The effect of timing on chemosensitization by clinical levels of SR-2508.

The nitroimidazole SR-2508 is currently being tested clinically as a radiosensitizer. Its relatively low toxicity allows it to be used at higher doses than misonidazole so that its potential as a chemosensitizer is also of considerable interest. Multiple injections of SR-2508 were given to SCC VII/St tumor-bearing mice to achieve a clinically realistic plasma concentration of approximately 300 micrograms/ml over 8 hrs. Single doses of melphalan (L-PAM) or cyclophosphamide (CY) were given at different times after the first SR 2508 injection. With L-PAM, a delay of at least 2 hr was necessary before enhancement of L-PAM cytotoxicity was observed. A similar result was obtained when a simulation was carried out with SCC VII/St tumor cells in vitro. Results with CY were less clear, although the most consistent enhancement was observed when a 4 to 8 hr interval elapsed between the beginning of SR 2508 exposure and the CY injection. In general, although precise timing was not essential for enhancement, an interval of at least 4 hr is recommended between the administration of SR 2508 and either alkylating agent. This is particularly important for L-PAM where no enhancement would be expected if the drugs were given simultaneously.