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), SR-2508, 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 (SERvivo) on solid tumors increased linearly with the square root of administrated dose (Ds). The specific activity (A) in vivo of nitroazoles was evaluated from the square-root empirical relationship, SERvivo = 1.00 + A D1/2S. The intratumor concentration of nitroazoles at a given time t after administration was in proportion to the DS, in which the proportional constant was defined as the tumor-affinity factor FT,t. The absolute molar activity alpha M defined by A(M/FT,t)1/2, where M is the molecular weight of nitroazoles, showed a linear relationship with the SER in vitro (SERvitro) at 1 mM of sensitizers. The sensitizer dose required to achieve an SERvivo of 1.5 (DS,1.5) decreased and thus the overall sensitizing efficiency on animal solid tumors increased as the FT,t became greater.