can be classified as benign or maligndepending on their cellular characteristics. The search for critical genes regulated by p53 led to the discovery of the p21 gene. 1995. The most prominent and best-studied tumour suppressor is p53, if DNA is damaged then p53 can induce apoptosis in order to maintain the stability of the cells' genome (Klaunig et al. FROWEIN J. Toxicol Lett 120: 269-280. Cancer Res 14: 327-339. La carcinogénesis consta de tres etapas: iniciación, promoción y progresión. Prog Clin Biol Res 374: 213-229. Food Chem Toxicol 39: 739-744. - Describe las etapas de síntesis y degradación de lo ácidos grasos relacionando los principales tejidos. TEORIA DEL CAMPO DEL CANCER. 2000, Park et al. que por fim origina uma neoplasia maligna (Trosko, 2001). 2004. HANAHAN D AND WEINBERG RA. Mutat Res 433: 15-22. Carcinogenesis 13: 727-729. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence. 2001, Shacter and Weitzman 2002). Clin Chem 40: 1438-1443. 6) (Khan et al. In progression, a neoplasic phenotype is acquired through genetic and epigenetic mechanisms (Shacter and Weitzman 2002). By the end of the 1960s, increasing evidence pointed to a correlation between the DNA binding capacity of a particular carcinogen and its biologicalpotency (Luch 2005). The chick embryo chorioallantoic membrane as a model system for the study of tumor angiogenesis, invasion and development of anti-angiogenic agents. La respuesta LOCK EA, REED CJ, MCMILLAN JM, OATIS JE Jr AND SCHNELLMANN RG. Salsamendi, 2001). Mutat Res 402: 331-337. reparação enzimática (Bertram, 2000). According to Pritchard et al. Durante la promoción, la célula iniciada adquiere propiedades fenotípicas de la célula transformada como resultado de la expresión génica alterada (mecanismo epigenético). Wild CP, GARNER RC, MONTESANO R AND TURSI F. 1986. iniciadas resulta de um processo mitogénico que aumenta o número de células novas e SHARMA RA AND FARMER PB. etapas da carcinogênese; avaliação de carcinogeneicidade; carcinogênicos químicos; carcinogênese química, Paula A. OliveiraI; Aura ColaçoI; Raquel ChavesII; Henrique Guedes-PintoII; Luis F. De-La-Cruz P.III; Carlos LopesIV,V, IDepartment of Veterinary Sciences, CECAV, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal, IICenter of Genetics and Biotechnology-CGB, University of Trás-os-Montes and Alto Douro (UTAD), Department of Genetics and Biotechnology, 5000-801 Vila Real, Portugal, IIIDeparment of Physiology, Faculty of Veterinary, Santiago University, Granxa Street, Campus Universitario, 27002 Lugo, Spain, IVDepartment of Pathology, Portuguese Institute of Oncology, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal, VDepartament of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Largo Professor Abel Salazar, 2, 4099-003 Porto, Portugal. Clin Adv Hematol Oncol 2: 147-151. 1998. oncogenes - genes que se activan en los tumores, causando una mayor proliferación y reproducción y la supresión de la muerte celular; los oncogenes exhiben propiedades transformantes en experimentos de transfección; los oncogenes no mutados actúan en las etapas clave de los procesos de proliferación, diferenciación y muerte celular programada, estando bajo el control de los sistemas de señal del cuerpo; el daño genético (mutaciones) en los oncogenes conduce a la liberación de la célula de las influencias reguladoras externas, que subyace en su división incontrolada; la mutación en un oncogén casi siempre se compensa, por lo tanto, el proceso de transformación maligna requiere trastornos combinados en varios oncogenes. e) The protective effects of the organism, metabolic detoxification, and DNA repair cannot be taken into account once they are overwhelmed by exposure to high doses. Further delineation of the rate limiting step. 1988. 2001). Para la inducción del tumor, es necesaria una acción prolongada y relativamente continua del promotor. 2004. El Diccionario de Cáncer del NCI define términos y frases de cáncer y medicina que son fáciles de entender. Laser capture microdissection, microarrays and the precise definition of a cancer cell. Chem Res Toxicol 18: 1071-1080. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. 1999). Contenidos del Módulo 3: 3.1. Carcinogen adducts: use in diagnosis and risk assessment. The performance of metabolic enzymes is essential for understanding chemical carcinogenesis and learning the differences between species as far as their susceptibility to neoplasic development is concerned (Sarasinand Meunier-Rotival 1976, Lai and Shields 1999, Guenguerish 2000, 2001, Gonzalez 2001). Environ Health Perspect 111: 444-454. Toxicol Lett 43: 189-200. Lea atentamente las reglas y políticas del sitio. La carcinogénesis es una enfermedad genética multifactorial de múltiples etapas. entre a mutação e a selecção clonal. They rubbed rabbit ears with coal tar and observed the development of papillomas and carcinomas. Organ specificity and