Therapeutic advantage from combining paclitaxel with the hypoxia-selective cytotoxin NLCQ-1 in murine tumor- or human xenograft-bearing mice

Purpose: The antitumor effect of paclitaxel was investigated against murine tumors and human xenografts in combination with the hypoxia-selective cytotoxin NLCQ-1. Methods: The tumor regrowth assay was used as the endpoint and an optimal administration schedule was followed, based on previous studies. In certain cases the hypoxia-selective cytotoxin tirapazamine (TPZ) was included for comparison. NLCQ-1 was given i.p. in saline, whereas paclitaxel was given i.p. (C3H) or i.v. (athymic mice) in an appropriately formulated vehicle. Results: In the SCCVII/C3H model, when NLCQ-1 (10 mg/kg) was given 90 min after paclitaxel (8 mg/kg) twice a day 4 h apart on days 0 and 9, tumor regrowth delay was increased by 10.3 days compared to paclitaxel alone, at fivefold the original tumor size. This corresponds to 1.51 log cell kill. In the same study, TPZ resulted in 4.6 days of extra delay compared to paclitaxel alone, which corresponds to 0.91 log cell kill. Paclitaxel alone resulted in 3.9 days of tumor growth delay compared to control, or 0.42 log cell kill, but this delay was not statistically significant (P < 0.2). In the FSaIIC/C3H model, when NLCQ-1 (10 mg/kg) was given 90 min after paclitaxel (12 mg/kg) on day 0, tumor regrowth delay was increased by 5.8 days compared to paclitaxel alone, at 20-fold the original tumor size. In athymic nude mice bearing PC-3 prostate xenografts, NLCQ-1 (10 mg/kg) given 90 min before paclitaxel (8 mg/kg) for five consecutive days, increased tumor regrowth delay by 5.6 days compared to paclitaxel alone, at threefold the original tumor size. This corresponds to 0.95 log cell kill whereas the log cell kill for paclitaxel alone was 0.52. No improvement was observed in the tumor regrowth delay at any lower paclitaxel doses given in combination with NLCQ-1. No concurrent enhancement in paclitaxel-induced toxicity was observed in any of the combination treatments or in any of the models tested. NLCQ-1 alone was ineffective at the doses given. Conclusions: These results suggest that an enhancement in tumor growth delay can be achieved both in murine tumors and in human xenografts due to a synergistic interaction between NLCQ-1 and paclitaxel.

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