Zidovudine Antagonizes the Antiviral Effects of Ganciclovir against Cytomegalovirus Infection in Cultured Cells and in Guinea Pigs

Abstract

The antiviral effects of ganciclovir (DHPG) combined with zidovudine (AZT) at several dosages against cytomegalovirus infection were evaluated in cultured cells and in Hartley guinea pigs. Combinations of DHPG and AZT at fixed ratios ranging from 1:0.1 to 1:1 showed reduced antiviral effects of DHPG in cultured human lung fibroblast (HEL) cells and guinea pig embryo (GPE) cells infected with human cytomegalovirus and guinea pig cytomegalovirus, respectively. Synergistic cytotoxicity (CI values < 1) was noted in HEL and GPE cell cultures at all DHPG/AZT combinations tested. In vivo experiments using a fixed ratio at three dosage levels for treatment of GPCMV infected guinea pigs for 5 days did not show significant antagonistic antiviral nor synergistic toxic effects at lower dosages. When GPCMV infected guinea pigs were treated with DHPG and AZT in combinations at 40/20, 40/40 and 40/80 mg kg−1 day 1 for 7 days, a significant increase of GPCMV infectivity titres in the salivary gland, lung and spleen were noted when compared with those animals treated with DHPG 40mg kg−1 day−1 alone. In addition, histopathological findings showed more cytotoxicity in the bone marrow of infected and non-infected animals treated wth DHPG/AZT combinations than animals treated with each drug alone. These results suggest that AZT antagonizes the antiviral effects of DHPG against HCMV and GPCMV replication in cultured cells and GPCMV infection in guinea pigs with increased cytotoxicity in cultured cells and in bone marrow of animals receiving the drug combinations.