title: In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]-guanine and related phosphonate nucleotide analogues.
abstract: Phosphonylmethoxyalkylpurine analogues were evaluated for their antitumor activity in murine tumor models. Three compounds, (S)-9-[(3-hydroxy-2-phosphonylmethoxy)propyl]adenine (HPMPA), 9-[(2-phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[(2-phosphonylmethoxy)ethyl]guanine (PMEG) were modestly active with treated versus control (T/C) values of 125%-175% versus intraperitoneal P388 leukemia, but were inactive versus intravenously implanted P388. The most active and most potent of the three was PMEG, which was also evaluated against subcutaneously (SC) implanted B16 melanoma. In confirmatory experiments, optimal therapy with PMEG yielded reproducible increases in life span (T/C values of 164%-170%) and delays in primary tumor growth (7.3- to 13.0-day T-C values). PMEG is representative of a new class of antitumor antimetabolites heretofore recognized only for their antiviral properties.
authors.affiliation: Pharmaceutical Research and Development Division, Bristol-Myers Squibb Company.
authors.forename: W C
authors.initials: WC
authors.lastname: Rose
authors.forename: A R
authors.initials: AR
authors.lastname: Crosswell
authors.forename: J J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: J C
authors.initials: JC
authors.lastname: Martin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; C063380:9-((2-phosphonylmethoxy)ethyl)guanine; D006147:Guanine