Cytogenetic genotoxicity of antiherpes virostatics in Chinese hamster V79-E cells. I. Purine nucleoside analogues.
The antiherpes virostatics acyclovir (ACV), valaciclovir (VACV), penciclovir (PCV), famciclovir (FCV) and ganciclovir (GCV), which belong to the group of purine acyclic nucleoside analogues, were tested for clastogenic and sister chromatid exchange (SCE)-inducing activity in Chinese hamster V79-E cells upon chronic application with and without a recovery period. ACV induced borderline effects in both cytogenetic assays, a dose-dependent reduction of the mitotic index and an increasing cell cycle delay. With VACV and PCV only a decrease of the mitotic index and an increase of cell cycle delay were observed. FCV was negative with respect to the four parameters studied, presumably due to the incapacity of the target cells of metabolizing FCV to PCV. GCV was a very potent genotoxin in both assays. It induced a statistically significant SCE response even in the range of the cytomegalovirus IC50 of < 10 microM. By variation of the experimental protocol it was shown that SCEs are induced in the second cell cycle following exposure to GCV but not in the first one. It is assumed that the drugs under study are metabolized to their respective triphosphates and then inhibit DNA replication as detected by decreasing mitotic index and increasing cell cycle delay. In the case of GCV it is suggested that GCV-TP is incorporated into the target cell DNA and that chromosomal aberrations and SCEs are secondary lesions due to repair processes at the substituted template.
Thust
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Institute for Antiviral Chemotherapy, Friedrich Schiller University of Jena, Erfurt, Germany.
Schacke
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Wutzler
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D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000633:toxicity; D000212:Acyclovir / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000077595:Famciclovir; D015774:Ganciclovir / Q000633:toxicity*; D006147:Guanine; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000633:toxicity
D009153:Mutagens; C053539:penciclovir; D015075:2-Aminopurine; D006147:Guanine; D014633:Valine; D000077483:Valacyclovir; D015774:Ganciclovir; D000077595:Famciclovir; D000212:Acyclovir