RPR-115135, a farnesyltransferase inhibitor, increases 5-FU- cytotoxicity in ten human colon cancer cell lines: role of p53.

Abstract

A new non peptidic farnesyltransferase inhibitor, RPR-115135, in combination with 5-FU was studied in 10 human colon cancer cell lines (HCT-116, RKO, DLD-1, Colo-320, LoVo, SW-620, HT-29, HCT-15, Colo-205 and KM-12) carrying several mutations but well characterized for p53 and Ras status. We found that there was a slight tendency (not statistically significant) for the p53 inactivated cells to be less sensitive to 5-FU after 6 days continuous treatment. Simultaneous administration of RPR-115135 and 5-FU, at subtoxic concentrations, resulted in a synergistic enhancement of 5-FU cytotoxicity in the p53 wildtype cells (HCT-116, RKO, DLD-1, Colo-320, LoVo). In the p53 mutated cells (SW-620, HT-29, HCT-15, Colo-205, KM-12) the effect was very complicated. In HCT-15 the combination resulted in antagonism, in KM-12 in antagonism or in synergy (at different concentrations) and in SW-620, HT-29 and Colo-205 cells in synergy but only when 5-FU was administered at high concentrations. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G2-M arrest), as assayed by flow cytometry, only in the p53 functioning cell lines. The combination RPR-115135 + 5-FU increases apoptotic events only in these cell lines. In the mutated cell lines no major alterations on cell cycle arrest phenotype and no induction of apoptosis was observed. Although RPR-115135 can potentiate the effect of 5-FU in cells in which p53 function is disrupted, these data suggest strongly that RPR-115135 significantly enhances the efficacy of 5-FU only when p53 is functioning.

• Authors: Patrizia Russo, Davide Malacarne, Carla Falugi, Sonya Trombino, Patrick M O'Connor
• Journal: International journal of cancer (Int J Cancer) Vol. 100 Issue 3 Pg. 266-75 (Jul 20 2002) ISSN: 0020-7136 [Print] United States
• PMID: 12115540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Wiley-Liss, Inc.

Chemical References

• Antimetabolites, Antineoplastic
• Enzyme Inhibitors
• Indoles
• RPR115135
• Tumor Suppressor Protein p14ARF
• Tumor Suppressor Protein p53
• Alkyl and Aryl Transferases
• Farnesyltranstransferase
• Fluorouracil

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Antimetabolites, Antineoplastic (pharmacology)
• Cell Cycle (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Enzyme Inhibitors (pharmacology)
• Farnesyltranstransferase
• Fluorouracil (pharmacology)
• Humans
• Indoles (pharmacology)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p14ARF (genetics)
• Tumor Suppressor Protein p53 (physiology)