5-iodo-2-pyrimidinone-2'-deoxyribose-mediated cytotoxicity and radiosensitization in U87 human glioblastoma xenografts.

Abstract

PURPOSE:

5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a novel orally administered (p.o.) prodrug of 5-iododeoxyuridine. Because p.o. 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 or 9 athymic male nude mice (6-8 weeks old) were implanted with s.c. U87 xenograft tumors (4 x 10(6) cells) and then randomized to 10 treatment groups receiving increasing doses of p.o. IPdR (0, 100, 250, 500, and 1000 mg/kg/d) administered once daily (q.d.) x 14 days with or without radiotherapy (RT) (0 or 2 Gy/d x 4 days) on days 11-14 of IPdR treatment. Systemic toxicity was determined by body weight measurements during and after IPdR treatment. Tumor response was assessed by changes in tumor volumes.

RESULTS:

IPdR alone at doses of > or =500 mg/kg/d resulted in moderate inhibition of tumor growth. The combination of IPdR plus RT resulted in a significant IPdR dose-dependent tumor growth delay, with the maximum radiosensitization using > or =500 mg/kg/d. IPdR doses of 500 and 1000 mg/kg/d resulted in transient 5-15% body weight loss during treatment.

CONCLUSIONS:

In U87 human glioblastoma s.c. xenografts, p.o. IPdR given q.d. x 14 days and RT given 2 Gy/d x 4 days (days 11-14 of IPdR treatment) results in a significant tumor growth delay in an IPdR dose-dependent pattern. The use of p.o. IPdR plus RT holds promise for Phase I/II testing in patients with high-grade gliomas.

• Authors: Timothy J Kinsella, Michael T Kinsella, Yuji Seo, Gregory Berk
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 69 Issue 4 Pg. 1254-61 (Nov 15 2007) ISSN: 0360-3016 [Print] United States
• PMID: 17967315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Prodrugs
• Pyrimidine Nucleosides
• Radiation-Sensitizing Agents
• ropidoxuridine

Topics

• Animals
• Body Weight (drug effects)
• Brain Neoplasms (drug therapy, pathology, radiotherapy)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Glioblastoma (drug therapy, pathology, radiotherapy)
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Prodrugs (therapeutic use)
• Pyrimidine Nucleosides (therapeutic use)
• Radiation-Sensitizing Agents (therapeutic use)
• Random Allocation
• Tumor Burden (drug effects, radiation effects)
• Xenograft Model Antitumor Assays (methods)