Comparison of the genotoxic and apoptosis-inducing properties of ganciclovir and penciclovir in Chinese hamster ovary cells transfected with the thymidine kinase gene of herpes simplex virus-1: Implications for gene therapeutic approaches

We studied the genotoxic and apoptosis-inducing properties of ganciclovir ( GCV) and penciclovir (PCV) using Chinese hamster ovary cells stably transfe cted with the thymidine kinase (tk) gene of herpes simplex virus-1 (HSV-1). Cells expressing HSVrk were 300 and 100 times more sensitive than their is ogenic HSVtk(-) counterparts to the cytotoxic effects of CCV and PCV, respe ctively. Using radiolabeled drugs, CCV was found to be incorporated into th e genomic DNA much more effectively than PCV. CCV was highly potent in indu cing chromosomal aberrations compared with PCV, which provoked less sister chromatid exchanges and chromosomal changes using equimolar or equitoxic do ses. For both agents, apoptosis was shown to be the major route of cell kil ling. Time course experiments revealed that neither genotoxicity nor apopto sis were induced within the cell cycle exposed to the drug; they are late e vents provoked in the following cell cycle(s). This indicates that the inco rporation/exposure step of CCV or PCV into DNA is not decisive for triggeri ng genotoxicity and apoptosis, but that events occurring subsequently, pres umably during replication of a DNA containing the nucleotide analogs, are o f major importance. Because PCV, unlike CCV, induced highly effectively apo ptosis without exerting much genotoxicity, the use of PCV as a relatively s ale alternative drug for suicide gene therapy of malignant diseases is reco mmended.