title: Assessment of the chemosensitizing activity of TAT-RasGAP317-326 in childhood cancers.
abstract: Although current anti-cancer protocols are reasonably effective, treatment-associated long-term side effects, induced by lack of specificity of the anti-cancer procedures, remain a challenging problem in pediatric oncology. TAT-RasGAP317-326 is a RasGAP-derived cell-permeable peptide that acts as a sensitizer to various anti-cancer treatments in adult tumor cells. In the present study, we assessed the effect of TAT-RasGAP317-326 in several childhood cancer cell lines. The RasGAP-derived peptide-induced cell death was analyzed in several neuroblastoma, Ewing sarcoma and leukemia cell lines (as well as in normal lymphocytes). Cell death was evaluated using flow cytometry methods in the absence or in the presence of the peptide in combination with various genotoxins used in the clinics (4-hydroperoxycyclophosphamide, etoposide, vincristine and doxorubicin). All tested pediatric tumors, in response to at least one genotoxin, were sensitized by TAT-RasGAP317-326. The RasGAP-derived peptide did not increase cell death of normal lymphocytes, alone or in combination with the majority of the tested chemotherapies. Consequently, TAT-RasGAP317-326 may benefit children with tumors by increasing the efficacy of anti-cancer therapies notably by allowing reductions in anti-cancer drug dosage and the associated drug-induced side effects.
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nadja
authors.initials: N
authors.lastname: Chevalier
authors.affiliation: Paediatric Oncology Research Unit, University Hospital Center (CHUV), Lausanne, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Gross
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Widmann
mesh_terms: D000367:Age Factors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D020690:GTPase-Activating Proteins / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008214:Lymphocytes / Q000187:drug effects; D009153:Mutagens / Q000494:pharmacology; D009369:Neoplasms / Q000473:pathology; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000494:pharmacology*; D012512:Sarcoma, Ewing
chemical_list: D000970:Antineoplastic Agents; D020690:GTPase-Activating Proteins; D009153:Mutagens; D010446:Peptide Fragments; C525242:TAT-RasGAP(317-326)
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