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, whereas MMUdR and acycloguanosine (ACG) combination was antagonistic against herpes viruses. 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 = 105 microM). The ACG-resistant (ACGR) mutant was 160-fold less sensitive to MMUdR (ID50 greater than 1138 microM). 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/mouse) of MMUdRR virus or wild-type HSV-1. F3TdR decreased incorporation of tritiated deoxyuridine [( 3H]UdR) in RK-13 cells by 50% at 0.068 microM. Under similar conditions, MMUdR (up to 600 microM) and PFA (up to 208 microM) were without effect on incorporation of [3H]UdR into DNA. In combination chemotherapy experiments, MMUdR (up to 300 microM) used along with F3TdR (up to 1.08 microM) neither decreased nor enhanced cytotoxicity of F3TdR as measured by incorporation of [3H]UdR into cellular DNA. Similarly, MMUdR (up to 300 microM) in combination with PFA (up to 166 microM) was nontoxic to host cells.