Recombinação homóloga como a principal resposta ao dano induzido por doxorrubicina em Drosophila melanogaster

Abstract

Doxorubicin hydrochloride (DXR), commercially known as adriamycin, is a chemotherapeutic agent used in the treatment of some types of solid tumors. When administered, it remains active throughout mitotic division and its cytotoxic action comes from the conversion of quinone ring into semiquinone, interacting and damaging enzymes, especially topoisomerase II. This, when inhibited, prevents the re-ligation of the double strands of DNA, provoking leasions that may lead to an apoptosis, carcinogenic process or may be amenable to repair. Thus, the toxic and recombinogenic potential of different concentrations of DXR (0.1, 0.2, 0.4, 0.8 and 1.0 mM) in 72 ± 4h larvae of D. melanogaster, obtained through the crosses used at SMART (Somatic Mutation and Recombination Test), originated from Standard Cross (ST) - with basal levels of metabolism - and High Bioactivation (HB), with high cytochrome P450 (CYP450) levels. Survival tests demonstrated that, concentrations of 0.8 and 1.0 mM were toxic in ST and HB crosses, when compared to the negative control, however, in the HB cross, the concentration of 0.4 mM was also toxic. Based on the results obtained it is possible to infer that the greater mortality of individuals in the HB cross, may be related to the fact that they have a higher expression of CYP450 levels, due to the interaction between DXR with this enzyme complex, is associated with the increased production of free radicals, promoting greater toxicity and consequent mortality. The recombinogenic evaluation revealed that, in individuals from ST cross, the concentration of 0.1 mM results in 75.3% recombination-induced spots. At the concentration of 0.2 mM, it was 82.8% and at a concentration of 0.4 mM it was 84.9%. The concentration of 0.1 mM was 88.23% and for the 0.2 and 0.4 mM concentrations, were, respectively, 86.60%, 96.24%. In view of the foregoing, it can be inferred that the response to DXR-induced cell damage is preferentially repaired by homologous recombination (HR), since that mechanism may lead to loss of heterozygosity, increasing the frequency of mutant spots in the wings of D. melanogaster and, on the other hand, the increase in HR is related to survival rate increase in both crosses.