Pronounced cytostatic activity and bystander effect of a novel series of fluorescent tricyclic acyclovir and ganciclovir derivatives in herpes simplex virus thymidine kinase gene-transduced tumor cell lines

A number of tricyclic acyclovir (ACV) and ganciclovir (GCV) derivatives substituted with bulky lipophilic groups have been identified as potent and highly selective cytostatic agents against herpes simplex virus type 1 (HSV-1)-thymidine kinase (TK) gene-transduced human osteosarcoma and murine mammary carcinoma tumor cells. Although their affinity for HSV-1 TK was inferior to that of ACV or GCV, their cytostatic potency and selectivity was at least as high as observed for the parental ACV and GCV compounds. The tricyclic ACV and GCV derivatives were also endowed with a very pronounced bystander effect in cell culture, albeit at relatively high drug concentrations. Unlike ACV and GCV, the tricyclic purine derivatives are endowed with intrinsically strong fluorescent properties, which allow simple and sensitive monitoring of drug concentrations in biological fluids and tissues. Also, the lipophilicity of the tricyclic purine derivatives is much higher than that of ACV and GCV, and this may allow better uptake of these derivatives from the blood into the central nervous system.