indiferenciadas, e resistentes à apoptose, podem contribuir para o desequilíbrio entre o These agents increase cell proliferation in susceptible tissues, contribute towards fixing mutations, enhance alterations in genetic expression and cause changes in cellular growth control (Mehta 1995, Gomes-Carneiro et al. A acumulação de danos no ADN tem particular importância nas células Promoter compounds do not interact directly with DNA and unchain biological effects without being metabolically activated (Yuspa et al. Molecular Epidemiology of Lung Cancer in Female Passive Smokers. Interestingly, these epigenetic changes in chromatin can also alter the sensitivity of DNA sequences to mutation, thus rendering genes more susceptible to toxic insult (Dixon and Kopras 2004). MOSTAFA MH, SHEWEITA SA AND O'CONNOR PJ. 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). A common feature of all the known genetic cancer syndromes is that they are predisposed only to selective types of malignancy. Experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals. El daño en la célula puede tener una naturaleza genética o epigenética. LUTZ WK. Gutiérrez e Salsamendi, 2001; Pitot, 2001). They proliferate autonomously, differentiate themselves, invade adjacent tissues and frequently metastasize on tissues that are not related to the primary neoplasia (Hanahan and Weinberg 2000, Shacter and Weitzman 2002). IARC Sci Publ 146: 123-150. Genetic alterations and DNA repair in human carcinogenesis. [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Cancer 53: 2034-2040. 2005. 2003, Babenko et al. VAN LEEUWEN IM AND ZONNEVELD C. 2001. These have lead to incorrect interpretations when animal models are used in the research and analysis of carcinogenic properties of chemical compounds (Guengerich 2000, Gonzalez 2001, Gonzalez and Kimura 2001). Chem Res Toxicol 18: 1071-1080. 1981,Butterworth et al. Nature and nurture - lessons from chemical carcinogenesis. Cells, which are part of benign neoplasias, grow more slowly, and in general, they do not disturb normal tissue function, unless they compress vital structures (Player et al. By the end of the nineteenth century it had become evident that occupational exposure to certain chemicals or mixtures of chemicals had carcinogenic effects (Luch 2005). RICHARDSON FC, BOUCHERON JA, DYROFF MC, POPP JA AND SWENBERG JA. 1997. BEREMBLUM I AND SHUBIK P. 1947. Cad Saúde Pública 13 (Suppl): 27-38. proliferação celular, invasibilidade, metastização, e modificações nas características 1999. Meanwhile, others researchers studied carcinogenesis of the bladder, liver, kidney, pancreas and lung usinglaboratory animals. a dose aumenta a incidência, a multiplicidade das neoplasias e diminui o período de Absorption depends on the physicochemical properties of the substance and can take place via passive or active transport. GOLKA K, KOPPS S AND MYSLAK ZW. Environ Health Perspect 61: 69-96. Mutations linked to adducts can appear through deletion, frameshift, or by nucleotide substitution (Garner 1998). Chemical carcinogenesis: from animal models to molecular models in one decade. As lesões identificados durante a iniciação e a promoção designam-se em 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. Human life is led under very different conditions from these experimental procedures. 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). Cell proliferation and chemical carcinogenesis: symposium overview. CAMARGO JLV, SALVADORI DMF, ROCHA NS, BAEBISAN LF AND RIBEIRO LR. 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. 2000, Hanawalt et al. 2003). 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. 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). 1984. Gatekeepers and caretakers. La última de estas etapas, progresión, es exclusiva de la transformación maligna e implica la capacidad de invadir tejidos vecinos o a distancia. Mutat Res 437: 105-112. La información publicada en el portal es solo para referencia y no debe utilizarse sin consultar a un especialista. FARMER PB. 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). Res Microbiol 154: 375-385. celular menos controlado e com maior potencial metastático. La alteración de cualquiera de estos tres procesos puede iniciar el proceso de la carcinogénesis. A true threshold dose in chemical carcinogenesis cannot be defined for a population, irrespective of the mode of action. Current strategies to identify the carcinogenic potentiality of certain compounds include experimental protocols lasting a minimum of two years (Payne and Kemp 2003). A progressão caracteriza-se pela irreversibilidade, instabilidade genética, Br J Cancer 44: 1-14. Cell proliferation is essential for this stage, if cellular division occurs before DNA repair systems can act then the injury becomes permanent and irreversible. 