Acute exercise in 5‐Fluorouracil cardiotoxicity: Effects on cardiac function and reverse phase protein analysis

Abstract

Background5‐Fluorouracil (5FU) is a commonly administered chemotherapeutic agent used in the treatment of numerous cancers. Though efficacious in treatment of malignancies, 5FU is associated with dose limiting cardiotoxicity that often necessitates deviation from preferred treatment regimens and increases reliance on other, less effective treatment alternatives. The mechanisms driving these toxicities are poorly understood, but leading theories include direct myocardial damage and coronary vasospasm. Data to support these theories have historically been derived from pre‐clinical animal models utilizing i.p injection of 5FU rather than protocols designed to mimic the drug delivery route utilized in clinical practice (i.v. infusion). Further, others have demonstrated the effectiveness of acute exercise in prevention of cardiotoxicity induced by other chemotherapies, however there are no studies evaluating the efficacy of exercise in prevention of 5FU cardiotoxicity.Purpose & HypothesisThe present investigation assessed the effect of 4 moderate intensity treadmill running bouts prior to administration of a clinically relevant dose of 5FU on the functional cardiovascular wellbeing of rats. We tested the hypotheses that a 2‐hr infusion of 5FU would reduce echocardiographic measures of ejection fraction (EF) and fractional shortening (%FS) compared to a saline infusion, and that completion of an acute exercise protocol prior to 5FU treatment would mitigate these cardiotoxic effects.MethodsMale Sprague‐Dawley rats were randomized to receive 5FU (n=15) or saline (CON, n=11) via a 50 mg/kg jugular bolus followed by a 2‐hr 265 mg/kg continuous infusion. A subset of each group (n=7 ex5FU, n=4 exCON) completed 4 bouts of moderate intensity treadmill running (25 min each) commencing 3 days prior to 5FU/saline treatment with the final run ending 1‐hr prior to treatment onset. The remaining animals acted as sedentary controls (n=7 s5FU, n=8 sCON). Echocardiographic variables were compared between groups at baseline and 2‐hr time points (mixed‐model design). Reverse phase protein analysis (RPPA) was conducted on cardiac tissue excised immediately following completion of the infusion for insight into molecular alterations induced by 5FU and/or exercise.ResultsEF at 2‐hr was reduced in sCON (92±2 vs 86±3%, P=.01), s5FU (91±2 vs 86±2%, P=.03), and ex5FU (87±2 vs 82±1%, P=.02), but not in exCON (91±2 vs 87±1%, P=.35) with no timepoint differences between groups (P=0.23). Similarly, %FS decreased from baseline to 2‐hr in sCON (60±3 vs 52±4%, P=.00), s5FU (59±3 vs 51±3%, P=.03), and ex5FU (53±3 vs 45±1%, P=.04), but not in exCON (58±4 vs 52±1, P=.28) with no differences between groups at either time point (P=0.97). RPAA analysis identified graded key changes in CAV‐1, SMAD, and BCL2L1.ConclusionThe present findings suggest small reductions in EF and %FS following completion of a 2‐hr infusion of 5FU or saline, with no differences between the treatments. Further, reductions in EF and %FS were mitigated by prior exercise in exCON, but not in ex5FU. Future work will place emphasis on quantifying the molecular changes indicated by RPPA to better understand alterations induced by 5FU within the heart at the cellular level.