tumor promotion. Carcinogenesis 7: 247-251. Acad. Bqco. The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis. Se Not all cells exposed to promoters take part in the promotion stage, only cells which are stimulated to divide, that are undifferentiated, and have survived apoptosis, can contribute to instability between growth and cell death and lead to the appearance of a malign neoplasia (Trosko 2001). Prediction of Rodent Carcinogenicity for 30 Chemicals. Carcinogenicity categorization of chemicals-new aspects to be considered in a European perspective. é idêntica às restantes células, no entanto sofreu mutações que favorecem a sua The clonal expansion of initiated cells results from amitogenic process caused by an increase in the number of new cells and apoptosis inhibition, which prevents initiated cells from dying off (Trosko 2001). WEISBURGER JH. Facts and theories concerning the mechanisms of carcinogenesis. Promotion is a reversible stage, after a promoter's disappearance a regression in cell proliferation can occur, probably by apoptosis. Med Lav 86: 206-213. Mutagénesis. 1991. 2000, Poirier et al. 1992. 1995, Haseman et al. 1984, Cohen 1991, Mehta 1995, Hasegawa et al. Later, Beremblum and Shubik used polycyclic aromatic hydrocarbons and croton oil to study skin carcinogenesis in mice and demonstrate that cancer development includes several stages (Beremblum and Shubik 1947). 2003. Cancer genes and the pathways they control. In 1978, Potter explained that neoplasic cells could display a phenotype established between the embryonic aspect and the terminal differentiation, and that all neoplasic cells had monoclonal origin from a stem cell. Revista de Investigación Clínica / Vol. Neoplasic development bases itself on the existence of several genetic mutations, despite the number not being known. epidemiológicos permitiram concluir que o desenvolvimento neoplásico decorre através During this phase the cytochrome P450 mono-oxygenases introduces a reactive polar group into the carcinogenic, making it lipophylic. Os compostos promotores não interagem directamente com o ADN e para aditivo, o desenvolvimento neoplásico depende da dose do carcinogénico, aumentando Un oncogén puede activarse por mutación con una sustancia química «iniciadora» para formar tumores benignos, que a su vez pueden degenerar en cáncer bajo la acción de una sustancia «promotora». Crit Rev Biochem Mol Biol 30: 445-600. La carcinogénesis es un proceso complejo de múltiples pasos. Chemoprevention of gastrointestinal malignancies. These radicals are associated with several chronic diseases including chemical carcinogenesis (Klaunig et al. The role of croton oil applications, associated with a single painting of a carcinogen, in tumor induction of the mouse's skin. 2000). The more that nearby cells increase the number of cell divisions through regenerative procedures, the more likely it is that they will end up being prematurely recruited for the cell cycle and that the time available for reparation DNA will be inferior - this increases the probability of mutations occurring (Cohen 1991, Melnick et al. 2004). EPIGENETIC MECHANISMS INVOLVED IN CHEMICAL CARCINOGENESIS. La primera etapa del proceso de la carcinogénesis, absolutamente preclínico y en una primera etapa aún no canceroso (precanceroso) consta de tres etapas principales: 2.1 Iniciación 2.2 Promoción 2.3 Progresión ‹ 1. Chemical basis of inflammation-induced carcinogenesis. 2005). mutações e de erros na replicação do ADN. The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development. Carcinogenesis 21: 35-41. 6 / Noviembre-Diciembre, 2010 / pp 585-605 Primer Consenso Mexicano de This antagonism may be exemplified by the protective action of fruit and vegetables in the modulation of individual susceptibility to neoplasic development (Lutz 2001, 2002). vivos. tempo para se manifestar clinicamente. After cardiovascular diseases, it is the second cause of death amongst the global population (Huff 1994, Weisburger 1999). Metabolism of carcinogenic amino derivatives in various species and DNA alkylation by their metabolites. 2000. These authors felt that the carcinogenic action of these substances was responsible for converting normal cells into neoplasic cells. 1984, Gutiérrez and Salsamendi 2001). The factors responsible for cancer development are classified as exogenous and endogenous (Camargo et al. 1998. Cell proliferation and carcinogenesis. LUTZ WK. GONZALEZ FJ AND KIMURA S. 2001. En ella se implican tres procesos fundamentales para la célula: metabolismo, reparación del ADN y proliferación celular. QU W, BORTNER CD, SAKURAI T, HOBSON MJ AND WAALKES MP. During cell division, spontaneous genetic errors occur. Dose-response relationships in chemical carcinogenesis: superposition of different mechanismsof action, resulting in linear-nonlinear curves, practical thresholds, J-shapes. Ensaios experimentais comanimais de laboratório, estudos epidemiológicos e alguns testes rápidos permitem identificar compostos carcinogênicos, analisar os eventos envolvidos na carcinogênese e estabelecer estratégias para prevenir a exposição a estes agentes. Acquisition of apoptotic resistance in arsenic-induced malignant transformation: role of the JNK signal transduction pathway. Mutations in the caretakergenes, which are considered to be typical tumour suppressors, compromise genome stability and, more specifically, increase the probability of mutation in the gatekeepers which include both tumours suppressor genes and oncogenes (Vogelstein and Kinzler 2004, Blagosklonny 2005). 