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Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
IPdR: a novel oral radiosensitizer
Muhammad Wasif Saif1, Greg Berk, Yung-Chi Cheng
1Yale University School of Medicine, Division of Medical Oncology, New Haven, CT 06520, USA. wasif.saif@yale.edu
Expert Opinion on Investigational Drugs
|August 24, 2007
Summary
5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is an oral radiosensitizer that converts to IUdR, showing superior efficacy and safety over IV IUdR in preclinical cancer models. Further studies confirmed its potential for human trials, with tolerable toxicity profiles in rats and monkeys.
Area of Science:
- Oncology
- Pharmacology
- Radiosensitization
Background:
- 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a novel, orally available, halogenated thymidine analog.
- IPdR functions as a prodrug, efficiently converted to the intravenous radiosensitizer 5-iodo-2'-deoxyuridine (IUdR) via hepatic aldehyde oxidase.
- This conversion leads to sustained high plasma levels of both IPdR and IUdR.
Purpose of the Study:
- To evaluate IPdR as a potential radiosensitizer for various human tumors, including rectal, pancreas, sarcoma, and glioma.
- To compare the safety and efficacy of oral IPdR with intravenous IUdR in preclinical cancer models.
- To assess the pharmacokinetics and host toxicities of IPdR in non-rodent species in preparation for human clinical trials.
Main Methods:
- Preclinical in vivo studies using human cancer xenografts (colon, glioblastoma) in mice.
- Toxicity and pharmacokinetic assessments in athymic mice, ferrets, Fischer-344 rats, and Rhesus monkeys.
- Comparison of IPdR's radiosensitizing effects against IUdR's efficacy and toxicity profiles.
Main Results:
- IPdR demonstrated superior radiosensitization compared to intravenous IUdR, with significantly lower gastrointestinal and hematologic toxicities.
- Effective radiosensitization was observed in drug-resistant and proficient DNA mismatch repair colon cancer xenografts and glioblastoma xenografts.
- Non-rodent species showed varied responses; ferrets exhibited dose-limiting toxicities, while rats and monkeys displayed manageable systemic toxicities and pharmacokinetic profiles similar to mice.
Conclusions:
- IPdR is a promising orally available radiosensitizer with a favorable safety and efficacy profile compared to intravenous IUdR in preclinical settings.
- Further investigation in non-rodent species revealed manageable toxicities and pharmacokinetic profiles suitable for clinical development.
- The data supports the rationale for conducting a Phase I clinical trial to evaluate IPdR in human cancer patients.
