Somatic recombination: a major genotoxic effect of two pyrimidine antimetabolitic chemotherapeutic drugs in Drosophila melanogaster.
Two deoxycytidine analogues, 1-beta-D-arabinofuranosylcytosine (cytosine arabinoside, citarabine, araC) and 5-aza-2'-deoxycytidine (decitabine, DAC, 5-aza-dC), are the drugs of choice in the treatment of acute myeloid leukaemia. The araC-induced cytotoxicity is a direct result of its interference with nucleic acids synthesis, whereas 5-aza-dC is a potent suppressor of DNA methylation. We employed the standard version of the wing somatic mutation and recombination test (SMART) in Drosophila melanogaster to evaluate the genotoxic potential of these two antimetabolites as a function of exposure concentration. In addition, we determined the relative contributions of mutational and recombinational events to total genotoxicity. The compounds were administered by chronic feeding of 3-day-old larvae. Our results indicate that recombinagenicity is the major genotoxic effect of araC and 5-aza-dC (approximately, 77 and 81%, respectively, recombination). The standardised clone induction frequencies (per mM concentration per cell per cell division) show that 5-aza-dC is 85 times more powerful then araC (inducing approximately 58 mutant clones per 10(5) cells per mM). The high recombinagenic activity of these two drugs suggests that--despite their therapeutic effects against cancer--a question is raised whether these drugs should be considered for adverse effects in cancer chemotherapy.
Cunha
Kênya Silva
KS
Departamento de Ciências Fisiológicas, Universidade Federal de Goiás, CP 131, 74001-970, GO, Goiânia, Brazil.
Reguly
Maria Luíza
ML
Graf
Ulrich
U
de Andrade
Heloisa Helena Rodrigues
HH
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000633:toxicity*; D003561:Cytarabine / Q000633:toxicity*; D000077209:Decitabine; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005260:Female; D008297:Male; D015394:Molecular Structure; D009152:Mutagenicity Tests; D011995:Recombination, Genetic
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D000077209:Decitabine; D001374:Azacitidine