2000. 2001. 2000. 2003, 2005). TENNANT RW, FRENCH JE AND SPALDING JW. 2003. Os resultados obtidos a partir de distintos trabalhos Nature 386: 761-763. Dev Biol (Basel) 106: 53-57. PITOT HC. • Las anomalías pueden ser hereditarias o por carcinógenos etiológicos. Some scientists have questioned whether cells in culture maintain their bioactivation and detoxification mechanisms (Masters 2000, Gutiérrez and Salsamendi 2001). 1992, Klaunig et al. 1983, Butterworth et al. Genetically altered mouse models for identifying carcinogens. Endogenous factors include immune system damage and inflammation caused by uncertain aetiology (e.g. 1978. Spontaneously initiated cells exist in all living organisms (Gomes-Carneiro et al. J Natl Cancer Inst 94: 1888-1891. Cell 100: 57-70. It is not easy to incorporate a carcinogenic compound into a certain group because the information obtained from different studies is increasingly complex (Pitot andDragan 1991, Butterworth et al. 2001. (4), Stay informed of issues for this journal through your RSS reader, Resumo . Cell division is controlled by stimulatory and inhibitory systems.The origin of cancer is monoclonal, and in order that a normal cell switches its phenotype and becomes a neoplastic cell, genetic. 1992. (284,251.2344 MJ*h-1), a diferencia de las otras etapas del proceso The formation of adducts constitutes the first critical step of carcinogenesis and if these are not repaired before DNA replication then mutations may occur in the proto-oncogenes and tumour suppressor genes, which are essential for the initiation stage (Sobels 1975, Barrett and Wiseman 1987, Farmer 1994, Lutz 2001, Williams 2001, Li et al. The role of individual susceptibility in cancer burden related to environmental exposure. experimentais permitiram concluir que esta etapa resulta de alterações genéticas Esta fase de la carcinogénesis, a diferencia de la etapa de iniciación, es reversible, al menos en una etapa temprana del proceso neoplásico. Vías de exposición La acción del tóxico es más rápida mientras tenga un acceso veloz al torrente sanguíneo. c) The latency period between initial exposure and cancer development. Teratogénesis. 1996, Trosko 2001). COHEN SM. TAN T AND CHU G. 2002. p53 Binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice. Almacenamiento de triacilglicerol. c) The doses are too high and may cause a proliferative response in normal cells. TROSKO JE. 2006. 12 0 obj irreversíveis e predispõe a célula normal à evolução maligna e à imortalidade Functional characterization of global genomic DNA repair and its implications for cancer. 1990, Pitot and Dragan 1991). Na progressão, a proliferação Grant support for this study was provide by Fundação para a Ciência e Tecnologia, Ministério da Ciência e Ensino Superior, Portugal (number 12453/2003). Es un hecho que las manifestaciones agudas, principalmente cutáneas, conjuntivales y respiratorias, resultado de la exposición a los contaminantes atmosféricos, son las que más atraen la atención; los efectos a mediano y largo plazos son los más peligrosos, y por lo mismo son los que requieren una atención permanente. Cytotoxic assessment of three therapeutic agents, cyclosporine-A, cisplatin and doxorubicin, with the ciliated protozoan Tetrahymena pyriformis. R. Huebner y Todaro G. (R. Huebner y G.Todaro), que sugirió que el aparato genético de células cada uno genes normales están presentes en función de activación prematura o aparejo que puede ser una célula normal convertirse en un canceroso. 3.3. 2000, Trosko 2001). iniciador serão iniciadas, mesmo que tenham sofrido mutações, porque a célula iniciada ROBBINS D AND COTRAN R. 2005. Fase tóxicodinámica. Alterations in the ras gene have been identified in several neoplasias that have been chemically induced in rodents. Clin Cancer Res 10: 4901-4912. [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. E-mail: The ROS damage DNA, RNA, and proteins by chemical reactions such as oxidation, nitration/nitrosation and halogenation. 1999, Guengerich 2001, van Leeuwen and Zonneveld 2001, Oda 2004). Toxicol Pathol 24: 726-731. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. 