Effects of SCH 59228, an orally bioavailable farnesyl protein transferase inhibitor, on the growth of oncogene-transformed fibroblasts and a human colon carcinoma xenograft in nude mice

The products of the Ha-, Ki-, and N-ras proto-oncogenes comprise a family o f 21 kDa guanine nucleotide-binding proteins which play a crucial role in g rowth factor signal transduction and in the control of cellular proliferati on and differentiation. Activating mutations in the I ns oncogenes occur in a wide variety of human tumors. Ras proteins undergo a series of posttrans lational processing events. The first modification is addition of the 15-ca rbon isoprene, farnesyl, to a Cys residue near the carboxy-terminus of Ras. Prenylation allows the Ras oncoprotein to localize to the plasma membrane where it can initiate downstream signalling events leading to cellular tran sformation. Inhibitors of the enzyme which catalyzes this step, farnesyl pr otein transferase (FPT), are a potential class of novel anticancer drugs wh ich interfere with Ras function. SCH 59228 is a tricyclic FPT inhibitor whi ch inhibits the farnesylation of purified Ha-Ras with an IC50 Of 95 nM and blocks the processing of Ha-Ras in Cos cells with an IC50 of 0.6 mu M. SCH 59228 has favorable pharmacokinetic properties upon oral dosing in nude mic e. The in vivo efficacy of SCH 59228 was evaluated using a panel of tumor m odels frown in nude mice. These included several rodent fibroblast lines ex pressing mutationally-activated (val(12)) forms of the Ha-Ras oncogene. In some cases, these proteins contain their native C-terminal sequence (CVLS) which directs farnesylation. In one model, the C-terminal sequence was alte red to CVLL, making the expressed protein a substrate for a distinct prenyl transferase, geranylgeranyl protein transferase-1. When dosed orally at 10 and 50 mg/kg (four times a day, 7 days a week) SCH 59228 significantly inh ibited tumor growth of cells expressing farnesylated Ha-Ras in a dose-depen dent manner; over 90% growth inhibition was observed at the 50 mg/kg dose. Tumor growth of cells expressing the geranylgeranylated form of Ha-Ras was less potently inhibited. Growth of tumors derived from a rodent fibroblast line expressing activated Ki-Ras containing its native C-terminal sequence (CVIM), which preferentially directs farnesylation, was also inhibited by S CH 59228. Inhibition in the Ki-Ras model was less than that observed in the Ha-Ras model. In contrast, tumors derived from cells transformed with the mos oncogene were not significantly inhibited even at the highest dose leve l. SCH 59228 also significantly and dose-dependently inhibited the growth o f human colon adenocarcinoma DLD-1 xenografts (which express activated Ki-r as). These results indicate that SCH 59228 possesses in vivo antitumor acti vity upon oral dosing in tumor models expressing activated ms oncogenes. Th is is the first report of oral antitumor activity with an FPT inhibitor. Th ese results are discussed in light of recent observations on alternative pr enylation of some Ras isoforms.