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Prolonged low-dose administration of the cyclooxygenase-2 inhibitor celecoxib enhances the antitumor activity of irinotecan against neuroblastoma xenografts
Cancer Science, 08/12/09

Kaneko M et al. - In a study to evaluate antitumor effect of irinotecan (CPT-11) treatment combined with prolonged very low-dose administration of celecoxib against 3 human neuroblastoma (NB) xenografts, TNB9, TS-N-2nu, and TS-N-5nu, it was shown that prolonged low-dose CPT-11 treatment combined with very low-dose celecoxib has promising antitumor activity through the blockage of multiple critical targets related to NB tumor cell survival and proliferation.

Methods

The effects of the celecoxib-combined treatment were examined on tumor cell proliferation, apoptosis, angiogenesis, and expression of vascular endothelial growth factor and apoptosis-related proteins in xenografts.
Antitumor effect of CPT-11 treatment combined with prolonged very low-dose administration of celecoxib was evaluated against 3 human NB xenografts, TNB9, TS-N-2nu, and TS-N-5nu.

Results

Celecoxib administered daily at 5 mg/kg body weight/day could not prevent growth of any of the NB xenografts; but the combination of daily low-dose CPT-11 (5.9 mg/kg body weight/day) and simultaneous very low-dose celecoxib resulted in highly significant suppression of tumor growth in all 3 xenografts compared not only with low-dose CPT-11 therapy alone but also with combination therapy of intermittent conventional-dose CPT-11 (59 mg/kg body weight) and celecoxib accompanied by decreased proliferation and increased induction of apoptosis in tumor cells.
Induction of apoptosis by CPT-11 with and without celecoxib was associated with up-regulation of Bax expression and down-regulation of Bcl-2 expression.
Enhanced antitumor effect of the combination against NB xenografts might be partially COX-2-independent and was probably mediated through multiple factors including diminished expression of VEGF and activation of caspase-dependent mitochondrial apoptosis pathway.

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