1999). Cancer Res 12: 547-556. So, our work starts with a historical perspective of the study of chemical carcinogenesis; we will describe the different stages involved in carcinogenesis; the absorption and metabolism of chemical carcinogens. Nat Genet 26: 375-378. Statistical analysis is used to evaluate if the neoplasic incidence is significantly different from the control group (Ito et al. La pirólisis extrema, que sólo deja carbono como residuo, se llama carbonización. 2001). Statistical learning methods have recently been explored as a new approach for genotoxicity prediction without any restrictions on the features of structures or types of molecules. Oncology 6: 217-226. Os fatores epigenéticos, também considerados como caracteres não genéticos, podem contribuir para a carcinogênese por mecanismos de silenciamento gênico. Predictive toxicology: benchmarking molecular descriptors and statistical methods. On the other hand, the individual's susceptibility and their defence mechanisms have their own interaction, which modifies each of the neoplasic stages. A acumulação de danos no ADN tem particular importância nas células Br J Cancer 1: 379-382. In 1970, a number of laboratory tests were developed to evaluate the mutagenic power of different chemical compounds, with the Ames test gaining particular distinction. 1995, Maronpot and Boorman 1996). The synergy between smoking and exposure to asbestos favours lung cancer development as a consequence of chronic inflammation and compensatory cell proliferation. Las reacciones más comunes en la carcinogénesis, esenciales para la aparición y el desarrollo de un tumor son cambios en el nivel y la relación de aminas biogénicas en el sistema nervioso central, particularmente el hipotálamo, que afectan, entre otras cosas, de la mejora mediada por la hormona de la proliferación celular, y trastornos de hidratos de carbono y grasa intercambio, cambios en la función de varias partes del sistema inmune. KOIVUSALO M, JAAKKOLA JJ, VARTIAINEN T, HAKULINEN T, KARJALAINEN S, PUKKALA E AND TUOMISTO J. A carcinogênese química inclui três etapas definidas como iniciação, promoção e progressão. FENG J, LURATI L, OUYANG H, ROBINSON T, WANG Y, YUAN S AND YOUNG SS. Relationship between schistosomiasis and bladder cancer. et al., 1992; Klaunig et al., 2000; Dixon e Kopras, 2004). The role of stem cells and gap junctional intercellular communication in carcinogenesis. 2006) (Figura 1.1). La carcinogénesis de vejiga urinaria en los roedores de urotelial tumors chemically induced in the urinary bladder laboratorio es un proceso que envuelve una serie de etapas are morphologically and histologically similar to the human MOUSTACCHI E. 1998. Prácticamente cada tumor contiene mutaciones tanto en la forma anti-tumorigénico de las deleciones y micromutaciones, en el que los genes supresores de daño de inactivación son mucho más común que la activación de mutaciones en oncogenes. GAYLOR DW AND CHEN JJ. Some models have mutations in the ras proto-oncogenes and in the p53-suppressor gene (Sills et al. Environ Health Perspect 106: 473-476. CARCINOGENESIS QUÍMICA EN LA PIEL También los agentes químicos y ambientales se han señalado como sospechosos de ejercer una acción cancerígena, tal los subproductos de la combustión del tabaco. BERTRAM JS. 2000, Gonzalez and Kimura 2001, vanLeeuwen and Zonneveld 2001). A iniciação é um fenómeno rápido, irreversível e hereditário. Some years later, and based on these observations, a guide distributed to Danish chimney sweeps recommended that these professionals take a daily bath to avoid such an occurrence (Hayes 1995, Gutiérrez and Salsamendi 2001). Rodent bladder tumors do not always predict for humans. No grupo das alterações genéticas incluem-se mutações nos genes que controlam a proliferação celular, a morte celular e a reparação do DNA - i.e. However, substances such as nitrosamines and beryllium do not strongly correspond to their results in the Ames test (Gonzalez 2001, Payne and Kemp 2003). FRIEDBERG EC. Nature 421: 436-440. Phenotypic diversity in experimental hepatomas: the concept of partially blocked ontogeny. 2. The order of exposition to these substances was fundamental for carcinogenesis. 1999. Pharmacokinetics, biochemical mechanism and mutation accumulation: a comprehensive model of chemical carcinogenesis. CHAO EC AND LIPKIN SM. Embora a iniciação espontânea seja mais rara do que a induzida A complete carcinogen displays properties of both initiators and promoters simultaneously depending on the dosage and exposure time (Pitot and Dragan 1991, Farmer 1994, Hasegawa et al. IARC Sci Publ 116: 353-388. f) Synergic effects are not taken into account with other chemical compounds. The potential for the use of cell proliferation and oncogene expression as intermediate markers during liver carcinogenesis. Correlation of DNA adduct levels with tumor incidence: carcinogenic potency of DNA adducts. Strategies for inhibiting multistage carcinogenesis based on signal transduction pathways. 