Enhanced antitumor effect of lower-dose and longer-term CPT-11 treatment in combination with low-dose celecoxib against neuroblastoma xenografts.

BACKGROUND: We have previously reported that the combination of low-dose (5.9 mg/kg/dose) irinotecan (CPT-11) and simultaneous low-dose (5 mg/kg/dose) celecoxib, a cyclooxygenase-2 inhibitor, administered for 20 consecutive days, had synergistic antitumor activity against human neuroblastoma xenografts in mice. Possible further antitumor efficacy of lower-dose and longer-term CPT-11 combined with simultaneous low-dose celecoxib was investigated for chemosensitive TNB9 and multi-drug resistant TS-N-2nu neuroblastoma xenografts.
METHODS: The time from initiation of drug treatment to tumor regrowth, tumor doubling time, and body weight change of mice were evaluated between treatments with lower-dose (3 mg/kg/dose) CPT-11 alone and the combination of the two drugs for 60 consecutive days. Induction of apoptosis and autophagy during treatments were analyzed by immunoblotting, real-time quantitative RT-PCR, TUNEL assay, and immunohistochemistry.
RESULTS: The combination of the two drugs administered for 60 consecutive days resulted in a significantly longer time to tumor regrowth (p < 0.011) and longer tumor doubling time (p < 0.013) in both xenografts than for the lower-dose CPT-11 therapy alone, without substantial side effects in mice. In particular, five of six TNB9 tumors treated with the combination of the two drugs showed no regrowth even 120 or 150 days after the initiation of therapy. The combined treatment suppressed the induction of autophagy leading to apoptosis in TNB9 tumors, and induced autophagy to enhance the antitumor effect in TS-N-2nu tumors.
CONCLUSION: Our findings demonstrate that lower-dose and longer-term CPT-11 treatment in combination with simultaneous low-dose celecoxib enhances antitumor activity and can successfully eradicate most of the neuroblastoma xenografts.