7) once the p53 has been mutated in a very large fraction of tumours from nearly every possible source. 6) (Khan et al. Progressão Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Carcinogenicity of azo colorants: influence of solubility and bioavailability. 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. menos tempo disponível para os reparar (Richardson et al., 1986; Frowein, 2000). 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). 2000, Poirier et al. Metabolic activation occurs predominantly in the liver at the plain endoplasmic reticulum where the cytochrome P450 is more abundant, and to a lesser degree in the bladder, skin, gastrointestinal system, oesophagus, kidneys, and lungs (Bartsch and Hietanen 1996, Mostafa et al. 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. ETAPAS DE LA CARCINOGÉNESIS Cuando el clínico se encuentra ante un tumor, no observa más que un pequeño momento de lavida del proceso canceroso, el denominado periodo clínico. Os fatores epigenéticos, também considerados como caracteres não genéticos, podem contribuir para a carcinogênese por mecanismos de silenciamento gênico. Cancer Res 51: 6493-6505. 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). 1999. Genetic variability in susceptibility and response to toxicants. and mortality worldwide for 36 cancers in 185 countries. Carrying out epidemiological studies of a scientific nature is difficult for several reasons (Farmer 1994, Tennant 1998): a) The difficulty in evaluating external and internal exposition to chemicals. Environ Health Perspect 76: 65-70. 2007. A symposium summary and perspective on comparative molecular biology of cancer. MARONPOT RR AND BOORMAN GA. 1996. A carcinogênese química inclui três etapas definidas como iniciação, promoção e progressão. Lack of p53-mediated G1 arrest in response to an environmental carcinogen. Contenidos del Módulo 3: 3.1. 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. Todos los derechos reservados. Na etapa intermédia. La primera etapa del proceso de la carcinogénesis, todavía no canceroso, consta de tres etapas principales: El proceso inicial supone la alteración de una célula a nivel del genoma de la misma. 2004. Biomed Mass Spectrom 8: 431-435. Universidad Universidad Juárez Autónoma de Tabasco Materia ANATOMÍA PATOLÓGICA (F1508) Libros listados Patologia Estructural Y Funcional Robbins y Cotran. Key words: cancer stages, carcinogenesis evaluation, chemical carcinogens, chemical carcinogenesis. HISTORICAL PERSPECTIVE OF CHEMICAL CARCINOGENESIS STUDY. DNA damage and repair. Is there a causal connection? 2005). monoclonal a partir de uma célula estaminal. Drug Metab Rev 30: 339-357. 2003. KINZLER KW AND VOGELSTEIN B. prolongada, designa-se por progressão (Klaunig et al., 2000; Williams, 2001). Genetic susceptibility and occupational cancer. 2005). According to Hayes (1995), it was the English surgeon Percivall Pott who first recognized in 1775 the casual relationship between exposure to environmental substances and neoplasic development. Angiogenesis, as an epigenetic occurrence, is essential to neoplasic progression. Fase tóxicodinámica. Phase II reactions are catalysed by hepatic and extra hepatic, cytoplasmic and cytochromic enzymes, acting separately or joined together (Gonzalez 2001). 1995, Maronpot and Boorman 1996). p53R2 is induced by p53 and p73, while R2 synthesis occurs during S phase. 2001. As we mentioned before, the classification of the carcinogenic compounds according to their mechanism of action continues to cause controversy. 2004. Oncogene 19: 4283-4289. 1997. la carcinogénesis es causada por alteraciones genéticas y epigenéticas que alteran la integridad del genoma, y que le permiten a la célula transformada violentar mecanismos como la senescencia celular, la apoptosis, el control de la proliferación, la estabilidad de la matriz extracelular, la dependencia de señales tróficas específicas del tejido … 1999, Guengerich 2001, van Leeuwen and Zonneveld 2001, Oda 2004). LUCH A. Environ Health Perspect 101: 3-7. Nucleic Acids Research 34: 840-852. diferenciação tornam-se iniciadas e acumulam-se nos tecidos como clones de células Cellular and molecular mechanisms of multistep carcinogenesis: relevance to carcinogen risk assessment. (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. TENNANT RW. By definition, stem cells are immortal cells until they differentiate, or death is induced. Mutat Res 591: 110-122. Drinking water mutagenicity and gastrointestinal and urinary tract cancers: an ecological study in Finland. BARRET JC AND WISEMAN RW. Os radicais livres de oxigénio (RLO) sintetizados MARONPOT RR. Este periodo, a su vez, puede ser subdividido en dos fases, una fase local, en la que el tumor se encuentra todavía localizado en las estructuras especial mención a la carcinogénesis hormonal, ya que los principios generales de la carcinogénesis química son aplicables a cualquier proceso carcinogénico, sea cual sea su etiología, siendo la etiología hormonal la más vinculada a la patología oncológica del aparato reproductor femenino. La carcinogénesis consta de tres etapas: iniciación, promoción y progresión. Clin Chem 40: 1438-1443. 