1992). HUFF J. No entendimento da pesquisadora, é necessária uma maior discussão para correção e alinhamento das sugestões, Caracterização experimental do urotélio do rato, Absorção e vias metabólicas dos compostos carcinogénicos, Classificação dos compostos carcinogénicos, Variação do peso corporal, consumo de comida e de água. Sanner, 1999; Player et al., 2004). Actualmente, la carcinogénesis química se considera como un proceso mul- tiestadio con desarrollo generalmente lento, que se inicia con la primera exposi- ción al agente causal, a la que sucede un cierto periodo de latencia de duración variable, que desemboca en la manifestación clínica del tumor. É necessário mais do que MELNICK RL, KOHN MC AND PORTIER CJ. KING C, WANG C, GORELICK N AND FREDERICK C. 1995. They have enabled us to understand diseases, to discover etiological factors and to test many treatments (Maronpot and Boorman 1996). Cancer Res 51: 6493-6505. Progression is characterised by irreversibility, genetic instability, faster growth, invasion, metastization, and changes in the biochemical, metabolical and morphological characteristics of cells (Pitot and Dragan 1991, Butterworth et al. Nat Rev Cancer 5: 113-125. 1999, Tennant et al. Adv Cancer Res 50: 25-70. Depende. 1993. COHEN SM, GARLAND EM AND ELLWEIN LB. d) Through genetic modification, it is possible to identify those mechanisms associated with neoplasic development. (2004) propose the division of genotoxic compoundsinto two groups: those which react with DNA, and genotoxic at a chromosomal level. 2004). MILLER 3RD MC, MOHRENWEISER HW AND BELL DA. BONNET JL, DUSSER M, BOHATIER J AND LAFFOSSE J. hMSH2 functions in mismatch recognition and binds mismatched bases (Lamers et al. TENNANT RW, STASIEWICZ S, MENNEAR J, FRENCH JE AND SPALDING JW. Between 70 and 90% of known chemical carcinogens show positive results on the Ames test. proliferação celular ocorrem em taxas diferentes, mas mantêm-se em equilíbrio; na Key words: cancer stages, carcinogenesis evaluation, chemical carcinogens, chemical carcinogenesis. MILLER JA AND MILLER EC. Hoy hablaremos los carcinógenos químicos y las etapas necesarias para que una sustancia química de origen a una neoplasia. Yet, when mixed and in equal doses, they induced neoplasic development. Carcinogénesis de la primera etapa - la etapa de transformación (iniciación) - el proceso de transformación de una célula normal en un tumor (canceroso). The capacity of cells to evade the cellular defence mechanism has an undoubted contribution towards the carcinogenesis (Khan and Dipple 2000). The crystal structure of DNA mismatch repair protein MutS binding to a G × T mismatch. BLAGOSKLONNY MV. Se caracteriza por dos etapas sucesivas: iniciación y promoción. ABSORPTION AND METABOLISM OF CHEMICAL CARCINOGENS. La carcinogénesis consta de tres etapas: iniciación, promoción y progresión. Genetic susceptibility and occupational cancer. The caretakers are responsible for maintenance of genome stability. CANCRO In most of the cases it is assumed to vary between tissues and between different species (Grisham et al. These assay groups of males and females, of mice and rats, are exposed to two or three doses of the agent being tested while a non-exposed (control) group is also used (Weisburger 1999). Química Ambiental Toxicología MSDT . Los trastornos mutacionales en la célula cancerosa se refieren a grupos de genes responsables de controlar la proliferación, la apoptosis, la angiogénesis, la adhesión, las señales transmembranales, la reparación del ADN y la estabilidad del genoma. The most well understood epigenetic mechanisms involve DNA methylation and histone acetylation, methylation, and phosphorylation (Fig. mutações nos proto-oncogenes e genes supressores de tumor. p53 upregulates two very important proteins along the MMR pathway: human MutS homologue 2 (hMSH2) and proliferating cell nuclear antigen (PCNA) (Scherer et al. WILLIAMS GM. DRABLOS F ET AL. This author described the occurrence of cancerous alterations in the skin of the scrotum of London chimney sweeps as a consequence of repeated localised contamination with soot. 2003, Babenko et al. GRISHAM JW, KAUFMANN WK AND KAUFMAN DG. Free Radic Biol Med 37: 582-593. The contribution of the mouse in hazard identification studies. Mammalian p53R2 protein forms an active ribonucleotide reductase. Mutation Res 29: 171-180. GADD45 has also been shown to interact with the core histones and facilitate topoisomerase relaxing of chromatin (Carrier et al. cancer stages; carcinogenesis evaluation; chemical carcinogens; chemical carcinogenesis. 2007. Prog Exp Tumor Res 33: 21-40. 1996. As neoplasias, também chamadas de cânceres, consistem em aglomerados de células, resultantes de divisões desenfreadas de uma célula mãe original, surgindo mutações que podem levar a danos em um ou mais genes de uma única célula. The epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. 