Journal of the National Cancer Institute Advance Access published online on May 26, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp100
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© The Author 2009. Published by Oxford University Press.
BRIEF COMMUNICATION |
Effect of RasGAP N2 Fragment–Derived Peptide on Tumor Growth in Mice
Affiliations of authors: Department of Physiology (DM, AA, CW), Department of Pathology (SS, CD), and Quantitative Mass Spectrometry Facility, University Hospital Center (BR), University of Lausanne, Lausanne, Switzerland
Correspondence to: Christian Widmann, PhD, Department of Physiology, University of Lausanne, Rue du Bugnon 7/9, 1005 Lausanne, Switzerland (e-mail: christian.widmann{at}unil.ch).
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.
| CONTEXT AND CAVEATS Prior knowledge Peptides that interfere with the natural resistance of cancer cells to genotoxin-induced apoptosis in vitro, such as TAT-RasGAP317–326, a cell-permeable RasGAP-derived peptide, may improve the efficacy of anticancer regimens in vivo. Study design Examination of the in vitro and 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. Contribution RI·TAT-RasGAP317–326 was stable in biological fluids, and after injection into mice, it persisted in the bloodstream for more than 1 hour, reached distant tissues and subcutaneous tumors, was effective at doses at least 150-fold below the dose lethal to 50% of mice, and improved the efficacy of genotoxins. Implications RI·TAT-RasGAP317–326 may be useful for improving the efficacy of chemotherapy in patients. Limitations Tumors in nude (ie, immunocompromised) mice may not behave the same as syngeneic tumors in immunocompetent mice. From the Editors
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D. Michod and A. Annibaldi contributed equally to this work.
We thank Dr Rudolf Kraftsik for the statistical analyses of the data.
Manuscript received April 30, 2008; revised February 19, 2009; accepted March 27, 2009.
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J Natl Cancer Inst 2009 101: 769.