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Fluorodeoxyuridine Modulation of the Incorporation of Iododeoxyuridine into DNA of Granulocytes: A Phase I and Clinical Pharmacological Study

Clinical Pharmacology [P. A. J. S., K. B., R. W. K., J. M. C.] and Radiation Oncology [T. J. K., R. S., J. B. R.] Branches, National Cancer Institute, Bethesda, Maryland

The amount of iododeoxyuridine (IdUrd) incorporated into DNA determines the degree of radiosensitization. Fluorodeoxyuridine (FdUrd) has been shown to biochemically modulate IdUrd incorporation into DNA in vitro and in vivo. In this Phase I study, these drugs were coadministered to patients during 14-day continuous i.v. infusion periods in order to investigate whether the incorporation of IdUrd into DNA in vivo could be increased without increasing the dose of IdUrd. IdUrd plasma concentrations and incorporation of IdUrd into DNA of granulocytes were measured by high-performance liquid chromatography. Up to 8.8% substitution of thymidine by IdUrd was observed. Even at 3.5 mg/m²/day FdUrd for 14 days (78% of the maximum-tolerated dose as a single agent), no clinically relevant enhancement of incorporation of IdUrd into DNA of granulocytes was observed. Also, no changes in plasma levels of IdUrd were observed with escalating doses of FdUrd. Toxicity patterns (stomatitis, diarrhea, and bone marrow depression) and isobologram analysis suggested that IdUrd and FdUrd had additive, rather than synergistic, effects.

¹ Supported by grants from the Niels Stensen Foundation, the NCI-EORTC exchang-eprogram, and the Netherlands Cancer Foundation, KWF. Present address: St. Radboud University Hospital, Department of Medical Oncology, Nijmegen, The Netherlands.

² Present address: Department of Human Oncology, University of Wisconsin, Madison, WI 53792.

³ Present address: Institut du Cancer de Montreal, Montreal, Canada H2L 4M1.

⁴ To whom requests for reprints should be addressed, at Clinical Pharmacology Branch, NCI, Building 10, Room 6N119; Bethesda, MD 20892.

Received 10/ 7/87. Revised 2/ 5/88. Accepted 2/15/88.

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