title: Evaluation of a new 2-nitroimidazole nucleoside analogue, RK-28 as a radiosensitizer for clinical use.
abstract: The experimental data previously reported on RK-28, a hypoxic cell sensitizer which is now being tested in a phase I clinical trial, are confusing. Some data indicate superiority of RK-28 over misonidazole (MISO), whereas others do not. This paper presents our experimental data on the efficacy, toxicity, and pharmacokinetics of RK-28, in comparison with those of MISO, and also summarizes the data of other investigators. In our experiments, RK-28 had a 1.5-2.5 times higher sensitizing activity in vitro on EMT6 and SCCVII cells than MISO, and the difference was larger when the pre-irradiation incubation time was longer. The latter was considered to be due to the time-dependent cellular uptake and reactivity of RK-28 with non-protein sulphydryls. In vivo, RK-28 was almost as efficient as or slightly inferior to MISO against SCCVII and EMT6 tumours when assayed with an in vivo/in vitro assay and a growth delay time assay. The LD50/7 by a single injection of RK-28 was half that of MISO, but when 60% of LD50/7 was injected into mice every day, the total dose that could be given was higher for RK-28 than for MISO. Pharmacokinetic studies using mice, rats, rabbits, and a dog showed that RK-28 was rapidly eliminated from the blood and various tissues. From our results it was concluded that the possible success of the clinical trial of RK-28 depends on its low cumulative toxicity.
authors.affiliation: Department of Radiology, Faculty of Medicine, Kyoto University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shibamoto
authors.forename: K
authors.initials: K
authors.lastname: Sasai
authors.forename: M
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: P
authors.initials: P
authors.lastname: Tamulevicius
authors.forename: Y
authors.initials: Y
authors.lastname: Kitakabu
authors.forename: C
authors.initials: C
authors.lastname: Streffer
authors.forename: M
authors.initials: M
authors.lastname: Abe
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004285:Dogs; D005069:Evaluation Studies as Topic; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: D011838:Radiation-Sensitizing Agents; C047778:1-(4'-hydroxy-2'-butenoxy)methyl-2-nitroimidazole; D008920:Misonidazole