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


METHODS
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.
Seo
Yuji
Y
Department of Radiation Oncology, Case Comprehensive Cancer Center/University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio 44106-6068, USA.
Yan
Tao
T
Schupp
Jane E
JE
Colussi
Valdir
V
Taylor
Kerri L
KL
Kinsella
Timothy J
TJ
D000818:Animals; D020137:Base Pair Mismatch; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D004247:DNA / Q000737:chemistry; D004260:DNA Repair; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000737:chemistry; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D013997:Time Factors
D011741:Pyrimidine Nucleosides; D011838:Radiation-Sensitizing Agents; C045889:ropidoxuridine; D004247:DNA