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The Clinical Effects of Prolonged Intravenous Infusion of 5-Fluoro-2'-Deoxyuridine¹

( Department of Cancer Research, Lahey Clinic Foundation, Boston, Massachusetts, and Department of Clinical Investigation, Hoffmann La Roche Inc., Nutley, New Jersey)

The current report describes a study of the evaluation of the effects of 5-fluoro-2'-deoxyuridine (5-FUDR)² in human cancer when this agent is given by 24-hr i.v. infusion. The drug was administered by continuous, 24-hr i.v. infusion in 71 patients—5 with advanced incurable forms of cancer of mesenchymal origin and 66 with advanced cancer of epithelial origin. Moderate toxicity developed in all but 2 patients. Sixty-nine patients were considered to have had adequate drug trials. Of 56 patients who had measurable disease and who were considered to have had adequate therapeutic trials, 24 achieved objective tumor regression and sustained clinical benefit for 1 month or more and were placed in the category of an objective response. Duration of remission varied from 1 to 3 months. Additional courses of therapy often resulted in a second remission.

When 5-FUDR was given by the 24-hr i.v. infusion method, doses of 1/30 to 1/60 of the usual single daily injection method of administration (30.0 mg/kg) produced comparable toxic and therapeutic effects.

These studies demonstrate that altering the duration of administration of 5-FUDR by prolonged i.v. infusion resulted in a marked enhancement of the biologic activity in terms of dose-toxicity response relationships. The increased biologic activity of 5-FUDR noted in this study is thought to result because prolonged administration permits maximal anabolic conversion of 5-FUDR to 5-FUDRP (5-fluoro-2'-deoxyuridine-5'-phosphate), the compound which inhibits thymidylate synthetase.

¹ Presented in part at the 53rd Annual Meeting of the American Association for Cancer Research, Atlantic City, N. J., April 13–15, 1962. Supported by funds from the Lahey Clinic Foundation and the American Cancer Society (grant T-279).

² The abbreviations used are: 5-FUDR, 5-fluoro-2'-deoxyuridine; 5-FU, 5-fluorouracil; 5-FUDRP, 5-fluoro-2'-deoxyuridine-5'-phosphate.

Received 12/ 2/64. Revised 4/ 1/65.