Effect of dipyridamole on fluorodeoxyuridine cytotoxicity in vitro and in cancer patients

Antonio C. Buzaid, David S. Alberts, Janine Eispahr, Kurt Mosley, Yei Mei Peng, Kendra Tutsch, Collin P. Spears, Harinder S. Garewal

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 μM 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.

Original languageEnglish (US)
Pages (from-to)124-130
Number of pages7
JournalCancer Chemotherapy And Pharmacology
Volume25
Issue number2
DOIs
StatePublished - Mar 1989

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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