STUDIES OF THE ANTIMITOTIC EFFECTS OF CARDIAC GLYCOSIDES: MOLECULAR FEATURES AND POTENCY

Abstract

Cardiac glycosides are known to inhibit spontaneous and induced human cell division. We have studied a large number of genin and glycoside congeners to determine (a) whether the saccharide or genin portion of the molecule contributes to its antimitotic effect, (b) whether the antimitotic effect is correlated with inhibition of Na+ K+ ATPase activity, and (c) whether antimitotic effects can be dissociated from cardiac arrhythmigenicity. The concentration of glycoside required to inhibit PHA stimulated thymidine incorporation into DNA at 72 hours in human lymphocytes was studied. The 50% inhibitory dose could be varied by greater than 10-fold by a change in either the genin or the saccharide. Therefore, both genin and saccharide were related to the antimitotic effect of the glycosides. The effect of varying genin or saccharide and the dose-inhibition curves indicated that the antimitotic effect was qualitatively similar to the known effects of these drugs on ATPase activity. Cardiac glycosides were much more potent and rapid-acting inhibitors of lymphoproliferation in vitro than glucocorticolds. The antimitotic effects of most of the agents studied appeared to be at concentrations which have a very high risk for arrhythmigenicity of the myocardium. However, these studies may provide incentive to explore structural variants of cardiac glycosides as pharmacologic agents to inhibit cell division.