E-12 Free Communication/Slide - Cancer and Exercise: JUNE 1,2007 8:00 AM - 10:00 AM ROOM: 264
Research has indicated that the antineoplastic effects of GW2974 (an ErbB2-inhibitor) are enhanced in the presence of Doxorubicin (DOX). However, combining DOX and GW2974 results in a dose-dependent cardiotoxicity, characterized by left ventricular dysfunction and symptomatic heart failure.
PURPOSE: The purpose of this investigation was to determine if endurance exercise training performed prior to GW2974 and DOX administration would be cardioprotective.
METHODS: Female Sprague Dawley rats (n=128) were initially divided into one of two experimental groups, exercise and sedentary. Animals in the exercise group (n=64) completed 10 weeks of exercise training, which consisted of running on a motorized treadmill 60 minutes a day, 5 d/week, at a speed of 30 m/min and an 18% incline; while rats in the sedentary group (n=64) were restricted to cage activity for 10 weeks. Following the exercise or sedentary period, rats were further randomized into treatment groups. Within each group, 30 rats received saline injections, and 34 received injections of 10 mg/kg DOX and 30 mg/kg GW2974. After injections, rats were sacrificed at 2, 5, or 10 days following injections. At the scheduled time of sacrifice, hearts were isolated and perfused using the working heart model for determination of ex vivo cardiac function. Portions of the left ventricle were obtained for biochemical analyses.
RESULTS: At 2- and 5-days post, sedentary animals receiving GW2974+DOX experienced significant cardiac dysfunction, as evidenced by significantly lower values of left ventricular developed pressure (LVDP) and rate of pressure development (dP/dt max) and relaxation (dP/dt min), compared to their saline-treated counterparts (p<0.05). Exercise training prevented this response, as cardiac function in trained animals receiving the GW2974+DOX was not significantly different than sedentary, saline-treated animals. At 10-days post, both the exercise and sedentary drug-treated groups had significant cardiac dysfunction. However, the exercise drug-treated group had a significantly higher LVDP, dP/dt min and dP/dt max values than their sedentary counterparts (p<0.05).
CONCLUSIONS: These data suggest that exercise training performed prior to GW2974+DOX administration may attenuate cardiac dysfunction.