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: W C Rose, F Y Lee, C R Fairchild, M Lynch, T Monticello, R A Kramer, V Manne
• Journal: Cancer research (Cancer Res) Vol. 61 Issue 20 Pg. 7507-17 (Oct 15 2001) ISSN: 0008-5472 [Print] United States
• PMID: 11606387 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Imidazoles
• Benzodiazepines
• Alkyl and Aryl Transferases
• Farnesyltranstransferase
• ras Proteins
• 7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Apoptosis (drug effects)
• Benzodiazepines (pharmacology, toxicity)
• Cattle
• Drug Administration Schedule
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (pharmacology, toxicity)
• Farnesyltranstransferase
• Humans
• Imidazoles (pharmacology, toxicity)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Neoplasms (drug therapy, pathology)
• Neoplasms, Experimental (drug therapy, pathology)
• Xenograft Model Antitumor Assays
• ras Proteins (antagonists & inhibitors, metabolism)