A peptidomimetic inhibitor of ras functionality markedly suppresses growth of human prostate tumor xenografts in mice. Prospects for long-term clinical utility.
OBJECTIVE
These studies sought to evaluate the antitumor properties of an inhibitor of ras functionality, L-744,832, which acts at the level of its associated protein farnesyltransferase.


METHODS
Studies were carried out to measure the effects of L-744,832 alone and in combination with paclitaxel (PTXL) 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 for 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 millimeters (4/3pir3) was measured 3 5 days after cessation of treatment and the increase in tumor volume in treated and control groups compared. Statistical analysis was carried out by the Chi-squared test.


RESULTS
L-744,832 at its MTD markedly inhibited the growth of all three tumors (TIC for increase 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. Estimated 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 untoward effects on the mice as determined by gross examination or necropsy. Administration of L-744,832 with this same dose and schedule potentiated the growth-inhibitory effect of PTXL at its MTD and induced some regression of TSU-PR1 with no obvious deleterious effects on the mice.


CONCLUSIONS
L-744,832 could be safely administered over a protracted period of time to mice at doses which were markedly inhibitory to the growth of three human prostate tumor xenografts and in combination with PTXL was also well tolerated and brought about some regression of the TSU-PR1 tumor. Overall, these results suggest that L-744,832 could be clinically useful for long-term treatment of early-stage prostate cancer in patients and as an adjunct to cytotoxic therapy for late stages of this disease.
Laboratory for Molecular Pharmacology and Experimental Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. sirotnaf@mskcc.org
F M
FM
Sirotnak
L
L
Sepp-Lorenzino
N E
NE
Kohl
N
N
Rosen
H I
HI
Scher
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D006131:Growth Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D018716:Molecular Mimicry; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D006131:Growth Inhibitors; C096898:L 744832; D008715:Methionine; D018631:ras Proteins; D017239:Paclitaxel