title: Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program.
abstract: 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.
authors.affiliation: Center for Children's Cancer, Nationwide Children's Hospital, Columbus, Ohio 43205, USA. Peter.Houghton@nationwidechildrens.org
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Amy W
authors.initials: AW
authors.lastname: Wozniak
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: Larry
authors.initials: L
authors.lastname: Rubinstein
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D020123:Sirolimus