In vitro and in vivo chromosomal aberrations induced by megazol.
With the re-emergence of Human African Trypanosomiasis (HAT) on the one hand, which are increasingly resistant to current therapies, and the stage-dependent effectiveness or even the prohibitive cost of these therapies on the other hand, megazol, a 5-nitroimidazole thiadiazole highly active against various trypanosomal species, was assessed for its genotoxic potential. Very little information has become available until now. Two batches of megazol were provided by two different suppliers: Far-Manguinhos, a part of the Fiocruz foundation, under the Brazilian Minister of Health, and Delphia, a French company. These two batches, obtained by different synthetic routes, were studied by means of the in vitro micronucleus assay on L5178Y mouse lymphoma cells, in its microscale version. Both batches of magazol displayed a strong genotoxic activity in this screening assay. A second batch from Delphia was then investigated by use of two tests, i.e. the in vitro metaphase analysis with human lymphocytes and the in vivo micronucleus test in rat bone-marrow. Megazol was shown to be a potent inducer of in vitro and in vivo chromosomal aberrations. Although megazol is a potent trypanocidal agent and is orally bio-available, its toxicity dictates that it should not be developed further for the treatment of HAT and Chagas disease. All development work has therefore been discontinued.
Nesslany
Fabrice
F
Laboratoire de Toxicologie Génétique--Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019 Lille Cedex, France.
Brugier
Serge
S
Mouriès
Marie-Annick
MA
Le Curieux
Frank
F
Marzin
Daniel
D
D000818:Animals; D001711:Biotransformation; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013830:Thiadiazoles / Q000633:toxicity*; D014344:Trypanocidal Agents / Q000633:toxicity*
D009153:Mutagens; D013830:Thiadiazoles; D014344:Trypanocidal Agents; C013378:megazol