Oncogenic transforming potential of nitroimidazole radiosensitizers

The oncogenic transforming potentials of a number of hypoxic cell radiosensitizers have been compared including misonidazole, SR-2508, Ro-03-8799, and RSU-1069, using the C3H 10T1/2 cell system. While the dual function bioreductive 2-nitroimidazole RSU-1069 is a particularly potent hypoxic cell radiosensitizer, both in vitro and in vivo, it is also more cytotoxic and has a considerably higher oncogenic transforming potential than the other nitroimidazoles tested. In combination with radiation, RSU-1069 produces a supra-additive transforming response in C3H 10T1/2 cells. For all the other sensitizers tested, the number of transformants produced by drug and radiation combined are simply additive. RB-6145, an analog of RSU-1069 with an equivalent sensitizing efficiency, is substantially less toxic and much less oncogenic than RSU-1069. At doses that produce similar in vitro enhancement ratios, RB-6145 is no more oncogenic than misonidazole and produces an additive transforming incidence in combination with radiation. RB-6145 appears to be a promising substitute for RSU-1069 for future clinical application(s) as a hypoxic cell sensitizer.