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

• Published in: The FASEB journal 2022-05, Vol.36 (S1), p.n/a
• Main Authors: Hammond, Stephen T., Baumfalk, Dryden R., Horn, Andrew G., Kunkel, Olivia N., Parr, Shannon K., Colburn, Trenton D., Schadler, Keri L., Ade, Carl J., Behnke, Bradley J.
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R5999

Background 5‐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 & Hypothesis The 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. Methods Male 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. Results EF 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