Details

Autor(en) / Beteiligte

• Houghton, Peter J
• Morton, Christopher L
• Gorlick, Richard
• Lock, Richard B
• Carol, Hernan
• Reynolds, C Patrick
• Kang, Min H
• Maris, John M
• Keir, Stephen T
• Kolb, E Anders
• Wu, Jianrong
• Wozniak, Amy W
• Billups, Catherine A
• Rubinstein, Larry
• Smith, Malcolm A

Titel

Stage 2 Combination Testing of Rapamycin with Cytotoxic Agents by the Pediatric Preclinical Testing Program

Ist Teil von

• Molecular cancer therapeutics, 2010-01, Vol.9 (1), p.101-112

Ort / Verlag

United States: American Association for Cancer Research

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek

Beschreibungen/Notizen

• Rapamycin demonstrated broad-spectrum tumor growth inhibition activity against the in vivo panels of childhood tumors used in the Pediatric Preclinical Testing Program (PPTP). Here we have evaluated rapamycin combined with agents used frequently in the treatment of childhood malignancies. Rapamycin was tested in vitro against 23 cell lines alone or in combination with melphalan, cisplatin, vincristine, or dexamethasone (leukemic models only). In vivo , the impact of combining rapamycin with a cytotoxic agent was evaluated using two measures: 1) the therapeutic enhancement measure, and 2) a linear regression model for time-to-event to formally evaluate for sub- and supraadditivity for the combination compared to the agents used alone. Combining rapamycin with cytotoxic agents in vitro gave predominantly subadditive or additive effects, except for dexamethasone in leukemia models for which supra-additive activity was observed. In vivo testing demonstrated that therapeutic enhancement was common for rapamycin in combination with cyclophosphamide and occurred for 4 of 11 evaluable xenografts for the rapamycin and vincristine combination. The combinations of rapamycin with either cyclophosphamide or vincristine were significantly more effective than the respective standard agents used alone at their maximum tolerated doses (MTD) for most evaluable xenografts. The combination of rapamycin and cisplatin produced excessive toxicity requiring cisplatin dose reductions, and therapeutic enhancement was not observed for this combination. Addition of rapamycin to either cyclophosphamide or vincristine at their respective MTDs appears promising, as these combinations are relatively well tolerated and as many of the pediatric preclinical models evaluated demonstrated therapeutic enhancement for these combinations. Mol Cancer Ther; 9(1); 101–12