R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 ؉ 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-weekoff schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/ schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras, 3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-␣ (TNF-␣) levels by day 7 showed a trend toward correlation with response (P ‫؍‬ .09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS.

Abstract. The two eosinophil ribonucleases, eosinophil-derived neurotoxin (EDN/RNase 2) and eosinophil cationic protein (ECP/RNase 3), are among the most rapidly evolving coding sequences known among primates. The eight mouse genes identified as orthologs of EDN and ECP form a highly divergent, species-limited cluster. We present here the rat ribonuclease cluster, a group of eight distinct ribonuclease A superfamily genes that are more closely related to one another than they are to their murine counterparts. The existence of independent gene clusters suggests that numerous duplications and diversification events have occurred at these loci recently, sometime after the divergence of these two rodent species (∼10-15 million years ago). Nonsynonymous substitutions per site (d N ) calculated for the 64 mouse/rat gene pairs indicate that these ribonucleases are incorporating nonsilent mutations at accelerated rates, and comparisons of nonsynonymous to synonymous substitution (d N / d S ) suggest that diversity in the mouse ribonuclease cluster is promoted by positive (Darwinian) selection. Although the pressures promoting similar but clearly independent styles of rapid diversification among these primate and rodent genes remain uncertain, our recent findings regarding the function of human EDN suggest a role for these ribonucleases in antiviral host defense.