Abstract 3584: Comparison of the severity of imatinib-induced cardiotoxicity in normotensive Sprague-Dawley (SD) and spontaneously hypertensive (SHR) rats

Abstract

Abstract Imatinib (IMNB) is a promising type of chemotherapeutic agent that specifically targets tyrosine kinase pathway-dependent tumors. However, cardiotoxicity has been reported with clinical use of IMNB. The characteristics of IMNB-induced cardiac alterations are not completely defined. The present study sought to examine the influence of a concomitant disease such as hypertension on the cardiotoxic effects of IMNB. Groups of adult male SD or SHR were dosed with 50 (5/group) or 100 mg/kg (10/group) IMNB or water (10/group)(p.o.) daily for 14 days (dose of 50 mg/kg is approximately 2x recommended human dose of 600 mg/m2). Tissues and blood samples were collected 24 hours after the last dosing. The 100 mg/kg dose caused a slight reduction in the rate of body weight gain. Serum levels of glucose were decreased and alanine transaminase (ALT) were increased in both SD and SHR dosed with IMNB. Changes from control were most pronounced in SD given 100mg/kg IMNB (ALT=175% vs 118% and glucose=81% vs 91% compared to SHR). White blood cell counts were depressed in SHR but not in SD rats. Dose-dependent cardiac lesions were noted in the groups of SD and SHR given either dose of IMNB (blinded evaluation). Cardiac lesions were characterized by cytoplasmic vacuolization, myofibrillar loss, interstitial infiltration with chronic inflammatory cells and fibrosis (proliferation of myofibroblasts). Mean lesion scores (based on a scale of 0 to 3) were higher in SHR than in SD (100mg/kg-1.9 vs 1.25 and 50 mg/kg-1.5 vs 1.1, p<0.05)(Tukey-Kramer test). Increased serum levels of cardiac troponin I were detected in all IMNB-treated groups. The overall mean cTnI levels were higher in SHR (31.5, 41.3 and 53.9 pg/ml) compared to SD (6.8, 25 and 30 pg/ml) at the vehicle control, 50 and 100 mg/kg doses, respectively. These results indicate that hypertension as expressed in SHR appears to be a factor that can intensify the cardiotoxic effects of IMNB and that monitoring for cardiac troponin I may provide a sensitive means of detecting IMNB toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3584.