Cytogenetic genotoxicity of anti-herpes purine nucleoside analogues in CHOcells expressing the thymidine kinase gene of herpes simplex virus type 1:comparison of ganciclovir, penciclovir and aciclovir

The three anti-herpes nucleoside analogues ganciclovir, penciclovir and aci clovir were investigated as to their recombinogenic [sister chromatid excha nge (SCE) inducing] and clastogenic activity in CHO cells expressing the th ymidine kinase gene of HSV-1, which is a precondition of therapeutic activi ty of these drugs. The compounds were applied for the duration of one cell cycle and cytogenetic end-points were measured between 0 and 42 h after exp osure, Although the nucleoside analogues are quite similar with respect to chemical structure, they differ basically in their genotoxic potency, aberr ation types induced as well as the time course of chromosomal damage, Acicl ovir induced SCEs and chromosomal aberrations immediately after exposure bu t only in a concentration range much higher than that reached in blood plas ma during antiherpes therapy. The direct genotoxic activity is explained by the obligate chain terminating property of aciclovir upon incorporation in to genomic DNA, On the other hand, genotoxic damage caused by ganciclovir a nd penciclovir is of the delayed type requiring at least one post-exposure cell cycle for its expression. Unlike aciclovir, ganciclovir is an extremel y potent inducer of SCEs and chromosome breaks and translocations at concen trations far below those impairing the proliferative activity and triggerin g apoptosis of the target cells las shown by our previous investigation). P enciclovir is essentially devoid of genotoxic activity. It induces SCEs onl y at cytotoxic/apoptotic concentrations, is only weakly clastogenic and ind uces premature chromosome condensation which appears to result from uncoupl ing of karyokinesis and cytokinesis, The genotoxic activity of ganciclovir is explained as due to repair processes triggered in the second post-exposu re replication cycle at the sites of nucleoside analogue incorporation into genomic DNA, The findings have considerable implications with respect to t he use of ganciclovir or other antiviral drugs in suicide gene therapy of m alignant diseases.