Teratogenesis, carcinogenesis, and mutagenesis最新文献

In this study, the anticlastogenic effects of ascorbic acid and the protective effect of folinic acid against the formation of chromosomal aberrations in humans by pyrimethamine were investigated. Pyrimethamine is a folic acid antagonist used for the treatment of malaria and toxoplasmosis. In this study, 18 different healthy people, who do not drink alcohol and are non-smokers, were chosen as an experimental group; 0.025 mg/ml pyrimethamine was given to the lymphocyte culture, which had been prepared with the peripheral blood taken from this group. After that each of the following doses were given to the same culture: 20, 40, and 80 mM of ascorbic acid and 25, 50, and 100 mM of folinic acid. The results of the cytogenetic evaluation showed that the aberrations due to pyrimethamine in the chromosomes were reduced by ascorbic acid and folinic acid significantly, depending on the given dose.

Experimental administration of chemical carcinogens to various mammals is highly effective in inducing malignant tumors. In contrast, treatment of regeneration-competent animals even with much higher doses of the same drugs only exceptionally leads to tumor-like growth. Usually, carcinogenic materials implanted or injected into a regenerating limb of urodele amphibia interfere with the regenerative process and frequently lead a). to growth retardation or arrest of regeneration, b). to development of a great variety of abnormal regenerates, and c). to generation of accessory, limb-like structures. Autonomous or experimental incidence of carcinogenesis is extremely low in animals endowed with strong regenerative capabilities. Of exceptional biological significance is the fact that such induced tumors usually regress spontaneously. This unique property of the regeneration-competent animals to resist carcinogenesis provides opportunities to compare non-cancerous alterations in the differentiated state of adult cells to those occurring in neoplasia. The mode of action of the chemical carcinogens on limb regeneration has not yet been clarified with certainty at the cellular and the molecular level. Several scientists claim that the above-mentioned effects might be attributed to local toxic influences of the drugs; therefore the present study was designed to investigate whether the administration of the carcinogen MNNG can affect cell proliferation, histogenesis, and morphogenesis at a region distant from the site of its implantation, even after a relatively long time period. To this end, 40 animals of the species Triturus cristatus had their right hindlimb surgically removed at the distal zeugopod. Then, a small microcrystal (approximately 5 micro g) of MNNG was inserted under the ventral aspect of the skin of the left tarsus in 20 of these animals (groups T and A; see below). Two months later, nine of the MNNG-treated animals were injected intraperitoneally with tritiated thymidine. After 2 h, six of these animals had their right hindlimb amputated at the distal zeugopod, whereas the rest were left to regenerate. The results were evaluated by camera lucida drawings, clearing in methyl benzoate, classical histology, and autoradiography. It was revealed that administration of MNNG at a somatic region (left hindlimb) reduces DNA synthesis and mitosis at a distant place (right hindlimb) even 2 months after MNNG implantation. Despite this, the rate of limb elongation is not substantially reduced. Classical histology revealed normal tissue structure throughout. All regenerated limbs displayed several teratogenic abnormalities.

Recently we have identified, cloned, and characterized the mouse Translation Initiation Factor 3 (TIF3, GenBank Accession Number AF 271072) as a novel cadmium-responsive proto-oncogene. Presently, additional studies regarding the oncogenic potential of TIF3 have been carried out. Transfection of NIH3T3 cells with the pcDNA3.1 expression vector containing the TIF3 cDNA in the sense (5'-->3') orientation resulted in overexpression of the encoded 36 kDa protein. Transfection-mediated overexpression of TIF3 protein resulted in transformation of the cells as evidenced from the appearance of transformed foci. Cotransfection of the cells with a mixture of plasmid DNA consisting of TIF3 cDNA in the sense and in the antisense orientation resulted in significant inhibition of translation of the TIF3 protein. Antisense (3'-->5') TIF3 mRNA-mediated inhibition of translation of TIF3 protein, furthermore, resulted in inhibition of TIF3-mediated transformation of NIH3T3 cells as evidenced from the decrease in the number of transformed foci. These results further confirm that overexpression of TIF3 is oncogenic and the antisense TIF3 mRNA expression reverses its oncogenic potential.

The fungal metabolite wortmannin (WM) is a potent and irreversible inhibitor of the enzyme DNA-dependent protein kinase (DNA-PK), a nuclear serine-threonine kinase, member of the phosphaditylinositol-3 kinase related kinase family. WM has been used in the last few years as a promising radiosensitizer mainly throughout cell survival experiments. However, few studies have addressed the role of DNA-PK inhibition in the repair of DNA lesions generated by antitumor agents. Bleomycin (BLM) is an antitumor agent used in the treatment of various neoplasia with a unique genotoxicity profile that mimics the ionizing radiation effects. In this study, we evaluated the effect of different concentrations of WM on the DNA damage induced by BLM. The cytokinesis-block micronucleus assay (CBMN) in V79 Chinese hamster cells was used as the end-point. WM significantly increased the frequency of micronucleated cells (%MNBN) by about 2.2-fold, the number of micronuclei per binucleated cell (MN/BN) by about 2.4-fold, and also changed the pattern of the distribution of micronuclei induced by BLM. The frequency of micronucleated cells with 2 MN per cell and with > or = 3 MN per cell increased, whereas the frequency of micronucleated cells with 1 MN per cell decreased. WM was not genotoxic but decreased cell proliferation as assessed by the frequency of binucleated cells. Our results show that WM clearly enhances the efficacy of BLM in terms of DNA damage inflicted and therefore reinforces its use as a chemosensitizer.

Chlorophyllin (CHL) has proven that there is antimutagenic and anticarcinogenic activity in several organisms without causing lethal effects. However, there is no information about its effects when it is administered in gestation. In the present study, we assessed possible effects of CHL when it was administered to CD-1 mice on the 8th day of gestation using the same doses and administration route used in ours previous antimutagenic and antigenotoxic studies. Females were exposed to a single dose of CHL by i.p. injection (20, 40, 50, or 100mg/kg b.w.). On day 18 all dams were subjected to cesarean section and the fetuses were examined with common teratological methods. Results show that CHL-treatment induced total litter loss and is dose-dependent, probably due to either the interaction between CHL and some general control mechanisms of embryo development or by an impairment of maternal-fetal interactions. The analysis of uterine horns of the CHL-treated females with total litter loss revealed the presence of green rings in the uterus. Results show the inverse relationship between the number of live implants and the frequency of green rings, indicating implantation sites where embryo death and early resorptions occurred. Although CHL was given in a single dose on day 8 in this study, the results indicate that CHL is associated with significant embryo lethality.