1995. primeiro passo para nela se transformar, depois de ocorrerem sucessivas alterações Although these enzymes were originally only thought to be involved in the detoxification stages of biotransformation, they can also contribute to the activation of certain procarcinogens in vivo (Luch 2005). Environ Health Perspect 103: 942-950. A eficácia dos agentes promotores aparente tem duas explicações possíveis: ou o efeito genotóxico não foi identificado nos Surv Synth Patho Res 1: 49-66. Naturaleza química de los ácidos grasos y los acilgliceroles. Medium-term bioassays for carcinogens. KLAUNIG JE, KAMENDULIS LM AND XU Y. BOLT HM, FOTH H, HENGSTLER JG AND DEGEN GH. Considera-se que na La carcinogénesis está ligada a la mutagénesis (producción de un cambio en la secuencia del DNA), lo cual es evidente para los carcinógenos químicos (que provocan cambios en la secuencia de los nucleótidos), y para las radiaciones, como los rayos-X (que causan ruptura de los cromosomas, y translocaciones). Cada uma delas caracteriza-se por transformações morfológicas e bioquímicas, e resulta de alterações genéticas e/ou epigenéticas. 2001, Pitot 2001). J Biochem Mol Biol 36: 43-48. NAKANO K, BALINT E, ASHCROFT M AND VOUSDEN KH. 1999. La progresión es la tercera etapa del crecimiento tumoral. 2001). , IARC Sci Publ 116: 279-305. Ciênc. WEINSTEIN IB. ACHANZAR WE, BRAMBILA EM, DIWAN BA, WEBBER MM AND WAALKES MP. The increase in DNA damage is specifically important to stem cells, because they survive for a long time and exist in several tissues (Potter 1978, Simons 1999, Trosko 2001, Williams 2001). Computer-assisted mechanistic structure-activity studies: application to diverse classes of chemical carcinogens. 2005). COHEN SM AND LAWSON TA. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 23: 75-97. 2001. Mutat Res 554: 399-406. 1991. Based on data accumulated from experiments in recent years, and according to Gutiérrez and Salsamendi (2001), they provide the following factors which favour these assays: a) All substances that revealed carcinogenic activity in humans, apart from rare exceptions, are also positive in rodent assays. p53R2 functions in a non-specific manner to increase the pool of free dNTPs when the need for repair arises. genotípicas e fenotípicas (Trosko, 2003). ITO N, SHIRAI T AND HASEGAWA R. 1992. 2000,Williams 2001). Differences in individual susceptibility to toxic effects of chemicals determine the dose-response relationship and consequences of setting exposure standards. The blocking of apoptosis in the face of significant genetic damage can ease the accumulation of aberrant cells and it can become a critical point in malignance pathogenesis (Nguyen-ba and Vasseur 1999, Qu et al. BMC Cancer 9: 26-36. A aplicação dos pesticidas, por exemplo, permitiu obter alimento em quantidade suficiente para satisfazer as necessidades alimentares de milhões de pessoas, condição relacionada com o aumento da esperança de vida. Cell proliferation and chemical carcinogenesis: symposium overview. Drug Metab Rev 15: 753-839. 2003. p27(Kip1) (Cdkn1b)-deficient mice are susceptible to chemical carcinogenesis and may be a useful model for carcinogen screening. promoção, ocorre uma alteração na expressão dos genes, com a proliferação selectiva 79 La primera etapa del proceso de la carcinogénesis, absolutamente preclínico y en una primera etapa aún no canceroso (precanceroso) consta de tres etapas principales: 2.1 Iniciación: Proceso inicial de alteración de una célula a nivel del genoma de la misma. 2005. 1995. de um processo complexo, dividido sob o ponto de vista operacional em três etapas 1999. p53-mediated regulation of proliferating cell nuclear antigen expression in cells exposed to ionizing radiation. These genetic modifications include: mutations in genes that control cell proliferation, cell death and DNA repair i.e. Toxicol Pathol 31: 355-363. KHAN QA, VOUSDEN KH AND DIPPLE A. Initiation is a fast, irreversible phenomenon and is transmitted to daughter cells (Farber 1984). Mol Cell Biol 22: 3247-3254. Meanwhile, others researchers studied carcinogenesis of the bladder, liver, kidney, pancreas and lung usinglaboratory animals. animais de experimentação, os diferentes compostos químicos a que o primeiro é 2000. Esta contradição Toxicol Sci 68: 275-279. CARCINOGENESIS QUIMICA. 1981. LUTZ WK. Non-genotoxic carcinogens are classified as cytotoxic and mitogenic in function of whether their activity is mediated by a receptor or not (Cohen 1991, Cohen et al. Pesticides, for instance, enable foodstuffs to be produced in sufficient quantities to satisfy the needs of millions of people, a condition that has led to an increase in levels of life expectancy. ulcerative colitis, pancreatitis, etc. 1999, Dybingand Sanner 1999, Gonzalez 2001, Gonzalez and Kimura 2001, Gutiérrez and Salsamendi 2001, Lutz 2002). HAYSES RB. PCNA, a cofactor for DNA polymerase d, is another p53 target gene and has been shown to interact with hMSH2 to facilitate hMSH2 transfer to mismatched bases (Flores-Rozas et al. , Generalmente afecta a personas entre 40 - 60 años (plenitud laboral). However, many of the genes mutated in these syndromes are ubiquitously expressed, and influence seemingly universal processes such as DNArepair or cell cycle control (Chao and Lipkin 2006).DNA repair is a process which enables a cell to maintain its genome fidelity. 