Biochemical modulation of fluorouracil by dipyridamole: preclinical and clinical experience.
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 labile 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.
Grem
J L
JL
Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
D003110:Colonic Neoplasms / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism; D003857:Deoxyuridine / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology*; D004347:Drug Interactions; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D009705:Nucleosides / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014542:Uridine Monophosphate / Q000378:metabolism
D004273:DNA, Neoplasm; D009705:Nucleosides; D009711:Nucleotides; D012334:RNA, Neoplasm; D004176:Dipyridamole; D014542:Uridine Monophosphate; D002955:Leucovorin; D005472:Fluorouracil; D013936:Thymidine; D003857:Deoxyuridine; D008727:Methotrexate