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 (po) prodrug of 5-iododeoxyuridine (IUdR). As po 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 8-9 athymic male nude mice (6-8 weeks old) were implanted with sc U87 xenograft tumors (4 × 10 6 cells) and then randomized to 10 treatment groups receiving increasing doses of po IPdR (0, 100, 250, 500, and 1000 mg/kg/d) administered once daily (qd) × 14 d with or without radiation therapy (RT) (0 or 2 Gy/d × 4 d) on days 11-14 of IPdR treatment. Systemic toxicity was determined by body weight measurements during and following IPdR treatment. Tumor response was assessed by changes in tumor volumes. Results-IPdR

Dependence of Cell Survival on Iododeoxyuridine Concentration in 35-keV Photon-Activated Auger Electron Radiotherapy

“…The IUdR incorporations in our CHO cell experiments had a maximum thymidine replacement of 16 replacements are obtainable-e.g., Lawrence et al (24) reported a maximum of 30% thymidine replacement-such incorporations are probably therapeutically unrealistic. In our experiments, longer incubation times (36 hours) resulted in higher IUdR toxicity but insignificantly greater incorporation because IUdR began to inhibit cell growth.…”

“…Whereas rapid division of cancer cells in comparison to their healthy counterparts should result in preferential DNA incorporation in cancer, previous studies have reported in vivo IUdR incorporation levels less than our lowest value of 9.2% thymidine replacement (7,25). However, more recent studies of Kinsella et al (11,16) showed considerable improvement in IUdR uptake when an IUdR derivative with more favorable kinetics was used.…”

“…The effectiveness of external beam radiation therapy is increased by IUdR, in part via a mechanism that is related to the biochemistry of DNA damage and its repair (3,16,17) and in part because of dose enhancement to the DNA from the localized dose created by Auger electrons. Hence, knowing how to best use monochromatic x-rays to increase the local dose and its biologic effect is important for the clinical success of IUdR or other future high-Z labeled drugs.…”

Enhancement of IUdR Radiosensitization by Low-Energy Photons Results from Increased and Persistent DNA Damage

“…The increased effectiveness of external radiation therapy induced by IUdR incorporation partially occurs via mechanisms related to the biochemistry of DNA damage and repair [14–16], corresponding to radiosensitization, and partially through enhancement of the dose directed at DNA from the localized dose created by Auger electrons which corresponds to the photoactivation contribution. This increase depends on the percentage of base replacement and on the initial photon spectrum [4, 6, 17–25].…”

Modulation of the activity of methyl binding domain protein 4 (MBD4/MED1) while processing iododeoxyuridine generated DNA mispairs

“…18,19 Currently, an oral (po) prodrug of IUdR (5-iodo-2-pyrimidinone-2-deoxyribose, IPdR) is being tested in phase 0/I clinical trials at the National Cancer Institute, based on an improved pre-clinical therapeutic index for po IPdR compared to continuous infusions of IUdR using human glioblastoma xenograft models. 20,21 Over the last decade, our laboratory has found that two different DNA repair pathways, A naturally occurring frameshift mutation resulting in the formation of truncated MED1 having only the MBD has been reported in human gastrointestinal cancers. 31 These truncated proteins, if expressed, would lack the GD but retain the N-terminal half of the protein including the MBD.…”