COMPARISON OF THE SELECTIVITY OF ANTI-VARICELLA-ZOSTER VIRUS NUCLEOSIDE ANALOGS

We compared the selectivity of six anti-varicella-zoster virus (VZV) d rugs, which are clinically available or of which clinical efficacy for the treatment of VZV infections has been reported. Sorivudine (BV-ara U) had the most potent anti-VZV effect in the plaque inhibition assay, followed by brivudine (BVDU) and 5-propynyl-arabinofuranosyluracil (P ry-araU). All test compounds, except vidarabine (AraA), had only a ver y weak effect on human embryonic lung cell growth. The selectivity ind exes (ID50 for cell growth/ED(50) for VZV plaque inhibition) of BV-ara U, BVDU, and Pry-araU were > 1,000,000, 20,000, and > 10,000, respecti vely, while those of acyclovir and penciclovir ranged from 600 to 800. AraA was much less selective than any of the other drugs tested. We m easured the amount of [H-3] thymidine incorporated into the acid-insol uble fraction of VZV-infected cells to determine the ability of these drugs to selectively inhibit viral DNA synthesis. [H-3]Thymidine incor poration was markedly inhibited by all anti-VZV compounds, except BVDU . Treatment of infected cells with drugs from 32 to 38 hr after infect ion inhibited the DNA synthesis to the same extent as VZV plaque forma tion, except that AraA inhibited the DNA synthesis at a lower dose tha n for VZV plaque formation. DNA synthesis in non-infected growing cell s was inhibited to the same extent as cell growth. A particularly high selectivity index for the inhibition of DNA synthesis was noted for B V-araU, which was defined as the ratio of inhibitions of DNA synthesis in VZV-infected and non-infected. The highest selectivity indexes wer e recorded for BV-araU > Pry-araU > acyclovir greater than or equal to penciclovir) AraA.