ZD6126-induced hemodynamic changes and cardiovascular events can be prevented by anti-hypertensive therapy. OXFORD-March 26th., 2008

Although ZD6126 exhibits dramatic anti-tumor activity at well-tolerated doses, adverse cardiovascular events have been noted in a small number of patients in Phase I studies. In common with other vascular disrupting agents (VDA) that act by inhibiting tubulin polymerization, ZD6126 treatment is often associated with transient increases in blood pressure. In particular, pre-existing hypertension may be exacerbated and in rare instances, more severe cardiac events may occur including, most notably, increases in the circulating level of troponin I, a marker of cardiac damage.

Recently, Dr. Anderson Ryan and colleagues at AstraZeneca have employed a rat pre-clinical model to both investigate the mechanisms responsible for such cardiotoxicity and suggest ways in which it can be overcome. The results of these studies have recently been published in The Journal of the National Cancer Institute.

Briefly, administration of ZD6126 induced a rapid but short-lived increase in diastolic blood pressure in Wistar-derived Alpk:ApfSD rats. The timing and duration of this effect was similar to that seen in humans. In some animals, plasma troponin T levels were also elevated and histopathological examination of hearts removed 24 hours after treatment showed a corresponding increase in mild/moderate left ventricular myocardial necrosis. Importantly, pretreatment with the calcium channel blocker nifedipine and the beta-adrenoceptor antagonist atenolol ameliorated both the acute hemodynamic changes and the increase in troponin T levels and myocardial necrosis associated with ZD6126 administration. Most critically, such treatment did not inhibit the anti-tumor activity of ZD6126 as determined by the induction of tumor necrosis in a xenograft model.

Together these studies suggest that the induction of acute hemodynamic changes in response to ZD6126 administration is required for cardiac damage to occur. Further, although the application of careful patient selection criteria similar to those employed in relation to current VEGF-targeted anti-angiogenic therapies may avoid the need for intervention, the findings reported in this manuscript nevertheless suggest that ZD6126-induced cardiac events can be prevented through the use of simple and established anti-hypertensive therapies.

Reference

1. Gould, S., Westwood, F.R, Curwen, J.O. Ashton, S.E., Roberts, D.W., Lovick, S.C. and Ryan, A.J. (2007) Effect of pre-treatment with atenolol and nifedipine on ZD6126-induced cardiac toxicity in rats. J Natl Cancer Inst 99(22): 1724-1728. (read abstract)

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