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). Rhen: Cancer de vejiga: pintores usando anilina MODELOS EXPERIMENTALES 1915. The role of DNA adducts in chemical carcinogenesis. They are tissue- and species-specific (Farmer 1994, Melnick et al. La carcinogénesis es un proceso complejo de múltiples pasos. 1992,Nguyen-ba and Vasseur 1999, Klaunig et al. BALMAIN A AND HARRIS CC. 3.3. Genetically altered mouse models for identifying carcinogens. Finalmente, la cuarta etapa es el resultado del proceso tumoral. To validate the results obtained from these assays it is important to check if these results occur under physiological conditions considered as normal. Diverse chemical carcinogens fail to induce G(1) arrest in MCF-7 cells. IARC Sci Pub 147: 211-225. La alteración de cualquiera de estos tres procesos puede iniciar el proceso de la carcinogénesis. During cell division, spontaneous genetic errors occur. Mol Carcinog 7: 1-13. During the next decade, Foulds (1954) introduced the term progression by studying breast adenocarcinoma in female mice. Thus it is best to think of mutated cancer genes as contributing to, rather than causing, cancer (Vogelstein and Kinzler 2004). Other available tests concern the use of protozoa cultures and the chorioallantoic membrane. ulcerative colitis, pancreatitis, etc. The role of interindividual variation in human carcinogenesis. ¿Cuáles son las tres etapas de la carcinogénesis? Int J Hyperthermia 19: 236-251. 1999. The common and distinct target genes of the p53 family transcription factors. Br J Cancer 38: 1-23. 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. Diaz de Santos, Madrid, p. 155-177. These genetic modifications include: mutations in genes that control cell proliferation, cell death and DNA repair – i.e. ou então podem crescer de forma clonal e autónoma (Scott et al., 1984; Dybing e A expansão clonal das células celular é independente da presença do composto carcinogénico e resulta da associação Environ Health Perspect 106: 473-476. GOMES-CARNEIRO MR, RIBEIRO-PINTO LF AND PAUMGARTTEN FJ. LOCK EA, REED CJ, MCMILLAN JM, OATIS JE Jr AND SCHNELLMANN RG. Cada uma delas caracteriza-se por transformações morfológicas e bioquímicas, e resulta de alterações genéticas e/ou epigenéticas. ITO N, SHIRAI T AND HASEGAWA R. 1992. POIRIER MC, SANTELLA RM AND WESTON A. Free Radic Biol Med 37: 582-593. cancer stages; carcinogenesis evaluation; chemical carcinogens; chemical carcinogenesis. 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. 2005). 3) (Hayes 1995, Bartsch and Hietanen 1996, Mostafa et al. %���� 2004. The conclusions reached from several experiments enabled the conclusion to be drawn that initiation is caused by irreversible genetic changes which predispose susceptible normal cells to malign evolution and immortality (Beremblum and Shubik 1947, Stenbäck et al. (Beremblum e Shubik, 1947). The specificity of the activation systems of different tissues regulate neoplasic development and is dependent on genetic polymorphism, which requires the expression and distribution of the enzymes involved in phase I and II reactions, and the resulting susceptibility to cancer development (Schut and Castonguay 1984, Hayes 1995, Henglster et al. Quuíímmiiccooss. Na progressão, a proliferação O conceito de promoção foi introduzido quando se identificaram substâncias Ej., Mutaciones genéticas o aberraciones cromosómicas) o cambios en el número de copias de genes o la integridad de los cromosomas. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. DYBING E AND SANNER T. 1999. These are defined as initiation, promotion and progression. Toxicidade celular << XU J AND MORRIS GF. The caretakers are responsible for maintenance of genome stability. The crystal structure of DNA mismatch repair protein MutS binding to a G × T mismatch. 1994. Mayo Clin Proc 59: 107-117. HEIDELBERGER C. 1977. Nature 421: 436-440. 