Lovastatin enhances the genotoxicity of doxorubicin in Chinese hamster V79 cells via noncovalent DNA binding.
The 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase inhibitor, lovastatin (lova), has been reported to both sensitize to, and protect against, the toxic effects of the antitumor anthracycline doxorubicin (dox) in cellular and in vivo systems. The mechanism by which these effects occur has not yet been determined. In the present study, lova is shown to enhance the genotoxicity of dox in the V79 cell in vitro micronucleus assay and to do so, most likely, via noncovalent interaction with DNA adjacent to sites of dox binding. These studies confirm and extend the experimental evidence strongly suggesting the importance of noncovalent drug/DNA interactions in cellular responses to genotoxic stimuli.
Snyder
Ronald D
RD
Schering-Plough Research Institute, Summit, New Jersey, USA. ronald.snyder@spcorp.com
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004357:Drug Synergism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity; D008148:Lovastatin / Q000633:toxicity*; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*
D000903:Antibiotics, Antineoplastic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009153:Mutagens; D004317:Doxorubicin; D004247:DNA; D008148:Lovastatin