9-(2-Phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP): a novel agent with anti-human immunodeficiency virus activity in vitro and potent anti-Moloney murine sarcoma virus activity in vivo.
9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) is a potent inhibitor of the replication of human immunodeficiency virus (HIV) in human T-lymphocyte MT-4 cells (50% effective dose: 2 microM). PMEDAP strongly inhibited Moloney murine sarcoma virus (MSV)-induced transformation of murine C3H/3T3 embryo fibroblasts and caused a dose-dependent suppression of tumor formation and mortality in newborn mice inoculated with MSV. Even at a dose as low as 0.25 mg/kg/day, PMEDAP effected a significant delay in tumor appearance and an enhancement of the survival rate of tumor-bearing mice. PMEDAP proved fivefold more efficacious as an anti-MSV agent than 9-(2-phosphonylmethoxyethyl)-adenine (PMEA), which has been previously shown to exhibit strong antiretroviral efficacy in vivo. However, PMEDAP was also more toxic, so that its therapeutic index was equivalent to that of PMEA.
Naesens
L
L
Rega Institute for Medical Research, Katholieke Universiteit, Leuven, Belgium.
Balzarini
J
J
Rosenberg
I
I
Holý
A
A
De Clercq
E
E
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004622:Embryo, Mammalian / Q000166:cytology; D006678:HIV / Q000502:physiology*; D006801:Humans; D051379:Mice; D008980:Moloney murine sarcoma virus / Q000378:metabolism / Q000502:physiology*; D009053:Sarcoma Viruses, Murine / Q000502:physiology*; D013601:T-Lymphocytes / Q000382:microbiology*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D000225:Adenine