Exercise pre-conditioning prevents vascular toxicity caused by infusion of 5-fluorouracil in male rats.

Abstract

5-fluorouracil (5-FU) is one of the most common chemotherapies used in cancer treatment yet is often associated with acute cardiotoxicity (e.g., angina, vasospasm). To date, countermeasures to prevent 5-FU cardiotoxicity are lacking. Therefore, we tested the hypothesis that short-term, moderate-intensity exercise completed before 5-FU administration would prevent 5-FU-induced alterations in vascular and cardiac function. Male Sprague-Dawley rats were randomized to sedentary control (SEDCON, n = 9), sedentary 5-FU (SED5FU, n = 10), exercise control (EXCON, n = 8) or exercise 5-FU (EX5FU, n = 8) groups. Rats remained sedentary or completed 4-days of treadmill running (20-25 min, 20 m/min, 5% grade) with the final bout ending ~90-min before treatment with a clinically relevant dose of 5-FU (50 mg/kg bolus + 265 mg/kg 2-hr infusion) or volume matched saline. Echocardiographic indices of left ventricular function and Doppler measurements of aortic pulse wave velocity (PWV) were completed at baseline (BL) and after the 2-hr (2-hr) infusion. 5-FU did not induce changes in left ventricular function. PWV increased from BL to 2-hr in SED5FU (BL: 396 ± 39 cm/s; 2-hr: 452 ± 54 cm/s; P = 0.002), but not SEDCON (BL: 417 ± 55 cm/s; 2-hr: 392 ± 64 cm/s; P = 0.35), EXCON (BL: 408 ± 35 cm/s; 2-hr: 410 ± 46 cm/s; P > 0.99), or EX5FU (BL: 398 ± 13 cm/s; 2-hr: 417± 23 cm/s; P = 0.67). Additionally, PWV at the 2-hr time point was significantly higher in SED5FU compared to SEDCON (P = 0.002). These findings suggest that moderate-intensity exercise preconditioning may protect against 5-FU-induced alterations in arterial PWV-potentially mitigating early signs of cardiotoxicity. Future studies are warranted to identify the mechanisms of 5-FU-induced cardiotoxicity and the feasibility and efficacy of pre-treatment exercise regimens in human patients.