IPdR (5-iodo-2-pyrimidinone-2'-deoxyribose) is a novel orally available, halogenated
thymidine (TdR) analog and is a potential radiosensitizer for use in human
tumors, such as rectal, pancreas,
sarcoma and
glioma tumors.
IPdR is a
prodrug that is efficiently converted to
IUdR (5-iodo-2'-deoxyuridine), an intravenous radiosensitizer by a hepatic
aldehyde oxidase, resulting in high
IPdR and
IUdR plasma levels in mice for > or = 1 h after oral
IPdR. Athymic mice tolerated oral
IPdR to doses up to 1500 mg/kg/day t.i.d. for 6 - 14 days without significant systemic toxicities. A number of in vivo preclinical studies have demonstrated that
IPdR is a superior radiosensitizer compared with
IUdR given as a continuous infusion in terms of safety and efficacy with a significantly lower toxicity profile, including gastrointestinal and hematologic side effects. A preclinical study has shown that
IPdR is effective in inducing human
colon cancer xenograft radiosensitization in
drug-resistant DNA mismatch repair-proficient and -deficient
tumor models, as well as in human globlastoma xenograft. In anticipation of performing a clinical Phase I trial in humans, investigators also studied the
drug pharmacokinetics and host toxicities in two non-rodent, animal species during a 14-day treatment course. Dose-limiting systemic toxicities (
diarrhea,
emesis,
weight loss and decreased motor activity) were observed in ferrets receiving
IPdR at 1500 mg/kg/day on a 14-day schedule that were not found previously in athymic mice. Recently, a once-daily
IPdR dosing up to 2000/mg/kg for 28 days in Fischer-344 rats showed reversible mild-to-moderate systemic toxicities without any severe or life-threatening toxicities. However, in all preclinical toxicity studies so far, no significant hematologic, biochemical or histopathologic changes have been found. Hepatic
aldehyde oxidase activity was reduced in a dose-dependent fashion in the ferret liver, suggesting partial
enzyme inactivation by this IPdwR schedule, but that is not found in Fischer-344 rats. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance are similar to previously published data in athymic mice. In this paper, the authors review the development, mechanism of action, preclinical data and rationale for clinical studies.