1999, Klaunig et al. The search for critical genes regulated by p53 led to the discovery of the p21 gene. (Portuguese), Text Epidemiological studies provide a great deal of information about exposure to those chemicals present in food, the environment and at work, but are limited as far as the identification of etiological factors are concerned, especially in cases where neoplasic development results from the interaction of multiple agents (Garner 1998, Tennant 1998, Weinstein 1991). Las principales disposiciones de las teorías oncogenes se formularon en la década de 1970. 5). 2001. FOULDS L. 1954. Todos los tumores conocidos están compuestos por células con alteraciones genéticas que los hacen rendir de manera diferente a sus células progenitoras (progenitoras). Carcinogenesis in mouse and human cells: parallels and paradoxes. MINAMOTO T, MAI M AND RONAI Z. Cancer 40: 430-433. Fuentes de ácidos grasos. Instead of focusing on specific structural features or a particular group of related molecules, these methods classify molecules into genotoxic positive or non-genotoxic agents based on their general structural and physicochemical properties, regardless of their structural and chemical types (Li et al. Mutations cause an undefined number of cell changes, translated into aberrant protein expression and in changes in cell cycle control. TUFAN AC AND SATIROGLU-TUFAN NL. YANG M AND SCHLUETER R. 2005. WEINSTEIN IB. ROBBINS D AND COTRAN R. 2005. 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. The enzymes in phase I participate in the reactions of oxidation, reduction and hydrolysis, and are classified as oxidoreductases (cytochrome P450 dependent monooxygenases, flavine monooxygenases, cyclooxygenases and alcohol dehydrogenase) and hydrolases (epoxide hydrolases) (Hayes 1995, Garner 1998, Galati et al. Chemical carcinogenesis is a multistage and multicausal process in which normal cells become first initiated, then malignant and invasive. In their role as genomic protectors, it is not surprising that the p53 family have a part to play in DNA repair (Fig. They rubbed rabbit ears with coal tar and observed the development of papillomas and carcinomas. Most mutagenic chemicals in vitro are carcinogenic in vivo. Phase II enzymes participate in theconjugation and inactivation of chemical carcinogensand include transferases (glutathione S-transferases, N-acetyltransferases, UDP-glucuronosyltransferases, sulphotransferases) (Oesch et al. 1997). A aquisição do fenótipo angiogénico precede o desenvolvimento CARCINOGENESIS QUIMICA. 1999. Mutat Res 433: 15-22. BARRETT JC AND ANDERSON M. 1993. TEORIA DEL CAMPO DEL CANCER. Apesar da essência do processo de carcinogénese ser o mesmo, entre o Homem e os Bell: Cáncer de piel en trabajadores alquitrán y parafina 1895. HARTWING A, ASMUSS M, EHLEBEN I, HERZER U, KOSTELAC D, PELZER A, SCHWERDTLE T AND BURKLE A. Tenemos pautas de abastecimiento estrictas y solo estamos vinculados a sitios de medios acreditados, instituciones de investigación académica y, siempre que sea posible, estudios con revisión médica. Toxicol Lett 151: 203-210. Pharmacokinetics, biochemical mechanism and mutation accumulation: a comprehensive model of chemical carcinogenesis. Embora a iniciação espontânea seja mais rara do que a induzida Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. There are several routes towards DNA repair. ANZ J Surg 73: 680-686. The experimental study of tumor progression: a review. Para que se lleve a cabo el proceso metastásico, se requiere The role of metabolic activation in drug-induced hepatotoxicity. OTTENEDER M AND LUTZ WK. Mutagenesis 13: 405-408. 1997). Drug Metabol Drug Interact 17: 311-349. Pott. Phenotypic diversity in experimental hepatomas: the concept of partially blocked ontogeny. Genotoxicity in the rodent urinary bladder. La aparición de una célula cancerosa en el cuerpo no conduce inevitablemente al desarrollo de una enfermedad tumoral y a la muerte del organismo. IARC Sci Pub 116: 437-475. Cancer Res 14: 327-339. 1995. 1995. 2000, Park et al. 1993. Cancer Lett 123: 185-191. Opin Chem Biol 5: 383-388. These chemical properties are related to the molecular structure of chemical, physical, and toxicological properties (Barratt and Rodford 2001, Feng et al. Chronic inflammation and cancer. impede, por inibição da apoptose, a morte das células iniciadas (Trosko, 2001). Environ Mol Mutagen 31: 248-56. 2005). Expert Rev Mol Diagn 4: 831-840. Carcinogen binding to DNA. mutations in proto-oncogenes and tumour suppressing genes. JENG JH, CHANG MC AND HAHN LJ. BONDY M. 2004. OHSHIMA H, TAZAWA H, SYLLA BS AND SAWA T. 2005. 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). Cada uma delas caracteriza-se por transformações morfológicas e bioquímicas, e resulta de alterações genéticas e/ou epigenéticas. Chemical basis of inflammation-induced carcinogenesis.