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

TY - JOUR

T1 - 5-fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity

AU - Jensen, Søren Astrup

AU - Sørensen, Jens Benn

PY - 2012/1

Y1 - 2012/1

N2 - 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.

AB - 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.

U2 - 10.1007/s00280-011-1669-x

DO - 10.1007/s00280-011-1669-x

M3 - Journal article

C2 - 21603868

SN - 0344-5704

VL - 69

SP - 57

EP - 64

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

IS - 1

ER -