5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR) is a novel orally administered (po) prodrug of 5-iododeoxyuridine (IUdR). As po IPdR is being considered for clinical testing as a radiosensitizer in patients with high grade gliomas, we performed this in vivo study of IPdR-mediated cytotoxicity and radiosensitization in a human glioblastoma xenograft model, U87.
Methods and Materials
Groups of 8–9 athymic male nude mice (6–8 weeks old) were implanted with sc U87 xenograft tumors (4 × 106 cells) and then randomized to 10 treatment groups receiving increasing doses of po IPdR (0, 100, 250, 500, and 1000 mg/kg/d) administered once daily (qd) × 14 d with or without radiation therapy (RT) (0 or 2 Gy/d × 4 d) on days 11–14 of IPdR treatment. Systemic toxicity was determined by body weight measurements during and following IPdR treatment. Tumor response was assessed by changes in tumor volumes.
IPdR alone at doses of ≥500 mg/kg/d results in moderate inhibition of tumor growth. The combination of IPdR + RT results in a significant IPdR dose-dependent tumor growth delay with the maximum radiosensitization using ≥500 mg/kg/d. IPdR doses of 500 and 1000 mg/kg/d did result in transient 5–15% body weight loss during treatment.
In U87 human glioblastoma sc xenografts, po IPdR given qd × 14 d and RT given 2 Gy/d × 4 d (days 11–14 of IPdR treatment) results in a significant tumor growth delay in an IPdR dose-dependent pattern. The use of po IPdR + RT holds promise for phase I/II testing in patients with high grade gliomas.