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

David Michod1, Alessandro Annibaldi, Stephan Schaefer

  • 1Department of Physiology, University of Lausanne, Lausanne, Switzerland.

Journal of the National Cancer Institute
|May 28, 2009
PubMed

Insights

A new peptide, RI.TAT-RasGAP(317-326), enhances chemotherapy by sensitizing colon cancer cells to genotoxins. This peptide shows in vivo stability and improves tumor growth inhibition with cisplatin and doxorubicin.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cancer cells possess natural resistance to genotoxin-induced apoptosis, limiting chemotherapy efficacy.
  • Previous studies identified a RasGAP-derived peptide (TAT-RasGAP(317-326)) that sensitizes tumor cells to genotoxins in vitro.
  • The development of protease-resistant peptide analogs is crucial for in vivo applications.

Purpose of the Study:

  • To evaluate the in vivo stability of a protease-resistant D-form peptide, RI.TAT-RasGAP(317-326).
  • To assess the effect of RI.TAT-RasGAP(317-326) on human colon cancer HCT116 xenograft tumor growth in nude mice.
  • To determine if RI.TAT-RasGAP(317-326) can enhance the efficacy of genotoxic chemotherapeutic agents.

Main Methods:

  • Intraperitoneal injection of RI.TAT-RasGAP(317-326) in nude mice to assess pharmacokinetic properties.
  • Treatment of HCT116 xenograft tumor-bearing mice with RI.TAT-RasGAP(317-326) in combination with cisplatin or doxorubicin.
  • Tumor growth inhibition was measured and analyzed using repeated measures analysis of variance (ANOVA).

Main Results:

  • RI.TAT-RasGAP(317-326) demonstrated persistence in mouse blood for over 1 hour and was detectable in tissues and tumors.
  • Combined treatment with RI.TAT-RasGAP(317-326) and cisplatin or doxorubicin significantly reduced tumor growth compared to genotoxin alone (P = .004 and P = .005, respectively).
  • Enhanced tumor growth inhibition was observed even at peptide doses 150-fold lower than the median lethal dose (LD50).

Conclusions:

  • The protease-resistant peptide RI.TAT-RasGAP(317-326) exhibits favorable in vivo stability and pharmacokinetic properties.
  • RI.TAT-RasGAP(317-326) effectively enhances the anti-tumor activity of genotoxic chemotherapy agents like cisplatin and doxorubicin.
  • These findings support the potential clinical utility of RI.TAT-RasGAP(317-326) for improving chemotherapy outcomes in cancer patients.

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