Journal of the National Cancer Institute Advance Access published online on November 13, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm202
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© The Author 2007. Published by Oxford University Press.
Effect of Pretreatment With Atenolol and Nifedipine on ZD6126-Induced Cardiac Toxicity in Rats
Affiliation of authors: AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, U.K
Correspondence to: Anderson J. Ryan, PhD, Department of Cancer Bioscience, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, Cheshire, U.K. (e-mail: anderson.ryan{at}astrazeneca.com).
Antivascular agents that act by destabilizing microtubules, such as ZD6126 (N-acetylcolchinol-O-phosphate), are associated with adverse cardiovascular effects, including transient hypertension, cardiac ischemia, myocardial infarction, and increases in circulating levels of markers of cardiac damage (e.g., troponins). We investigated mechanisms underlying these effects of ZD6126 in rats by continuously monitoring their heart rate and blood pressure and by assessing heart histopathology and plasma troponin T levels. ZD6126 induced acute transient hemodynamic changes (hypertension and delayed tachycardia), which were associated with statistically significant increases in circulating troponin T levels (median level 3 hours after treatment with vehicle or 12.5 mg/kg ZD6126: <9 pg/mL and 563 pg/mL, respectively; P <.001 [two-sided Wilcoxon rank sum test]) and in the incidence of left ventricular myocardial fiber necrosis (incidence 24 hours after treatment with vehicle or 12.5 mg/kg ZD6126: 0/10 rats and 9/10 rats, respectively; P <.001 [two-sided Wilcoxon rank sum test]). Pretreatment of rats with atenolol and nifedipine ameliorated the acute hemodynamic changes and prevented ZD6126-induced increases in both troponin T and myocardial necrosis but did not prevent ZD6126-induced tumor necrosis in an Hras5 tumor xenograft model in nude rats. Our findings suggest that ZD6126-induced acute hemodynamic changes are a prerequisite for cardiac damage in rats.
| CONTEXT AND CAVEATS Prior knowledge Antivascular agents selectively destroy the existing tumor vasculature. However, some vascular disrupting agents in early clinical development that act by destabilizing microtubules, such as ZD6126, are associated with adverse cardiovascular effects. Study design A rat preclinical model was used to examine the underlying mechanisms responsible for the adverse cardiac events associated with ZD6126. Contribution ZD6126 induces acute hemodynamic changes that are a prerequisite for cardiac damage in rats. Implications Clinical investigations of approaches that reduce the acute hemodynamic effects of microtubule-destabilizing vascular disrupting agents are warranted. Limitations Not all patients who receive ZD6126 experience cardiovascular adverse events, suggesting that the underlying biologic mechanisms in patients may differ from those in rats. The direct relevance of this rat model to patients treated with ZD6126 is unclear.
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The authors are employees of AstraZeneca, which funded this work. No external funding was received.
Manuscript received January 16, 2007; revised August 29, 2007; accepted September 11, 2007.
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J Natl Cancer Inst 2007 99: 1653.