title: Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor.
abstract: BMS-214662 is a potent and selective inhibitor of farnesyltransferase (FTI). In rodent fibroblasts transformed by oncogenes, BMS-214662 reversed the H-Ras-transformed phenotype but not that of K-Ras or other oncogenes. In soft agar growth assays, BMS-214662 showed good potency in inhibiting H-ras-transformed rodent cells, A2780 human ovarian carcinoma tumor cells, and HCT-116 human colon carcinoma tumor cells. Inhibition of H-Ras processing in HCT-116 human colon tumor cells was more rapid than in H-Ras-transformed rodent fibroblast tumors. BMS-214662 is the most potent apoptotic FTI known and demonstrated broad spectrum yet robust cell-selective cytotoxic activity against a panel of cell lines with diverse histology. The presence of a mutant ras oncogene was not a prerequisite for sensitivity. Athymic and conventional mice were implanted s.c. with different histological types of human and murine tumors, respectively. BMS-214662 was administered both parenterally and p.o. and was active by all these routes. Curative responses were observed in mice bearing staged human tumor xenografts including HCT-116 and HT-29 colon, MiaPaCa pancreatic, Calu-1 lung, and EJ-1 bladder carcinomas. A subline of HCT-116, HCT-116/VM46, resistant to many standard cytotoxic agents by means of a multiple drug resistance mechanism, remained quite susceptible to BMS-214662, and borderline activity was achieved against N-87 human gastric carcinoma. Two murine tumors, Lewis lung carcinoma and M5076 sarcoma, were insensitive to the FTI. In a study performed using Calu-1 tumor-bearing mice, no obvious schedule dependency of BMS-214662 was observed. The FTI, BMS-214662, demonstrated broad spectrum activity against human tumors, but murine tumors were not as sensitive.
authors.affiliation: Pharmaceutical Research Institute, Oncology Drug Discovery, Bristol-Myers Squibb Company, Inc., Princeton, New Jersey 08543, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Rose
authors.forename: F Y
authors.initials: FY
authors.lastname: Lee
authors.forename: C R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: M
authors.initials: M
authors.lastname: Lynch
authors.forename: T
authors.initials: T
authors.lastname: Monticello
authors.forename: R A
authors.initials: RA
authors.lastname: Kramer
authors.forename: V
authors.initials: V
authors.lastname: Manne
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology* / Q000633:toxicity; D002417:Cattle; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D051231:Farnesyltranstransferase; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D001569:Benzodiazepines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine