Vol. 300, Issue 1, 220-226, January 2002

Nonpeptidomimetic Farnesyltransferase Inhibitor RPR-115135 Increases Cytotoxicity of 5-Fluorouracil: Role of p53

Patrizia Russo , Cristina Ottoboni , Davide Malacarne, Alessandra Crippa, Jean-Francois Riou¹ and Patrick M. O'Connor²

Laboratory of Molecular Pharmacology, Division Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (P.R., C.O., P.M.O.); Laboratory Experimental Oncology, Molecular Pathology Section, National Institute for Research on Cancer, Genova, Italy (P.R., C.O., D.M., A.C.); and Anticancer Research Program, Centre de Recherche Rhone-Poulenc Rorer-Aventis Pharma, Vitry sur Seine, France (J.-F.R.)

A new nonpeptidic farnesyltransferase inhibitor, RPR-115135, in combination with 5-fluorouracil (5-FU) was studied in an isogenic cell line model system consisting of human colon cancer HCT-116 cells. HCT-116 cells were transfected with an empty control pCMV vector and with a dominant-negative mutated p53 transgene (248R/W). We found that, relative to control transfectants, there was a slight tendency for the p53 inactivated cells to be less sensitive to 5-FU after 6 days of continuous treatment. Simultaneous administration of RPR-115135 and 5-FU, at equitoxic concentrations, resulted in an enhancement of 5-FU cytotoxicity, especially in the CMV-2 clone. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G₂-M arrest in CMV-2 and S arrest in mutated clones), as assayed by flow cytometry. The combination RPR-115135 + 5-FU increases apoptotic events only in the CMV-2 clone.