OPTICAL ISOMERS OF A NEW 2-NITROIMIDAZOLE NUCLEOSIDE ANALOG (PR-350 SERIES) - RADIOSENSITIZATION EFFICIENCY AND TOXICITY

Purpose: A new 2-nitroimidazole nucleoside radiosensitizer, PR-350 4'- trihydroxy-2'-butoxy]-methyl-2-nitroimidazole), has been reported to b e as efficient as and less toxic than etanidazole. This compound is ra cemic, and it was recently optically resolved into two isomers, PR-68 (2'R,3'S type) and PR-69 (2'S,3'R type). The other two isomers, PR-28 (2'S,3'S type) and PR-44 (2'R,3'R type), were asymmetrically synthesiz ed. In the present study, we investigated the properties, sensitizing activity, and toxicity of PR-350 and the four optical isomers in compa rison with those of other 2-nitroimidazole hypoxic cell radiosensitize rs, etanidazole, KU-2285, KIN-804, and RP-170. Because PR-350 and PR-2 8 can be industrially synthesized, we evaluated whether either of thes e two drugs are suitable for further investigation. Methods and Materi als: In an in vitro study, EMT-6 cells were irradiated at a dose of 1- 3 Gy under hypoxic conditions in the presence of the drugs at a concen tration of 1 mM. A combined cytokinesis-block micronucleus and chromos omal aberration assay was performed. To assess the in vivo effects, co lony assay and growth delay assay were performed using SCCVII tumor-be aring (CH)-H-3 mice. The mice received 16-24 Gy 10-40 min after admini stration of 50-200 mg/kg of the drugs. Toxicity and pharmacokinetics i n mice were also investigated. Results: The sensitizer enhancement rat io (SER) in the in vitro cytokinesis-block micronucleus assay increase d in the following order: PR-69 (1.27) similar or equal to PR-28 (1.31 ) similar or equal to PR-44 (1.38) similar or equal to PR-350 (1.41) s imilar or equal to PR-68 (1.47) < etanidazole (1.79) < KIN-804 (2.03) similar or equal to KU-2285 (2.30). The SER at a dose of 200 mg/kg and at an interval of 20 min (optimal interval) in the in vivo-in vitro c olony assay increased as follows: PR-44 (1.26) similar or equal to PR- 28 (1.29) < PR-69 (1.34) similar or equal to etanidazole (1.35) simila r or equal to PR-350 (1.36) < RP-170 (1.41) similar or equal to PR-68 (1.41) < KU-2285 (1.49). The growth delay assay also showed that PR-35 0 was less efficient than KU-2285 and more efficient than PR-28. PR-35 0 and the four isomers had similar reduction potentials, but PR-28 and PR-44 were more hydrophilic than PR-68 and PR-69. The LD(50) in mice were 5.8 g/kg for PR-350, approximately 7 g/kg for PR-28, 4 g/kg for P R-68, and 6 g/kg for PR-44 and PR-69. The concentration of PR-28 in th e murine sciatic nerve was lower than that of PR-350. Conclusion: In v ivo radiosensitizing activity differed among the four optical isomers, which appeared to be due, at least in part, to differences in lipophi licity. Although PR-28 was the least toxic, its low sensitization effi ciency does not warrant clinical trials. Among the PR compounds, PR-68 appears to be most efficient, but optical resolution of PR-68 from PR -350 is expensive, and asymmetrical synthesis of PR-68 is not establis hed. Therefore, PR-350 seems to be most suitable for further investiga tion among the PR-350 series compounds, considering its higher efficie ncy compared with PR-28 and PR-44, and established synthesis.