UNUSUAL POTENTIATION BY VINCA ALKALOIDS OF THE CYTOSTATIC AND CYTOCIDAL ACTION OF METHYL-3,5-DIIODO-4-(4'-METHOXYPHENOXY) BENZOATE (DIME) AND ITS NONHYDROLYZABLE ETHANONE ANALOG (DIPE) ON MDA-MB-231 HUMAN MAMMARY-CANCER CELLS

Drug interaction between DIME or DIPE 3,5-diiodo-4-(4'-methoxyphenoxy) -phenyl]-ethanone} with vincristine and vinblastine on the growth rate of MDA-MB-231 human mammary cancer cells was determined by the median effect kinetic method. Mutually exclusive cellular binding sites were identified kinetically and isobologram analyses showed potentiation. The combind effect of 0.75 mu M DIME and 2 nM vincristine demonstrated a nearly 'threshold' type of mutual activation. It was shown that the nonhydrolyzable DIME derivative DIPE is equivalent to DIME, but becau se of its biological stability is a preferred drug candidate. Vinblast ine-DIME cooperative action is similar to that of vincristine-DIME (or DIPE). Activation of caspase 3 by both DIME and vincristine is greatl y potentiated when both drugs are added simultaneously in a given prop ortion. We propose that following a primary binding of DIME and vinca alkaloids to microtubules, an as yet unrecognized mutual activation of caspase 3 apoptotic path-is initiated, explaining DNA fragmentation a nd cell death. A subpopulation of cancer cells, capable of slow growth at 1.5 mu M DIME was identified. This cell type was also killed by th e DIME-vincristine drug combination.