Corpus ID: 9924017

Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine-mediated radiosensitization in mouse and human tissues.

@article{Kinsella1998PreclinicalEO,
  title={Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine-mediated radiosensitization in mouse and human tissues.},
  author={Timothy J. Kinsella and Keith A. Kunugi and Kathleen Vielhuber and Douglas M. Potter and Michael E. Fitzsimmons and Jerry M. Collins},
  journal={Clinical cancer research : an official journal of the American Association for Cancer Research},
  year={1998},
  volume={4 1},
  pages={
          99-109
        }
}
  • T. Kinsella, K. Kunugi, +3 authors J. Collins
  • Published 1998
  • Biology, Medicine
  • Clinical cancer research : an official journal of the American Association for Cancer Research
We reported previously that p.o. administered 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was efficiently converted to 5-iodo-2'-deoxyuridine (IUdR) in athymic mice (T. J. Kinsella et al., Cancer Res., 54: 2695-2700, 1994). Here, we further evaluate IPdR metabolism, systemic toxicity, and percentage DNA incorporation in athymic mouse normal tissues and a human colon cancer xenograft (HT29) using higher p.o. doses of IPdR. These data are compared to results using a continuous infusion of IUdR at… Expand
5-iodo-2-pyrimidinone-2'-deoxyribose-mediated cytotoxicity and radiosensitization in U87 human glioblastoma xenografts.
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 aExpand
Schedule-dependent drug effects of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as an in vivo radiosensitizer in U251 human glioblastoma xenografts.
TLDR
Different drug dosing schedules improved the efficiency of enzymatic activation of IPdR to IUdR during treatment and changed the extent of tumor radiosensitization and/or systemic toxicity compared with a q.o.d. dosing schedule. Expand
Schedule-Dependent Drug Effects of Oral 5-Iodo-2-Pyrimidinone-2′-Deoxyribose as an In vivo Radiosensitizer in U251 Human Glioblastoma Xenografts
TLDR
Different drug dosing schedules improved the efficiency of enzymatic activation of IPdR to IUdR during treatment and changed the extent of tumor radiosensitization and/or systemic toxicity compared with a q.o.d. dosing schedule. Expand
Differential Radiosensitization in DNA Mismatch Repair-Proficient and -Deficient Human Colon Cancer Xenografts with 5-Iodo-2-pyrimidinone-2′-deoxyribose
TLDR
The 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. Expand
First-in-Human Phase 0 Trial of Oral 5-Iodo-2-Pyrimidinone-2′-Deoxyribose in Patients with Advanced Malignancies
TLDR
Adequate plasma levels of IdUrd were obtained to justify proceeding with a phase I trial of IPdR in combination with radiation, and shows the ability of a small, phase 0 study to provide critical information for decision-making regarding future development of a drug. Expand
IPdR: a novel oral radiosensitizer
TLDR
The development, mechanism of action, preclinical data and rationale for clinical studies are reviewed, including gastrointestinal and hematologic side effects, and the plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance are similar to previously published data in athymic mice. Expand
Toxicology and pharmacokinetic study of orally administered 5-iodo-2-pyrimidinone-2′deoxyribose (IPdR) × 28 days in Fischer-344 rats: impact on the initial clinical phase I trial design of IPdR-mediated radiosensitization
TLDR
A once-daily dosing schedule of po IPdR for 28 days with doses up to 2.0 g kg−1day−1 appeared to be well tolerated in Fischer-344 rats and the disposition was linear over the dose range studied. Expand
Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as Prodrug for Iododeoxyuridine-Mediated Tumor Radiosensitization in Advanced GI Cancer Undergoing Radiation
TLDR
Administration of IPdR orally every day × 28 days with RT is feasible and tolerable at doses that produce plasma IUdR levels ≥1 μmol/L, and these results support the investigation ofIPdR + RT in phase II studies. Expand
Five-chlorodeoxycytidine, a tumor-selective enzyme-driven radiosensitizer, effectively controls five advanced human tumors in nude mice.
TLDR
5-CldC coadministered with only H4U is an effective radiosensitizer of human tumors and may result in CldC possessing the dual advantageous properties of FdC on one hand and BrdU and IdU on the other hand. Expand
Metabolic profile of XK469 (2(R)-[4-(7-chloro-2-quinoxalinyl)oxyphenoxy]-propionic acid; NSC698215) in patients and in vitro: low potential for active or toxic metabolites or for drug–drug interactions
TLDR
Based upon the relative concentrations circulating in plasma, systemic exposure to parent drug was 100-fold higher than for the metabolites, and both toxicity and efficacy of XK469 are most likely to be produced by the parent molecule, rather than the metabolites. Expand
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IPdR offers a greater therapeutic index for tumor incorporation (and presumably radiosensitization) than a similar schedule of IUdR, and is associated with a > 10% weight loss and a high percentage ofIUdR-DNA incorporation into normal bone marrow and intestine. Expand
Conversion of 5-iodo-2-pyrimidinone-2'-deoxyribose to 5-iodo-deoxyuridine by aldehyde oxidase. Implication in hepatotropic drug design.
Abstract 5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) can be converted into 5-iodo-deoxyuridine (IUdR), a clinical radiosensitizer, by aldehyde oxidase in the liver. This conversion does not requireExpand
Conversion of 5-iodo-2-pyrimidinone-2'-deoxyribose to 5-iodo-deoxyuridine by aldehyde oxidase. Implication in hepatotropic drug design.
TLDR
Nucleoside analogues which could be activated by this enzyme to compounds capable of inhibiting DNA synthesis could be designed and should be explored as agents against cancer, viruses or parasites in the liver. Expand
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  • Chemistry, Medicine
  • Clinical cancer research : an official journal of the American Association for Cancer Research
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  • Clinical cancer research : an official journal of the American Association for Cancer Research
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Based on toxicity data and correlative laboratory studies, a meaningful increase in radiosensitization would not be achieved with the IdUrd infusion schedule and dose of LV investigated compared with Id Urd alone. Expand
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