A phase I study of intraarterial iododeoxyuridine in patients with colorectal liver metastases.

Chang, Alfred E.; Collins, Jerry M.; Speth, P. A. J.; Smith, Rebecca P.; Rowland, Jon M.; Walton, L.; Begley, Martin; Glatstein, Eli; Kinsella, Timothy J.

doi:10.1200/jco.1989.7.5.662

Cited by 24 publications

(3 citation statements)

References 13 publications

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“…(2). In 4 of 9 patients treated with intrahepatic arterial infusions of IdUrd, Cheng et al reported tumor shrinkage to be between 40 to 65% (13). Morgan et al reported disappearance of ascites in patients with ovarian cancer treated with intraperitoneal IdUrd (12).…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Phase 0 Trial of Oral 5-Iodo-2-Pyrimidinone-2′-Deoxyribose in Patients with Advanced Malignancies

Kummar

Anderson

Hill

et al. 2013

Clinical Cancer Research

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Purpose Iododeoxyuridine (IdUrd), a halogenated nucleoside analog, produced clinical responses when administered as a radiosensitizer via continuous intravenous (c.i.v.) infusion over the course of radiation therapy. We conducted a Phase 0 trial of 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR), an oral prodrug of IdUrd, in patients with advanced malignances to assess whether the oral route was a feasible alternative to c.i.v. infusion prior to embarking on large-scale clinical trials. Plasma concentrations of IPdR, IdUrd, and other metabolites were measured after a single oral dose of IPdR. Patients and Methods Eligible patients had advanced refractory malignancies. A single oral dose of IPdR was administered per patient and patients were followed for 14 days for safety assessments; dose escalations were planned (150, 300, 600, 1200, and 2400 mg) with one patient per dose level (DL) and 6 patients at the highest DL. Blood sampling was performed over a 24-hour period for pharmacokinetic analysis. Results There were no drug-related adverse events. Plasma concentrations of IdUrd generally increased as the dose of IPdR escalated from 150 to 2400 mg. All patients at the 2400 mg dose achieved peak IdUrd levels of (mean ± SD) 4.0 μM ± 1.02 μM (25% CV) at 1.67 ± 1.21 hours after IPdR administration. Conclusions Adequate plasma levels of IdUrd were obtained to justify proceeding with a Phase I trial of IPdR in combination with radiation. This trial demonstrates the ability of a small, Phase 0 study to provide critical information for decision-making regarding future development of a drug.

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Section: Discussionmentioning

confidence: 99%

First-in-Human Phase 0 Trial of Oral 5-Iodo-2-Pyrimidinone-2′-Deoxyribose in Patients with Advanced Malignancies

Kummar

Anderson

Hill

et al. 2013

Clinical Cancer Research

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“…No peak was observed at the origin, which may come from incompletely digested DNA fragments. In Table 1, the values of base compositions are compared with those reported by others (Hurst, Marko & Butler 1953, Harold & Ziporin 1958, Burton 1960, Rudner, Shapiro & Chargaff 1966, Fasman 1976. Overall, a reasonable agreement with other data in both calf thymus and E. coli DNA is observed.…”

Section: Resultsmentioning

confidence: 99%

A method for determination of iododeoxyuridine substitution of thymidine using reversed‐phase high‐performance liquid chromatography

Yabuki

Nath

1991

Cell Proliferation

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An assay for thymidine substitution by iododeoxyuridine (IdUrd) using reversed-phase high-performance liquid chromatography (HPLC) has been developed. Three principal steps in this procedure are: extraction of DNA from cell or tissues, hydrolysis of DNA into deoxynucleosides and separation using HPLC. Approximately 1 microgram of DNA was recovered from 10(5) cells by phenol extraction, and subjected to hydrolysis into deoxynucleosides which required a three-stage DNA digestion using enzymes DNAse I. phosphodiesterase I and alkaline phosphatase. The deoxynucleosides were separated on the Microsorb C18 column with isocratic elution; 90-100% of the DNA was recovered as deoxynucleosides on the column. The method was used to determine quantitatively the percent IdUrd substitution of thymidine in Chinese hamster lung cells in vitro and BA1112 rhabdomyosarcoma in WAG/Rij rats perfused with IdUrd. It was possible to determine the thymidine substitution by IdUrd as small as 1% using a few micrograms of DNA. The close correspondence between the percent substitutions determined by HPLC and those determined by radioactive assay using [125I]-labelled IdUrd, confirmed the accuracy of our HPLC method. The HPLC analysis is especially suitable for the determination of percent IdUrd substitution of thymidine in tissue biopsies from animals used in in vivo experiments or humans undergoing radiation treatment.

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“…IUdR is a halogenated thymidine analogue and can be incorporated into DNA, replacing thymidine. IUdR has been recognized as an effective in vitro/in vivo radiosensitizer since the 1960s (7)(8)(9)(10)(11)(12)(13)(14); however, its clinical use is limited by a narrow therapeutic window when the drug is given as a continuous infusion (2). We have previously shown that oral IPdR treatment can improve the therapeutic index in comparison with continuous infusion IUdR by using an athymic nude mice model with several different human tumor xenografts (1).…”

Section: Introductionmentioning

confidence: 99%

Differential Radiosensitization in DNA Mismatch Repair-Proficient and -Deficient Human Colon Cancer Xenografts with 5-Iodo-2-pyrimidinone-2′-deoxyribose

Seo

Yan

Schupp

et al. 2004

Clinical Cancer Research

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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.

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A phase I study of intraarterial iododeoxyuridine in patients with colorectal liver metastases.

Cited by 24 publications

References 13 publications

First-in-Human Phase 0 Trial of Oral 5-Iodo-2-Pyrimidinone-2′-Deoxyribose in Patients with Advanced Malignancies

First-in-Human Phase 0 Trial of Oral 5-Iodo-2-Pyrimidinone-2′-Deoxyribose in Patients with Advanced Malignancies

A method for determination of iododeoxyuridine substitution of thymidine using reversed‐phase high‐performance liquid chromatography

Differential Radiosensitization in DNA Mismatch Repair-Proficient and -Deficient Human Colon Cancer Xenografts with 5-Iodo-2-pyrimidinone-2′-deoxyribose

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