The farnesyl transferase inhibitor SCH 66336 induces a G(2) -> M or G(1) pause in sensitive human tumor cell lines

SCH 66336 is a potent farnesyl transferase inhibitor (FTI) in clinical deve lopment. It efficiently prevents the membrane association of H-ras, but not K- or N-ras. Yet, in soft agar, it reverts the anchorage-independent growt h of human tumor cell lines (hTCLs) harboring H-ras, R-ras, and N-ras mutat ions, implying that blocking farnesylation of proteins besides ras ma; be r esponsible for this effect. Experiments show that SCH 66336 altered the cel l cycle distribution of sensitive human tumor cells in two distinct ways. M ost sensitive hTCLs accumulated in the G(2)-->M phase after the FTI treatme nt, but those with an activated H-ras accumulated in G(1) phase, suggesting that the biological effects induced by FTIs in cells with an activated H-r as are distinct from other sensitive cells. A careful genotypic comparison of the hTCLs revealed that those cells with wild-type p53 are especially se nsitive to the FTIs. In these cells p53 and its downstream target gene p21( Cip1) are induced after treatment with SCH 66336 for 24 h. These data sugge st that cell cycle effects, either G(1) or G(2)-->M accumulation, and p53 s tatus are important for mediating the effects of FTIs on tumor cells. (C) 2 001 Academic Press.