Radiosensitization by a new nucleoside analogue: 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole...

A new potent hypoxic cell sensitizer, a 2-nitroimidazole nucleoside analogue having methoxyglycerol as a sugar moiety at the N-1 position of the imidazole ring (RP-170), has been synthesized. Its radiosensitizing activities in vitro and in vivo were investigated and compared with those of misonidazole (MISO) and etanidazole (SR-2508). As might be expected from the almost identical electron affinities of the three compounds, they were equally effective against hypoxic EMT6 cells in vitro. The in vivo-in vitro excision analysis showed that RP-170 was also as effective as MISO and etanidazole to radiosensitize solid tumor cells in vivo. An intraperitoneal administration of 200 mg/kg of RP-170 and an intravenous administration of the same dose of etanidazole showed an equal sensitizer-enhancement ratio of 1.51 to solid EMT6/KU tumors. Its effectiveness was also demonstrated by growth delay assay using solid SCCVII tumors. As predicted from the low partition coefficient, RP-170 and etanidazole showed apparently lower toxicity in vivo than MISO; their LD50/14 were 4.3, 4.8, and 1.8 g/kg in our experiment, respectively. Moreover, RP-170 showed fast clearance from serum in mice (t1/2 = 10.24 min) and poor penetration into neural tissues. Although RP-170 does not show any advantages over etanidazole in terms of sensitization or toxicity, RP-170 might be preferable under certain circumstances because it can be given orally.