Synergistic enhancement of the antitumor effect of taxol by the bioreductive compound NLCQ-1, in vivo: comparison with tirapazamine.

The antitumor effect of taxol was investigated in combination with the bioreductive compounds NLCQ-1 or tirapazamine (TPZ), in vivo. The EMT6/BALB/c and SCCVII/C3H murine tumor models were used. All drugs were given by IP injection: NLCQ-1 at 10 mg/kg (28% of its LD50), TPZ at 30 or 23 mg/kg (38% or 28% of its LD50, respectively), and taxol up to 25 mg/kg. Dose modification factors (DMF) were calculated at the optimal administration intervals for potentiation of taxol by NLCQ-1/TPZ, by using the in vivo-in vitro assay as the endpoint. Bone marrow toxicity studies were performed in parallel by using a modified CFU-GM assay. A schedule-dependent potentiation of taxol was observed with either hypoxic cytotoxin and in both tumor models. The percentage of tumor cells, P, that were killed beyond additivity was 59.2 and 29.5 when NLCQ-1 was administered 1-3 h after, and TPZ 3 h before taxol, respectively, in the EMT6/ BALB/c model. The P values in the SCCVII/C3H model were 31.0 and 24.6 for NLCQ-1 and TPZ, respectively, when either of them was administered ca. 2 h after taxol. At the above time schedules, therapeutic indexes [ThI = DMF(T)/DMF(BM), where DMF(T) and DMF(BM) are the DMF values for the antitumor effect and bone marrow toxicity, respectively] of 2.5 and 2.0 were obtained by NLCQ-1 in the EMT6 and SCCVII tumors, respectively, whereas a ThI of 1.2 was obtained by TPZ in both type of tumors. These results suggest a potential clinical use of NLCQ-1 as a potentiator of taxol againstsolid tumors possessing hypoxic regions.