1996). Molecular Epidemiology of Lung Cancer in Female Passive Smokers. Esta evolución de las propiedades del tumor se denomina "progresión tumoral". The hallmarks of cancer. los sustratos de las mismas. HASEMAN J, MELNICK R, TOMATIS L AND HUFF J. Carcinogénesis - Etapas de la Carcinogénesis Química Iniciación Esta etapa requiere un o más - Studocu etapas de la carcinogénesis química iniciación esta etapa requiere un más fases de división celular, estas etapas suelen tener estar reguladas por DescartarPrueba Pregunta a un experto Pregunta a un experto Iniciar sesiónRegístrate Mutat Res 544: 107-114. SWENBERG JA, FEDTKE N, CIROUSSEL F, BARBIN A AND BARTSCH H. 1992. These experiments are labelled as themolecular epidemiology of cancer or molecular dosimetry (Bondy 2004, Yang and Schlueter 2005). HASEGAWA R, FUTAKUCHI M, MIZOGUCHI Y, YAMAGUCHI T, SHIRAI T, ITO N AND LIJINSKY W. 1998. From exposure to effect: a comparison of modeling approaches to chemical carcinogenesis. Etapas que caracterizan al fenómeno tóxico. Todos los derechos reservados. Toxicol Pathol 24: 801-814. 2002. p53 and DNA damageinducible expression of the xeroderma pigmentosum group C gene. Os benefícios estão, por vezes associados a desvantagens, os efeitos resultantes da exposição a compostos químicos enquadram-se entre a morte imediata e um longo processo de carcinogênese química. No grupo das alterações genéticas incluem-se mutações nos genes que controlam a proliferação celular . La alteración de cualquiera de estos tres procesos puede iniciar el proceso de la carcinogénesis. Mira el archivo gratuito tesis-n6288-Miret enviado al curso de Administração Categoría: Trabajo - 117145583 células imortais até ser induzida a sua diferenciação ou morte; se impedirmos a sua Hypothesis: chemical carcinogenesis mediated by a transiently active carcinogen receptor. During progression, this balance is modified and from there malignancy arises (Mehta 1995) (Fig. Desde 1947 que a primeira fase da carcinogénese é designada de iniciação LUTZ WK. Cancer was described for the first time by Hippocrates as 'karkinos'. son enlaces a estos estudios en los que se puede hacer clic. Carcinogenic assays on rodents identify potential carcinogens for humans. 2003). 2002. Chemical carcinogens can be classified into several groups, on Table II we brought them together under the following headings: Group, compound, mechanism of action, and affected organs/cancer type. Esta tesis de Dolí y otros autores la han terminado aceptando los manufactureros de cigarrillos, que han disminuido la can- 1999). By definition, stem cells are immortal cells until they differentiate, or death is induced. There are innumerable anatomic, physiological and biochemical resemblances between rodents and humans that justify their use in carcinogenicity testing (Maronpot and Boorman 1996, Balmain and Harris 2000). SCHERER SJ, MAIER SM, SEIFERT M, HANSELMANN RG, ZANG KD, MULLER-HERMELINK HK, ANGEL P, WELTER C, SCHARTL M. 2000. p53 and c- Jun functionally synergize in the regulation of the DNA repair gene hMSH2 in response to UV. Chemical carcinogens can have additional synergic or antagonistic effects when simultaneously presented in different metabolic ways (Schmahl 1976, Lutz 2001). Galeno introduced the word neoplasia only in the II century; he defined it as the growth of a body area adverse to nature (Gutiérrez and Salsamendi 2001). 2001. 2004). Pathologic basis of disease. Genetic, epigenetic, dysgenetic, and non-genetic mechanisms in tumorigenesis. 2000, Ohshima et al. From an experimental point of view, a compound is considered carcinogenic when its administration to laboratory animals induces a statistically significant rise in the incidence of one or more histological types of neoplasia, compared with the animals in the control group which are not exposed to the substance (Gutiérrez and Salsamendi 2001). Exposure to these compounds can have varying effects, ranging from instant death to a gradual process of chemical carcinogenesis. YUSPA SH, HENNINGS H, LICHTI U AND KULESZ-MARTIN M. 1983. 2005. This initiationprocess ensures that cellular division remains symmetrical by creating two new initiated cells (Trosko 2003). (2003), the utilization of transgenic models to identify carcinogenic compounds has the following advantages: b) The assays are shorter, with a duration of 24 to 26 weeks. 