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.

Coordination of DNA Mismatch Repair and Base Excision Repair Processing of Chemotherapy and Radiation Damage for Targeting Resistant Cancers

“…Our goal is to use modeling data to increase IUdR-mediated radiosensitivity in MMR -cancers (damage tolerant). These mathematical models are now being modified and used to attempt to maximize the therapeutic gain in MMR -tumors (using xenograft models) versus MMR + normal tissues by predicting the optimal dose of IUdR (or its prodrug, 5-iodo-2-pyrimidinone-2'-deoxyribose) and the optimal timing for ionizing radiation treatment to increase the synergistic action (26,27).…”

“…As mentioned previously, my laboratory has recently focused on the preclinical and now clinical use of IUdR or the oral IUdR prodrug as a radiosensitizing drug for MMR -(damage tolerant) human cancers (9,10,25,26). Such a targeted approach to MMR -cancers can be extended to also targeting BER in these damage-tolerant cancers with the use of methoxyamine.…”

5-Iodo-2-Pyrimidinone-2′-Deoxyribose–Mediated Cytotoxicity and Radiosensitization in U87 Human Glioblastoma Xenografts

“…Based on other pre-clinical data from our group on IUdR (or IPdR)-mediated radiosensitization of human tumors (16,22,23), we also hypothesize that human glioblastoma tumors which have DNA mismatch repair defects (MMR − ) can be more "selectively" targeted for IPdR-mediated radiosensitization (24). Importantly, MMR − glioblastomas show drug resistance to methylating drugs such as temozolomide (TMZ) and the nitrosoureas, using in vivo pre-clinical models and in clinical trials (25)(26)(27).…”

“…We have determined the pharmacokinetics of po IPdR and the active metabolite, IUdR, in rodents (mice, rats) and non-rodents (ferrets, Rhesus monkeys) (12,13,15); confirmed efficient conversion of IPdR to IUdR using cytosolic extracts of normal human liver (13); and measured an improved therapeutic gain for human tumor radiosensitization by po IPdR given qd × 6-14 days compared to continuous intravenous infusions of IUdR using subcutaneous (sc) human colorectal (HT29; HCT116) (12,13,16) and human glioblastoma (U251) tumor xenografts (14,17) in athymic mice. Most recently, we completed a pre-clinical pharmacokinetic and toxicology study of a once-daily × 28 day po IPdR dose escalation schedule in anticipation of the use of this IPdR dosing schedule in the first phase I clinical trial (18).…”

“…We have been involved in the pre-clinical development of po IPdR as a radiosensitizing drug for over a decade (12)(13)(14)(15)(16)(17)(18). We have determined the pharmacokinetics of po IPdR and the active metabolite, IUdR, in rodents (mice, rats) and non-rodents (ferrets, Rhesus monkeys) (12,13,15); confirmed efficient conversion of IPdR to IUdR using cytosolic extracts of normal human liver (13); and measured an improved therapeutic gain for human tumor radiosensitization by po IPdR given qd × 6-14 days compared to continuous intravenous infusions of IUdR using subcutaneous (sc) human colorectal (HT29; HCT116) (12,13,16) and human glioblastoma (U251) tumor xenografts (14,17) in athymic mice.…”