Differential radiosensitization in DNA mismatch repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2'-deoxyribose.

Abstract

PURPOSE:

5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a pyrimidinone nucleoside prodrug of 5-iododeoxyuridine (IUdR) under investigation as an orally administered radiosensitizer. We previously reported that the mismatch repair (MMR) proteins (both hMSH2 and hMLH1) impact on the extent (percentage) of IUdR-DNA incorporation and subsequent in vitro IUdR-mediated radiosensitization in human tumor cell lines. In this study, we used oral IPdR to assess in vivo radiosensitization in MMR-proficient (MMR+) and -deficient (MMR-) human colon cancer xenografts.

EXPERIMENTAL DESIGN:

We tested whether oral IPdR treatment (1 g/kg/d for 14 days) can result in differential IUdR incorporation in tumor cell DNA and subsequent radiosensitization after a short course (every day for 4 days) of fractionated radiation therapy, by using athymic nude mice with an isogenic pair of human colon cancer xenografts, HCT116 (MMR-, hMLH1-) and HCT116/3-6 (MMR+, hMLH1+). A tumor regrowth assay was used to assess radiosensitization. Systemic toxicity was assessed by daily body weights and by percentage of IUdR-DNA incorporation in normal bone marrow and intestine.

RESULTS:

After a 14-day once-daily IPdR treatment by gastric gavage, significantly higher IUdR-DNA incorporation was found in HCT116 (MMR-) tumor xenografts compared with HCT116/3-6 (MMR+) tumor xenografts. Using a tumor regrowth assay after the 14-day drug treatment and a 4-day radiation therapy course (days 11-14 of IPdR), we found substantial radiosensitization in both HCT116 and HCT116/3-6 tumor xenografts. However, the sensitizer enhancement ratio (SER) was substantially higher in HCT116 (MMR-) tumor xenografts (1.48 at 2 Gy per fraction, 1.41 at 4 Gy per fraction), compared with HCT116/3-6 (MMR+) tumor xenografts (1.21 at 2 Gy per fraction, 1.20 at 4 Gy per fraction). No substantial systemic toxicity was found in the treatment groups.

CONCLUSIONS:

These results suggest that IPdR-mediated radiosensitization can be an effective in vivo approach to treat "drug-resistant" MMR-deficient tumors as well as MMR-proficient tumors.

• Authors: Yuji Seo, Tao Yan, Jane E Schupp, Valdir Colussi, Kerri L Taylor, Timothy J Kinsella
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 22 Pg. 7520-8 (Nov 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15569982 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• Animals
• Base Pair Mismatch
• Cell Cycle
• Cell Line, Tumor
• Colonic Neoplasms (genetics, radiotherapy)
• DNA (chemistry)
• DNA Repair
• Dose Fractionation, Radiation
• Dose-Response Relationship, Radiation
• Humans
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms (metabolism)
• Pyrimidine Nucleosides (chemistry)
• Radiation-Sensitizing Agents (pharmacology)
• Time Factors