Biochemical modulation of fluorouracil by dipyridamole

Preclinical and clinical experience

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

In the HCT 116 human colon carcinoma cell line, dipyridamole, an inhibitor of nucleoside transport, increases the toxicity of 5-fluorouracil (5-FU) in a dose-dependent manner. While dipyridamole inhibits thymidine transport, interference with thymidine salvage did not appear to be a critical factor. Dipyridamole altered 5-FU metabolism, producing a selective increase in fluorodeoxyuridine monophosphate levels by blocking the efflux of fluorodeoxyuridine. Deoxyuridine monophosphate levels were greatly increased when cells were exposed to 5-FU alone, and were even larger with the addition of dipyridamole. Dipyridamole did not alter the absolute amount of 5-FU incorporated into either RNA or DNA. Exposure to either 5-FU or dipyridamole alone was associated with the generation of alkaline labile sites in newly synthesized DNA. Concurrent exposure to 5-FU with dipyridamole resulted in a striking increase in the alkaline albile sites. Thus, increased DNA damage appears to correlate with the enhanced cytotoxicity of this combination. The results of a clinical trial evaluating concurrent intravenous infusion of 5-FU with dipyridamole over 72 hours are reviewed. At maximally tolerated doses of infusional dipyridamole, the steady-state concentration of bioactive, non-protein-bound drug is in the range of 25 nM. While this concentration may be sufficient to perturb thymidine salvage in some cell types, it is 20-fold lower than the optimal concentration of bioactive dipyridamole needed to modulate 5-FU toxicity, metabolism and DNA damage in the HCT 116 tissue culture model. In addition, an unexpected pharmacokinetic interaction was seen: dipyridamole increased 5-FU clearance and decreased its steady-state plasma concentration. It remains to be determined whether dipyridamole with 5-FU alone or with leucovorin will translate into an improved therapeutic outcome.

Original languageEnglish (US)
Pages (from-to)56-65
Number of pages10
JournalSeminars in Oncology
Volume19
Issue number2 SUPPL. 3
StatePublished - Jan 1 1992

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Dipyridamole
Fluorouracil
Floxuridine
Thymidine
DNA Damage
Deoxyuridine
Maximum Tolerated Dose
Leucovorin
DNA
Nucleosides
Intravenous Infusions
Colon
Pharmacokinetics
Clinical Trials
RNA

ASJC Scopus subject areas

  • Oncology

Cite this

Biochemical modulation of fluorouracil by dipyridamole : Preclinical and clinical experience. / Grem, Jean L.

In: Seminars in Oncology, Vol. 19, No. 2 SUPPL. 3, 01.01.1992, p. 56-65.

Research output: Contribution to journalArticle

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