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Radiosensitization by a new potent nucleoside analog:
1Department of Radiation Oncology, School of Medicine, Tokai University, Isehara, Japan.
Purpose:
A new hypoxic cell sensitizer has been synthesized; this is a 2-nitroimidazole nucleoside analog having erythritol as a sugar moiety at the N-1 position of the imidazole ring (RP-343). Its possibility as a potent hypoxic cell sensitizer was compared with those of RP-170 and etanidazole.
Methods And Materials:
Radiosensitization was tested in two murine tumors, EMT6 using in vitro and in vivo-in vitro assays and SCCVII using growth delay and TCD50 assays. Pharmacokinetic study was performed in Balb/c mice bearing EMT6 tumors and in Beagle dogs. LD50 of each sensitizer was obtained with ICR mice.
Results:
As might be expected from the almost identical electron affinities of the three sensitizers, they were equally effective against hypoxic EMT6 cells in vitro. While having the lowest partition coefficient (0.035), RP-343 exhibited almost equally effective distribution to tumors and sensitizing radiation activity. An intravenous (i.v.) injection of 100 mg/kg of RP-343, RP-170 and etanidazole showed an almost equal sensitizer enhancement ratio (SER) of about 1.4 to solid EMT6 tumor under in vivo-in vitro assay and a virtually equal SER of 1.33-1.44 to solid SCCVII tumor under both tumor growth delay assay and TCD50 assay. A great advantage of RP-343 over RP-170 and etanidazole is its very much lower toxicity; their LD50 in mice were > 6.0, 4.3 and 4.8 g/kg, respectively, on i.v. injection. The lower toxicity of RP-343 was supported by its lower concentrations in the brain; the RP-343 AUC for brain was 0.43 times that of RP-170. Three indices were selected to compare the three nitroimidazoles. SER at 5% LD50 doses of RP-343, RP-170 and etanidazole was 1.66, 1.59 and 1.56. At the same toxicity levels, RP-343 was found to have better sensitization of solid tumors over both etanidazole and RP-170. The maximum tumor concentration/AUC for brain (Cmax,tumor/AUCbrain) ratios for RP-343 and RP-170 were 9.62 and 3.98.
Conclusions:
This extremely high ratio of RP-343 could explain its lower toxicity than RP-170 or etanidazole. The therapeutic risk index defined as D1.5/LD50 (D1.5 is the sensitizer dose to obtain the SER of 1.5 in vivo) for RP-343, RP-170 and etanidazole were 0.022, 0.033 and 0.036, respectively. Especially, the effectively lower therapeutic risk index for RP-343 presents the possibility of clinical advantage over etanidazole.