Effects of monoclonal antibody combined with ganciclovir or (S)-1-[3-hydroxy-(2-phosphonylmethoxy)-propyl]cytosine against murine cytomegalovirus infections in cell culture and in severe combined immunodeficient mice.

The effects of monoclonal antibody used in combination with ganciclovir (GCV) or (S)-1-[3-hydroxy-(2-phosphonylmethoxy)propyl]cytosine (HPMPC) against murine cytomegalovirus (MCMV) were determined in vitro and in vivo, in mice. The antibody and drug were added to cell cultures 24 h after MCMV adsorption so as not to affect the initial infection rate. The antibody (at 1.25-20 micrograms/ml) combined with GCV (0.3-5 microM) or HPMPC (0.008-0.125 microM) caused synergistic inhibition of virus yield in C127I cells. No toxic effect on cell growth in culture was observed at these antibody/drug combinations. The effects of antibody and GCV treatments were studied in MCMV-infected severe combined immunodeficient (SCID) mice. Antibody treatments (2.5 mg/kg/day) given by intraperitoneal injection every 3 days starting 24 h after virus inoculation extended survival time by 1 day relative to placebo-treated animals. Once daily, intraperitoneal treatments with GCV (25 and 50 mg/kg/day) for 7 days starting at 24 h after virus inoculation extended survival time 9-11 days. The combination of antibody plus GCV was only slightly better than GCV alone, indicating an additive interaction.

Nucleotide analogs related to acyclovir and ganciclovir are effective against murine cytomegalovirus infections in BALB/c and severe combined immunodeficient mice.

Acyclovir phosphonate [9-(3-phosphono-propyloxymethyl)guanine; SR3722] and the S enantiomer (SR3772), R enantiomer (SR3773), and R,S enantiomeric mixture (SR3745A) of ganciclovir phosphonate (9-[((+/-)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine) were evaluated for their antiviral activities against murine cytomegalovirus. In severe combined immunodeficient mice infected with murine cytomegalovirus, SR3773 and SR3745A (12.5, 25, and 50 mg/kg of body weight per day) were superior to ganciclovir in extending the mean time to death, whereas SR3722 and SR3772 was less potent than ganciclovir. In normal BALB/c mice, SR3773 and ganciclovir were approximately equally active in preventing death. SR3773 caused renal tubular damage when administered at 50 mg/kg/day for 15 days. These results suggest that SR3773 may have potential for use in the treatment of human cytomegalovirus infections, but it may also exhibit renal toxicity.