Cutaneous Microvascular Impairment in 5‐Fluorouracil Treated Cancer Patients

Abstract

INTRODUCTION Despite frequent use and high efficacy in treatment of several cancers, 5-Fluorouracil (5-FU) chemotherapy is associated with acute and late occurring cardiotoxicity, ranging from vasospastic angina to increased risk of overt cardiovascular disease mortality. To date, the mechanisms by which these toxicities occur are not well understood, with leading theories implicating coronary vascular dysfunction by way of endothelial-dependent vasodilator impairment. PURPOSE & HYPOTHESIS Therefore, the purpose of the present research was to evaluate multiple mechanisms of endothelial function within the cutaneous microcirculation of 5-FU treated cancer patients (5-FU) and matched controls (CON) using the noninvasive measure of laser Doppler flowmetry (LDF). We hypothesized that 5-FU would attenuate both acetylcholine (ACh)-induced and local heating-induced cutaneous vasodilation. METHODS 17 5-FU (13 M, 4 F; age = 63.5 ± 12 yr) and 16 CON (8 M, 8 F; age = 58.1 ± 16 yr) volunteered for this study. Red blood cell flux was acquired via LDF in the forearm at baseline and following 1) iontophoresis of 200 µL of 2% ACh and 2) ~ 35 min of localized heating at 42°C. CVC was calculated from red blood cell flux divided by mean arterial pressure and presented as the percent increase from baseline to peak (%CVC). RESULTS ACh resulted in a significantly increased CVC in both groups, with no differences in %CVC between groups (CON = 920 ± 107%, 5-FU = 842 ± 113%; p = .62). Local heating, however, elicited a significantly lower %CVC in 5-FU treated patients (CON = 567.5 ± 77.7%, 5-FU = 256.7 ± 71.8%; p = .012). CONCLUSION Given the primary role of endothelial nitric oxide in local heating-induced cutaneous vasodilation, but not during ACh, our findings suggest that 5-FU chemotherapy treatment may result in endothelial dysfunction through nitric oxide mediated mechanisms. Experiments to corroborate these findings through iontophoresis of N-ω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and in human coronary endothelial cell culture are ongoing by our group and will provide additional mechanistic insight into 5-FU induced cardiotoxicity.