Potentiation of melphalan activity in the KHT sarcoma by the radiosensitizer RSU 1069

The radiation sensitizer misonidazole (MISO) has been shown to potentiate the cytotoxic action of a variety of anti-cancer agents. Even larger enhancement ratios than those observed with MISO have been found with certain other nitroimidazoles. One agent reported to be particularly effective in combination with the chemotherapeutic agent melphalan is the sensitizer RSU 1069. The present studies therefore were designed to evaluate the effect of combining these two agents in the treatment of intramuscularly growing KHT sarcomas. Tumor response was assessed using an in vivo to in vitro clonogenic cell survival assay. When given at times ranging from 60 min before to 30 min after melphalan exposure, RSU 1069 was found to increase the tumoricidal activity of the chemotherapeutic agent. Complete dose response curves combining RSU 1069 and a range of melphalan doses then were determined. For comparison the effects of combining MISO or benznidazole (BENZO) with melphalan also were evaluated. All sensitizers were administered i.p. either 30 min before (BENZO) or simultaneously with (MISO, RSU 1069) the chemotherapeutic agent. Survival of clonogenic tumor cells assessed 22 to 24 hr after treatment was used to assay tumor response. When combined with melphalan, doses of RSU 1069 (0.38 mmol/kg), BENZO (0.3 mmol/kg) and MISO (5.0 mmol/kg) were found to yield dose modifying factors of 1.6, 1.5, and 1.4, respectively. These results indicate that potentiation of melphalan activity occurs at RSU 1069 doses which are approximately 10-fold lower than those of MISO, making this sensitizer as effective a potentiator of melphalan as so far tested in the KHT sarcoma.