5-Iodo-2-Pyrimidinone-2′-Deoxyribose–Mediated Cytotoxicity and Radiosensitization in U87 Human Glioblastoma Xenografts
| Autor: | Yuji Seo, Gregory Berk, Timothy J. Kinsella, Michael T. Kinsella |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
Radiation-Sensitizing Agents Cancer Research Radiosensitizer medicine.medical_treatment Mice Nude Pharmacology Article Mice Random Allocation In vivo Cell Line Tumor medicine Animals Humans Prodrugs Radiology Nuclear Medicine and imaging U87 Cytotoxicity Radiation Dose-Response Relationship Drug Brain Neoplasms business.industry Body Weight Prodrug Pyrimidine Nucleosides medicine.disease Xenograft Model Antitumor Assays Tumor Burden Radiation therapy Oncology Toxicity Glioblastoma Nuclear medicine business Neoplasm Transplantation |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 69:1254-1261 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2007.08.004 |
| Popis: | 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 × 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.) × 14 days with or without radiotherapy (RT) (0 or 2 Gy/d × 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 ≥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 ≥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. × 14 days and RT given 2 Gy/d × 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. |
| Databáze: | OpenAIRE |
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