In vitro photogenotoxic activity of clinafloxacin: a paradigm predicting photocarcinogenicity.
Fluoroquinolone antiinfective drugs exhibit phototoxic, photogenotoxic, and photocarcinogenic activities in experimental systems which may be interrelated. Clinafloxacin (CLX), a new fluoroquinolone, is a potent antiinfective agent being developed for use in life-threatening infections. While this drug has previously been demonstrated to be phototoxic, this report evaluated the photogenotoxic and photocarcinogenic potential of CLX. When Skh-1 mice were administered CLX in the presence of ultraviolet light (UVA) at the maximum tolerated dose expected for a photocarcinogenicity bioassay, induction of DNA strand breakage was noted in keratinocytes isolated from these animals. When compared with other well-studied fluoroquinolones in vitro, CLX and Lomefloxacin (LMX) were equally effective in producing chromosome damage and DNA strand breakage in Chinese hamster ovary (CHO) cells exposed to UVA. Treatment of CHO cells with CLX in the presence of UVA also resulted in hydroxyl radical formation. However, coincubation of CHO cells with CLX and various antioxidants markedly reduced hydroxyl radical formation, but inhibited photogenotoxicity only to a limited extent. Thus, while reactive oxygen species contribute to the photogenotoxic activity of CLX, other factors may be involved. Since CLX exhibits both phototoxic and photogenotoxic activity, we predict that CLX would be photocarcinogenic in vivo. The present study suggests that under conditions of human exposure, the potential risk for CLX-induced photocarcinogenicity is small.
Bulera
S J
SJ
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan, USA.
Theiss
J C
JC
Festerling
T A
TA
de la Iglesia
F A
FA
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D016466:CHO Cells; D015197:Carcinogenicity Tests; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D024841:Fluoroquinolones; D016166:Free Radical Scavengers / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D014466:Ultraviolet Rays / Q000009:adverse effects*
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D016166:Free Radical Scavengers; D017665:Hydroxyl Radical; D000493:Allopurinol; C057477:clinafloxacin; D004247:DNA