Department of Oncology 5073, Rigshospitalet, Copenhagen University Hospital, 9 Blegdamsvej, 2100 Copenhagen, Denmark.
Cancer Chemother Pharmacol. 2012 Jan;69(1):57-64. doi: 10.1007/s00280-011-1669-x. Epub 2011 May 21.
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.
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.
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).
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.
本研究旨在阐明 5-氟尿嘧啶（5-FU）为基础的治疗对血管内皮的影响及其与 5-FU 诱导的心脏缺血的关系。
该研究前瞻性地纳入了 106 例完全切除结直肠癌并接受 5-FU、亚叶酸钙和奥沙利铂辅助治疗的患者。在化疗前、化疗期间和化疗后，连续评估血浆血管性血友病因子（vWf）、尿白蛋白/肌酐比（UACR）、凝血因子 II+VII+X 和纤维蛋白 D-二聚体的水平。
vWf 水平从中位数（范围）1.43 kU/l（0.48 至>3）升高至 2.64 kU/l（0.23 至>3）（P=0.001），UACR 从 1.1±0.2 mg/mmol（均值±SE）升高至 2.1±0.3 mg/mmol（P=0.001），凝血因子 II+VII+X 活性从 1.00±0.02 降至 0.94±0.02 U/l（P=0.001），纤维蛋白 D-二聚体水平从基线时的 1.1±0.2 升至化疗期间的 2.1±0.3 kU/l（P=0.001）。在有心脏毒性临床体征的 9 例（8.5%）患者中，vWf（P=0.3）、UACR（P=0.8）、凝血因子 II+VII+X（P=0.8）和纤维蛋白 D-二聚体（P=0.6）水平的变化与无心脏毒性的患者无显著差异。5-FU 诱导的血浆生物标志物升高与心血管发病率或其危险因素无显著相关性（P=0.9）。
5-FU 治疗诱导全身性可逆的内皮损伤，导致促凝状态。随之而来的内皮功能障碍可能对 5-FU 诱导的临床明显心脏毒性的发病机制具有重要意义。心血管疾病对内皮对 5-FU 为基础化疗的易感性没有显著意义。
