Effect of RasGAP N2 fragment-derived peptide on tumor growth in mice

Abstract

Peptides that interfere with the natural resistance of cancer cells to genotoxin-induced apoptosis may improve the efficacy of anticancer regimens. We have previously reported that a cell-permeable RasGAP-derived peptide (TAT-RasGAP317-326) specifically sensitizes tumor cells to genotoxin-induced apoptosis in vitro. Here, we examined the in vivo stability of a protease-resistant D-form of the peptide, RI·TAT-RasGAP317-326, and its effect on tumor growth in nude mice bearing subcutaneous human colon cancer HCT116 xenograft tumors. After intraperitoneal injection, RI·TAT- RasGAP317-326 persisted in the blood of nude mice for more than 1 hour and was detectable in various tissues and subcutaneous tumors. Tumor-bearing mice treated daily for 7 days with RI·TAT-RasGAP317-326 (1.65 mg/kg body weight) and cisplatin (0.5 mg/kg body weight) or doxorubicin (0.25 mg/kg body weight) displayed reduced tumor growth compared with those treated with either genotoxin alone (n=5-7 mice per group; P=.004 and P=.005, respectively; repeated measures analysis of variance [ANOVA, two-sided]). This ability of the RI·TAT-RasGAP317-326 peptide to enhance the tumor growth inhibitory effect of cisplatin was still observed at peptide doses that were at least 150-fold lower than the dose lethal to 50% of mice. These findings provide the proof of principle that RI·TAT-RasGAP317-326 may be useful for improving the efficacy of chemotherapy in patients.