Effect of tumor size on S-2-(3-aminopropylamino)ethylphosphorothioic acid and misonidazole alteration of tumor response to cyclophosphamide.

The influence of tumor size on the ability of S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) or misonidazole (MISO) to alter cyclophosphamide (CY) antitumor activity was investigated, using a chemically induced fibrosarcoma (FSA) and a spontaneous fibrosarcoma (NFSA) in C3Hf/Kam mice. Tumors were of two sizes at the time of treatment, 8-mm leg tumors and 4-day-old micrometastases in the lung. The antitumor activity of CY and its modification were assessed by growth delay of leg tumors and the reduction in the number of lung metastases. Both measures of tumor response were more pronounced as the dose of CY increased, and FSA was more sensitive to CY than was NFSA. WR-2721 (400 mg/kg), given 30 min before treatment with CY, reduced the effectiveness of CY on both FSA and NFSA. This reduction in effectiveness of CY was only minimal for leg tumors (dose-modifying factors were 1.1 for FSA and 1.03 for NFSA) but remarkable for lung micrometastases (dose-modifying factors were 1.81 for FSA and 1.55 for NFSA). Protection increased with the increase in the dose of WR-2721 and was also dependent on the time of injection relative to CY. The greatest protection occurred when WR-2721 was given within 30 min before to 15 min after CY. Tumor size had the opposite effect on MISO from that on WR-2721. MISO (1 mg/g) enhanced the effect of CY more effectively for leg tumors than for lung micrometastases: dose-modifying factors were 1.74 for FSA and 2.21 for NFSA growing in the leg and 1.27 for FSA and 1.11 for NFSA lung micrometastases. Therefore, tumor size appears to be a very important factor in determining the extent of WR-2721- and MISO-induced modification of CY antitumor effect.