A peptidomimetic inhibitor of ras functionality markedly suppresses growthof human prostate tumor xenografts in mice. Prospects for long-term clinical utility

Purpose: These studies sought to evaluate the antitumor properties of an in hibitor of ras functionality, L-744,832, which acts at the level of its ass ociated protein farnesyltransferase. Methods: Studies were carried out to m easure the effects of L-744,832 alone and in combination with paclitaxel (P TXL) against TSU-PR1, DU-145 and PC-3 human prostate tumors xenografted to NCR-nul (AT) mice. Tumor-bearing mice were treated on a schedule of daily f or 5 days x2 or 3 with the MTD of L-744,832 and every 3-4 days x4 with the MTD of PTXL starting 3-5 days after tumor implantation. Tumor volume in mil limeters (4/3 pi r(3)) was measured 3-5 days after cessation of treatment a nd the increase in tumor volume in treated and control groups compared. Sta tistical analysis was carried out by the Chi-squared test. Results: L-744,8 32 at its MTD markedly inhibited the growth of all three tumors (T/C for in crease in tumor mass varied from 11% to 15% and inhibition of growth had a rapid onset (within 1-2 days) and was independent of ras gene status. Estim ated tumor doubling times were 8-12-fold greater in treated animals than in control animals. Treatment with L-744,832 for as long as 3 weeks had no un toward effects on the mice as determined by gross examination or necropsy. Administration of L-744,832 with this same dose and schedule potentiated th e growth-inhibitory effect of PTXL at its MTD and induced some regression o f TSU-PR1 with no obvious deleterious effects on the mice. Conclusions: L-7 44,832 could be safely administered over a protracted period of time to mic e at doses which were markedly inhibitory to the growth of three human pros tate tumor xenografts and in combination with PTXL was also well tolerated and brought about some regression of the TSU-PR1 tumor. Overall, these resu lts suggest that L-744,832 could be clinically useful for long-term treatme nt of early-stage prostate cancer in patients and as an adjunct to cytotoxi c therapy for late stages of this disease.