Article: article from journal or magazin.
Effect of RasGAP N2 fragment-derived peptide on tumor growth in mice.
Journal of the National Cancer Institute
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-RasGAP(317-326)) 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-RasGAP(317-326), and its effect on tumor growth in nude mice bearing subcutaneous human colon cancer HCT116 xenograft tumors. After intraperitoneal injection, RI.TAT-RasGAP(317-326) 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-RasGAP(317-326) (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-RasGAP(317-326) 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-RasGAP(317-326) may be useful for improving the efficacy of chemotherapy in patients.
Amino Acid Sequence, Animals, Antineoplastic Agents/administration & dosage, Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Cisplatin/pharmacology, Colonic Neoplasms/drug therapy, Colonic Neoplasms/pathology, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor/methods, Drug Synergism, GTPase-Activating Proteins/administration & dosage, GTPase-Activating Proteins/pharmacology, HCT116 Cells, Humans, Infusions, Parenteral, Mice, Mice, Nude, Molecular Sequence Data, Mutagens/pharmacology, Peptide Fragments/administration & dosage, Peptide Fragments/pharmacology, Transplantation, Heterologous
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