COMBINATION CHEMOTHERAPY - INTERACTION OF 5-METHOXYMETHYLDEOXYURIDINE WITH TRIFLUOROTHYMIDINE, PHOSPHONOFORMATE AND ACYCLOGUANOSINE AGAINST HERPES-SIMPLEX VIRUSES

Methoxymethyldeoxyuridine (MMUdR) when used in combination with either trifluorothymidine (F3TdR) or phosphonoformate (PFA) showed synergistic activity against herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) in vitro; MMUdR and acycloguanosine (ACG) combination was antagonistic against herpesviruses. HSV-1 mutants resistant to ACG, arabinofuranosyladenine (Ara-A), MMUdR or PFA were isolated. Drug-resistant HSV-1 virus mutants were analyzed for cross sensitivity to ACG, Ara-A, F3TdR, MMUdR, MMUdR-5''-monophosphate (MMUdR-MP) and PFA. The Ara-A-resistant (Ara-AR) virus exhibited 3-fold resistance to MMUdR-MP (ID50 [median inhibitory dose] = 105 .mu.M). The ACG-resistant (ACGR) mutant was 160-fold less sensitive to MMUdR (ID50 > 1138 .mu.M). The MMUdR-resistant (MMUdRR) mutant remained sensitive to all other antiviral drugs in vitro. Ara-A provided protection against HSV-1 encephalitis in immunosuppressed mice inoculated with a low dose (200 PFU[plaque-forming units]/mouse) of MMUdRR virus or wild-type HSV-1. F3TdR decreased incorporation of 3H-deoxyuridine ([3H]UdR) in RK-13 cells by 50% at 0.068 .mu.M. Under similar conditions, MMUdR (up to 600 .mu.M) and PFA (up to 208 .mu.M) were without effect on incorporation of [3H]UdR into DNA. In combination chemotherapy experiments, MMUdR (up to 300 .mu.M) used along with F3TdR (up to 1.08 .mu.M) neither decreased nor enhanced cytotoxicity of F3TdR as measured by incorporation of [3H]UdR into cellular DNA. Similarly, MMUdR (up to 300 .mu.M) in combination with PFA (up to 166 .mu.M) was nontoxic to host cells.