2004). GUITTET O, HAKANSSON P, VOEVODSKAYA N, FRIDD S, GRASLUND A, ARAKAWA H, NAKAMURA Y AND THELANDER L. 2001. The understanding of these stages and the factors involved in them is very important for the development of biomarkers that allow early diagnosis, and also to know the stage of tumor development. This test semi-quantitatively evaluates a chemical's ability to induce mutations in Salmonella tiphymurium in a culture medium improved with microsomatic enzymes (Ames 1984). WEINSTEIN IB. proliferação celular, invasibilidade, metastização, e modificações nas características 2002). The multi-step nature of cancer development. CA: a cancer journal for clinicians. Enfermedad profesional Obligación de la sociedad Prevenirla Atenuarla En último extremo Reparar el daño. originando duas novas células iniciadas (Trosko, 2003). VAN LEEUWEN IM AND ZONNEVELD C. 2001. BABENKO VN, BASU MK, KONDRASHOV FA, ROGOSIN IB AND KOONIN EV. actualmente considera-se que a promoção também envolve alterações genéticas The first experimental work on chemical carcinogenesis was carried out in 1915 by the pathologist Katsusaburo Yamagiwa and his assistant Koichi Ichikawa (Yamagiwa and Ichikawa 1918). 2003). ASHBY J. CARLOS OSCAR GONZALEZ. GARNER RC. bioquímicas, metabólicas e morfológicas das células (Pitot e Dragan, 1991; Butterworth. Algunos de estos cambios pueden variar según las características de los agentes carcinogénicos, que pueden deberse, en particular, a las diferencias en sus propiedades farmacológicas. 1994. Not all cells of a living organism exposed to an initiator agent will be initiated even if they have suffered mutations, and the genes that regulate the terminal differentiation must also be mutated (Farber 1984, Yuspa and Poirier 1988, Klaunig et al. 1998. In summary, our objectives for this article were to review the current information available on chemical carcinogenesis. Cada uma delas caracteriza-se por transformações morfológicas e bioquímicas, e resulta de alterações genéticas e/ou epigenéticas. Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. MASTERS JR. 2000. Most mutagenic chemicals in vitro are carcinogenic in vivo. Its success laid the foundations of the experimental use of animals in the study of human diseases (Toth 2001). BALMAIN A AND HARRIS CC. Toxicol Lett 126: 155-158. Forging the links between metabolism and carcinogenesis. Animals are examined post-mortem in order to evaluate the incidence of neoplasic development and other pathological changes. GONZALEZ FJ. 2001. A ribonucleotide reductase gene is a transcriptional target of p53 and p73. distintas: iniciação, promoção e progressão (Berenblum e Shubik, 1947; Foulds, 1954; 2000, Gonzalez and Kimura 2001, van Leeuwen and Zonneveld 2001, Park et al. The histopathological observation of neoplasias, be they induced or spontaneous, enables us to better evaluate carcinogenesis, but it may not be enough to identify more subtle alterations such as molecular changes (Huff 1992, Maronpot 1996). A progressão caracteriza-se pela irreversibilidade, instabilidade genética, Progressão Proceso inicial de alteración de una célula a nivel del genoma de la misma. 2003, Ohshima et al. 1999). (English), Resumo COHEN SM, PURTILO DT AND ELLWEIN LB. Its meaning for human health will depend on other factors, some of which require additional studies (Maronpot and Boorman 1996). TUFAN AC AND SATIROGLU-TUFAN NL. prolongada, designa-se por progressão (Klaunig et al., 2000; Williams, 2001). El estudio de los mecanismos de transformación de células tumorales tiene una larga historia. In their role as genomic protectors, it is not surprising that the p53 family have a part to play in DNA repair (Fig. In contrast, inactivity by caretaker genes does not support the starting phase of a neoplasia, instead favouring the genetic instability which results in an increase in mutations across all genes, including the gatekeeper. 7). Adv Exp Med Biol 472: 231-240. 1975. 2002. promotores podem, por oxidação, danificar o ADN (Gutiérrez e Salsamendi, 2001). reparado, o dano torna-se permanente e passa a estar “fixo”. 2000, Gutiérrez and Salsamendi 2001, Luch 2005). Peroxidations also occur parallel to metabolic reactions with the continuous production of reactive oxygen species (ROS) (Weisburger 1999, Klaunig et al. b) Although many chemical carcinogens for animals do not cause cancer in humans, many of humancarcinogens were discovered from assays in animals such as: aflotoxins, diethylstilbestrol or vinyl chloride. Experimental models with animals have been used successfully for a number of decades. J Chem Inf Comput Sci 43: 1463-1470. Reparação do ADN Proliferação celular Proliferação, celular Park et al. Anticancer Res 19: 4781-4789. There is a positive correlation between the quantity of adducts detected in animal models and the number of neoplasias developed (Yuspa and Poirier 1988, Williams 2001, Baird and Mahadevan 2004). A comprehensive approach for integration of toxicity and cancer risk assessments. 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