Evaluation of a New 2-nitroimidazole Nucleoside Analogue, RK-28 as a Radiosensitizer for Clinical Use

Summary 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.