Importance of tumor affinity of nitroazoles in hypoxic radiosensitization

In vitro and in vivo sensitizing activities of a variety of nitroazole derivatives including misonidazole (MISO SR2508, and RSU-1069 were correlated by the aid of pharmacokinetic measurements of the drug uptake in animal solid tumors. The sensitizer enhancement ratio in vivo (SER vivo) on solid tumors increased linearly with the square root of administrated dose (D S). The specific activity (A) in vivo of nitroazoles was evaluated from the square-root empirical relationship, SER vivo = 1.00 + A D S 1 2 . The intratumor concentration of nitroazoles at a given time t after administration was in proportion to the D S, in which the proportional constant was defined as the tumor-affinity factor F T,t. The absolute molar activity α M defined by A(M/F T,t) 1 2 , where M is the molecular weight of nitroazoles, showed a linear relationship with the SER in vitro (SER vitro) at 1 mM of sensitizers. The sensitizer dose required to achieve an SER vivo of 1.5 (D S,1.5) decreased and thus the overall sensitizing efficiency on animal solid tumors increased as the F T,t became greater.