The influence of 5-fluorouracil and methotrexate on vascular endothelium. An experimental study using endothelial cells in the culture.
BACKGROUND
Cardiotoxicity still remains an unexplained toxic manifestation of 5-fluorouracil (5-FU). Clinical and experimental data suggest that endothelium of coronary arteries could be involved in the pathophysiological mechanisms of the syndrome. In order to further explain 5-FU induced cardiotoxicity, we investigated the influence of this drug on endothelial cells (EC) in a cell culture model.


METHODS
The influence of 5-FU on EC, with respect to DNA synthesis, cell death and release of prostacyclin by endothelial cells (EC) was studied. For comparison, we tested methotrexate (MTX), an antimetabolite without cardiotoxic properties, in the same way. Human endothelial cell lines (HEC) and bovine endothelial cells (BEC) were incubated with increasing concentrations of 5-FU and MTX for 48 hours. (3H)thymidine incorporation, total cellular protein, loss of (3H)thymidine from prelabelled cells and 6-keto-prostaglandin F1 were measured.


RESULTS
DNA synthesis decreased significantly in both HEC and BEC, and the release of prostacyclin by BEC increased significantly when incubated with 5-FU. This effect was not seen with MTX.


CONCLUSIONS
The results indicate specific susceptibility of benign EC to 5-FU. Such susceptibility was confirmed by the release of prostacyclin by the BEC, indicating leakage secondary to EC injury.
Department of Oncology, University Hospital, Lund, Sweden.
M
M
Cwikiel
J
J
Eskilsson
M
M
Albertsson
L
L
Stavenow
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D002417:Cattle; D002470:Cell Survival; D002478:Cells, Cultured; D003331:Coronary Vessels; D004247:DNA / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D011464:Epoprostenol / Q000096:biosynthesis*; D005472:Fluorouracil / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D008727:Methotrexate / Q000009:adverse effects* / Q000494:pharmacology; D008962:Models, Theoretical; D012016:Reference Values
D000964:Antimetabolites, Antineoplastic; D004247:DNA; D011464:Epoprostenol; D005472:Fluorouracil; D008727:Methotrexate