Effect of dipyridamole on fluorodeoxyuridine cytotoxicity in vitro and in cancer patients |
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| Authors: | Antonio C. Buzaid David S. Alberts Janine Eispahr Kurt Mosley Yei-Mei Peng Kendra Tutsch Collin P. Spears Harinder S. Garewal |
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| Affiliation: | (1) Department of Internal Medicine, Section of Medical Oncology, Yale University School of Medicine, 06510 New Haven, CT, USA;(2) Section of Hematology/Oncology, Department of Internal Medicine, Arizona Cancer Center, University of Arizona College of Medicine, 85724 Tucson, AZ, USA;(3) Pharmacology Research Program, Arizona Cancer Center, University of Arizona College of Medicine, 85724 Tucson, AZ, USA;(4) Veterans Administration Hospital, 85724 Tucson, AZ, USA;(5) Department of Human Oncology, University of Wisconsin Clinical Cancer Center, 53792 Madison, WI, USA;(6) Comprehensive Cancer Center, University of Southern California, 90033 Los Angeles, CA, USA |
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| Abstract: | Summary Dipyridamole (DP) has previously been studied both in vitro and in vivo in combination with various antimetabolites, including methotrexate and 5-fluorouracil (5FU). We evaluated in vitro and clinically the effects of adding DP to fluorodeoxyuridine (FUDR) in colorectal cancer. Using a human colony-forming assay, we observed that 0.05  M DP increased the cytotoxicity of FUDR by a median of 33.5-fold vs 1.5-fold for 5FU against human colon-cancer cell lines. The mechanism of the DP-enhanced antitumor activity of FUDR is not completely understood but appears to be related to a profound inhibition by DP of thymidine accumulation in and FUDR efflux from colon-cancer cell lines. On the basis of these in vitro results, 28 patients with metastatic colon cancer were entered in a clinical trial of monthly courses of 0.1 mg/kg FUDR daily for 14 days and 75 mg oral DP 5 times daily for 14 days starting on the 3rd day of continuous i.v. FUDR infusion. The pharmacokinetics of DP was studied in three patients; the results showed that 98% of total serum DP was protein-bound and that free DP levels were significantly lower than the concentrations necessary for the expected in vitro DP/FUDR modulation. Treatment was well tolerated, with only 12 patients developing mild to moderate toxicity. Of 27 evaluable patients, 4 achieved a partial response that lasted 2, 3, 5, and 6+ months. This relatively low response rate (15%), which is similar to that achieved with FUDR alone, may be explained by the low steady-state plasma concentrations of free DP achieved in our patients. Other means of DP administration, such as i.v., i.a., and i.p. injection, may be required to achieve free DP concentrations necessary for successful biochemical modulation of FUDR in patients.Supported in part by grants CA17094, CA23074, and CA39629 from the National Institutes of Health, Bethesda, Md 20205, and a grant from the Arizona Chronic Disease Commission. HSG is a recipient of an American Cancer Society Career Development Award |
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