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.