El uso de la genotoxicocinética y al citotoxicocinética para caracterizar la acción de radiosensibilizadores

Abstract

The aim of this study was to determine the effect of low doses of bromodeoxyuridine (BrdU) (0.125 mg/g) or cisplatin (cis-Pt) (1.0 µmol/Kg), on radiosensitization at low doses of radiation (0.5 Gy) and characterize its form of action in bone marrow cells of mice in vivo. This by using single cell gel electrophoresis (SCGE), and the kinetics of micronucleated reticulocytes induction (RET-MN) and of the reduction of reticulocytes (RET) determined by flow cytometry. In the case of BrdU, the effect proved by SCGE, indicated that low levels of BrdU incorporation into the DNA, increase the sensitivity to gamma radiation; particularly during DNA synthesis. The kinetics of induction of RET-MN induction, in peripheral blood samples along 72 h, indicated that gamma radiation causes two main peaks of induction of MN in animals treated or not with BrdU. In those not treated with BrdU, the first peak was not associated with cytotoxicity, but in those treated with BrdU cytotoxicity this was associated. In the cells substituted with BrdU prior to irradiation the second peak showed, an increase in the induction of MN associated with an increase in cytotoxicity. The pretreatment with BrdU seems to favour a radioinduced kind of lesion or an increase number of lesions difficult to repair, possibly cross-links as previously described. In the case of the cis-Pt first, the timing of damage was determined in peripheral blood leukocytes by SCGE, the results indicated that at 40 minutes occurred the maximum induction of breaks in the DNA. With this data, the analysis of the kinetics induction of RET-MN was performed, by administering cis-Pt 40 minutes before irradiation. The pretreatment with a low dose of cis-Pt, increased sensitivity to low dose of xvii radiation and evidenced three mechanisms of induction of MN, two of them being, the main ones, attributable to failures in the excision and recombination repair, respectively, both effects were associated with an increase in cytotoxicity.