Chemical carcinogenesis

The use of chemical compounds benefits society in a number of ways. 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. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Exposure to these compounds can have varying effects, ranging from instant death to a gradual process of chemical carcinogenesis. There are three stages involved in chemical carcinogenesis. These are defined as initiation, promotion and progression. Each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. These genetic modifications include: mutations in genes that control cell proliferation, cell death and DNA repair - i.e. mutations in proto-oncogenes and tumour suppressing genes. The epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. 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. 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.

A sociedade obtém numerosos benefícios da utilização de compostos químicos. 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. 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. A carcinogênese química inclui três etapas definidas como iniciação, promoção e progressão. Cada uma delas caracteriza-se por transformações morfológicas e bioquímicas, e resulta de alterações genéticas e/ou epigenéticas. 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. mutações nos proto-oncogenes e genes supressores de tumor. Os fatores epigenéticos, também considerados como caracteres não genéticos, podem contribuir para a carcinogênese por mecanismos de silenciamento gênico. A utilização de diferentes metodologias possibilita o reconhecimento e a compreensão dos mecanismos básicos envolvidos no desenvolvimento do cancro. 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.

Adaptive Change of AP DNA Endonuclease Against Genotoxic Agents in Normal and Transformed Cells / 대한암학회지

PURPOSE: AP DNA endonuclease (APE), an enzyme responsible for the repair of damaged DNAs, is essential for the maintenance of genetic information of cells. Deficiency of APE in certain hereditary skin tumor and senescent cells has been implicated but the regulation of APE activity as well as the expression of APE gene in response to DNA damage has not been well documented. Genotoxic agents including ultimate carcinogens that can damage DNA were treated to cultured normal and transformed human cells and adaptive response of APE gene expression to these treatments was measured in order to evaluate the role of APE in chemical carcinogenesis. MATERIALS AND METHODS: Hydroxyl radical ('OH) generated from H2O2 (60 uM) through Fenton reaction, each 100 uM of N-nitrosomethylurea (NMU), 3-methyl-4-monomethyl- aminoazobenzene (3'-MeMAB) and N-acetoxy-2-acetaminofluorene (AAAF) were treated to umbilical cord blood cells (UCBC), HepG2 cells and HL-60 cells. APEX mRNA and APEX protein contents expressed in these cells exposed to each of these agents were measured by Northern blot hybridization and Western blot immunodetection analysis. The changes of APE activity in cells exposed to these genetoxic agents were measured. RESULTS: Treatment of H2O2 (60 uM) to UCBC, HepG2, and HL-60 cells increased APE activity significantly and pretreatment of a catalytic agent for OH, FeSO4 (60 pM) to the cells prior to H2O2 exposure did not further increase the APE activity in cells. Adaptive response to H2O2 in HL-60 cells increased in proportion to the concentration of H2O2 up to 60 pM. However, further increase in H2O2 concentration had no effect on the enzyme activity. Treatment of NMU (100 pM), 3-MeMAB (100 pM) and AAAF (100 pM) to these cells brought about a slight increase in the APE activity. APEX mRNA expression in UCBC and HepG2 cells exposed to H2O2, NMU, 3-MeMAB was markedly increased in APEX mRNA expression. APEX mRNA expression was also increased in HL-60 cells exposed to H2O2 (60 pM) and 3-MeMAB (100 uM) but NMU (100 pM) exposure to the cells resulted in a slight increase of it (Fig. 2). APEX protein expression was increased in all UCBC, HepG2 and HL-60 cells exposed to these genotoxic agents (Fig. 3). CONCLUSION: These results implicate that exposure of genotoxic agents to the cultured cells may cause DNA damage and lead to adaptive increase in APE activity as well as APE gene expression. It is probable that APE gene is transcriptionally regulated in response to the exposure of H2O2 or 3-MeMAB in cultured human cells as a consequence of activation of DNA repair system for the adaptation to the crisis.

Models of Experimental Brain Tumors

Despite concentrated basic and clinical research efforts including the initial successful combination of surgery, radiotherapy and chemotherapy with BCNU, significant progress in the treatment of human brain tumors have been slow and looks for more successful strategies developed based upon the information from animal model system. It is to recreate in the laboratory under experimental condition a model of human brain tumors. Although no unique model of the numerous animal tumors resembling the spontaneous human brain tumors developed in these days, experimental animal models to have own specific adventages can be induced by exposure to oncogenic viruses or chemical carcinogens. Intracerebral injection of oncorna viruses can produce glioblastoma mutiformes, astrocytomas and sarcomas, while medulloblastoma, choroids plexus papilloma and ependymomas can be induced by papova viruses, and human adenovirus may cause neuroblastoma, medulloepithelioma and retinoblastomas. Chemical induction in adult animals and transplacental chemical induction were ependymoblastomas, glioma, gliosarcoma and malignant neurinomas. Reproducibility of location, cell type, and time of tumor appearances;expense;growth in tissue culture;trauma to brain;nature of vasculature, and amount of brain and tumor tissue available for examination are the variables to be considered in choosing a model to use in evaluating drug and other therapies, cell kinetics and immunological studies.