Treatment of murine cytomegalovirus infections in severe combined immunodeficient mice with ganciclovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, interferon, and bropirimine

Abstract

Severe combined immunodeficient (SCID) mice were found to be highly susceptible to murine cytomegalovirus (MCMV) infection. Treatment of infected mice with ganciclovir (12.5, 25, and 50 mg/kg of body weight for 10 days) starting 24 h after virus challenge resulted in delays in death by 2 to 8 days, and no animals survived the infection. (S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) was much more potent, with doses of 1, 3.2, and 10 mg/kg/day (for 10 days) increasing the mean survival time by 15 to 30 days. Twenty-day treatments with HPMPC starting 5 days after virus inoculation increased the mean survival time by 24 to 32 days, with once-weekly (50-mg/kg) treatments being equivalent to daily (10-mg/kg) treatments.Delays in the development of liver, lung, and spleen virus titers in ganciclovir-and HPMPC-treated groups correlated with extensions in the mean survival times relative to the survival times of the placebo controls. The two compounds were approximately equally toxic to uninfected BALB/c mice treated for 10 days, causing 80 to 1001% mortality after a dose of 150 mg/kg and 0%o mortality after a dose of 75 mg/kg. Thus, the relative therapeutic index of HPMPC was 50-fold greater than that of ganciclovir. Recombinant alpha interferon A4al/ai2 (1 x 1i0 and 5 x 104 units per mouse per day) and bropirimine (100 and 300 mg/kg/day) provided no protection from the lethal MCMV infection. The severe combined immunodeficient mouse MCMV infection is an important new model that will permit chemotherapy regimens to be studied over several months.Human cytomegalovirus (HCMV) causes generally benign disease in normal adult individuals with competent immune systems, but it causes serious infections in newborns (32) and immunosuppressed adults (17, 19). The two U.S. Food and Drug Administration-approved drugs for the treatment of HCMV infections (ganciclovir [GCV] and foscarnet) have toxic side effects (11,29), and the emergence of drugresistant viruses (6) In the study described here, we investigated the antiviral activities of GCV, HPMPC, recombinant alpha interferon A/D (rIFN-a A/D), and bropirimine against MCMV infections in genetically immunosuppressed mice. Since HCMV does not infect rodents, the related MCMV (9, 10) was used to evaluate these antiviral agents. Recent National Institutes of Health recommendations (12)

Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses

“…After treatments were discontinued, the live mice remaining in the cidofovir-treated group were dead by day 44 (data not shown). The fact that cidofovir could not prevent mortality in SCID mice infected with cowpox-WT virus corresponds to the results reported for cidofovir treatment of vaccinia virus (20) and murine cytomegalovirus (28) infections in this mouse strain.…”

Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections

“…Members of our group and others have used SCID mice inoculated with MCMV as a model for CMV infection in the murine compromised host (13,19,30,42,45). Since SCID mice are profoundly immunocompromised, approximately 1 to 3 PFU will result in a lethal infection.…”

Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections

“…Wherever cidofovir was directly compared for its antiviral efficacy with other antiviral drugs (acyclovir or ganciclovir), it proved clearly superior; e.g., to acyclovir, in the treatment of mice infected intracerebrally with HSV (69,227) and to ganciclovir in the treatment of both immunocompetent and immunodeficient mice infected with murine CMV (152,153,187). In the treatment of acute murine CMV-induced myocarditis in mice, with treatment beginning 24 h postinfection, cidofovir was also clearly more efficacious than ganciclovir (125).…”