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5-Fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity

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Abstract

Aim

This study aimed to elucidate the influence of 5-fluorouracil (5-FU)-based therapy on the vascular endothelium and its association with 5-FU-induced heart ischemia.

Methods

The study prospectively accrued patients (n = 106) having completely resected colorectal cancer and receiving adjuvant treatment with 5-FU, folinic acid, and oxaliplatin. The levels of plasma von Willebrand factor (vWf), urine albumin-to-creatinine ratio (UACR), coagulation factor II + VII + X, and fibrin D-dimer were serially assessed before, during, and after chemotherapy.

Results

The vWf level increased from median (range) 1.43 kU/l (0.48 to >3) to 2.64 kU/l (0.23 to >3) (P = 0.001), the UACR increased from 1.1 ± 0.2 mg/mmol (mean ± SE) to 2.1 ± 0.3 mg/mmol (P = 0.001), the coagulation factor II + VII + X activity decreased from 1.00 ± 0.02 to 0.94 ± 0.02 U/l (P = 0.001), and the fibrin D-dimer level increased from 1.1 ± 0.2 to 2.1 ± 0.3 kU/l (P = 0.001) at baseline and during chemotherapy, respectively. The changes in the levels of vWf (P = 0.3), UACR (P = 0.8), coagulation factor II + VII + X (P = 0.8), and fibrin D-dimer (P = 0.6) in nine (8.5%) patients having clinical signs of cardiotoxicity were not significantly different from that of the patients not having cardiotoxicity. The 5-FU-induced rise in plasma biomarkers was not significantly related to the cardiovascular morbidity or its risk factors (P = 0.9).

Conclusions

5-FU therapy induces global reversible endothelial injury leading to a procoagulant state. The ensuing endothelial dysfunction may be of significance to the pathogenesis of 5-FU-induced clinically overt cardiotoxicity. Cardiovascular disease is not significant for the vulnerability of the endothelium to 5-FU-based chemotherapy.

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Acknowledgments

Desiree and Niels Yde Foundation, Manufacturer Einar Willumsen Foundation, Dagmar Marshall Foundation, Aase and Ejnar Danielsen Foundation, A. P. Møller Foundation for the Advancement of Medical Science, Merchant M. Brogaard and Wife’s Foundation, Director Jacob Madsen and wife Olga Madsen Foundation, Director Ib Henriksen Foundation, Merchant M. Kristian Kjaer and wife Foundation, the Foundation of 1870, Merchant Svend Hansen and wife Ina Hansen Foundation and Max, Anna Friedmann Foundation and Lykfeldt Foundation supported this study.

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The authors claim no conflicts of interest.

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  1. Department of Oncology 5073, Rigshospitalet, Copenhagen University Hospital, 9 Blegdamsvej, 2100, Copenhagen, Denmark

    Søren Astrup Jensen & Jens Benn Sørensen

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Correspondence to Søren Astrup Jensen.

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Jensen, S.A., Sørensen, J.B. 5-Fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother Pharmacol 69, 57–64 (2012). https://doi.org/10.1007/s00280-011-1669-x

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