PROTEIN FARNESYLTRANSFERASE INHIBITORS BLOCK THE GROWTH OF RAS-DEPENDENT TUMORS IN NUDE-MICE

The posttranslational addition of a farnesyl moiety to the Ras oncopro tein is essential for its transforming activity. Cell-active inhibitor s of the enzyme that catalyzes this reaction, protein farnesyltransfer ase, have been shown to selectively block ras dependent transformation of cells in culture. Here we describe the protein farnesyltransferase inhibitor S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl] pentylox y-3-phenylpropionylmethioninesulfone methyl ester (L-739,749), which s uppressed the anchorage independent growth of Rat1 cells transformed w ith viral H-ras and the human pancreatic adenocarcinoma cell line PSN- 1, which harbors altered K-ras, myc, and p53 genes. This compound also suppressed the growth of tumors arising from ras-transformed Rat1 cel ls in nude mice by 66%. Under the same conditions, doxorubicin inhibit ed tumor growth by 33%. Control tumors formed by v-raf or v-mos transf ormed Rat1 cells were unaffected by L-739,749. Furthermore, mice treat ed with L-739,749 exhibited no evidence of systemic toxicity. This is a demonstration of antitumor activity in vivo using a synthetic small molecule inhibitor of protein farnesyltransferase.