Effect of molecular modification on the inhibition of lymphocyte blastogenesis by cardiac glycosides.

Cardiac glycosides are potent inhibitors of cell division. They may be useful as antitumor agents if the antimitotic effect can be dissociated from their cardiotoxic effect. We studied congeners of cardiac glycosides to determine whether the saccharide or the genin portion of the molecule contributes to its antimitotic effect. The concentration of glycoside required to inhibit PHA-stimulated 3H-thymidine incorporation into DNA at 72 hr in human lymphocytes was studied. The inhibiting concentration varied by over tenfold if either the genin or the saccharide portion of the molecule was altered. Therefore either the genin or the saccharide influences independently the antimitotic effect of the glycosides. The relative inhibitory dose of specific genins or glycosides on lymphocyte blastogenesis was similar to the relative arrhythmogenic effects. Therefore development of congeners with antimitotic action but without arrhythmogenicity may be difficult. The arrhythmogenic effect of cardiac glycosides has been shown to be related to their ability to inhibit the plasma membrane Na-K ATPase of myocardial cells. The antimitotic effects parallel closely the arrhythmogenicity of individual glycosides. This relationship provides added evidence to support the concept that the antimitotic effect of glycosides is related to inhibition of Na-K ATPase. Moreover, these findings support the critical role of the transport ATPase in cell division.