Radiosensitization by a new nucleoside analogue: 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole (RP-170).
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.
Murayama
C
C
Department of Radiation Oncology, School of Medicine, Tokai University, Japan.
Suzuki
A
A
Suzuki
T
T
Miyata
Y
Y
Sakaguchi
M
M
Tanabe
Y
Y
Tanaka
N
N
Mori
T
T
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D017341:Etanidazole; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D008920:Misonidazole / Q000494:pharmacology / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009705:Nucleosides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D009593:Nitroimidazoles; D009705:Nucleosides; D011838:Radiation-Sensitizing Agents; C060996:RP 170; D017341:Etanidazole; D008920:Misonidazole