l-744832 and Prostatic-Neoplasms

Ras activation by mutation, overexpression, or receptor signaling can increase tumor cell survival after irradiation.. We examined whether inhibiting Ras activity with farnesyltransferase inhibitors (FTI) altered the radiosensitivity and tumor micro-environment in prostate tumors.. Treatment with FTIs L-744,832 or FTI-277 reduced clonogenic survival of prostate tumor cells expressing oncogenic H-ras after irradiation. PI3-kinase/Akt and MAPK signaling pathways were downregulated by FTIs in these cells. FTI treatment reduced tumor hypoxia and also reduced MMP-9 expression in tumors with activated mutant H-ras. FTI treatment did not, however, increase apoptosis in irradiated intestine, demonstrating that acute radiation injury of this normal tissue was not enhanced by FTIs.. FTIs can enhance the killing of prostate tumors with activated H-Ras. Together with the absence of increased acute toxicity to normal bowel, these results imply that FTI treatment should be further studied as a possible adjuvant to radiotherapy in the treatment of abdominal cancers with activated Ras signaling.

Topics: Alkyl and Aryl Transferases; Animals; Apoptosis; Cell Line, Tumor; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Humans; Male; Matrix Metalloproteinase 9; Methionine; Mice; Mice, Nude; Mitogen-Activated Protein Kinases; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; Xenograft Model Antitumor Assays

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.. 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.. 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.. 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.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Growth Inhibitors; Humans; Male; Methionine; Mice; Mice, Nude; Models, Chemical; Molecular Mimicry; Neoplasm Transplantation; Paclitaxel; Prostatic Neoplasms; ras Proteins; Transplantation, Heterologous; Tumor Cells, Cultured