Ethacrynic Acid and Piriprost as Enhancers of Cytotoxicity in Drug Resistant and Sensitive Cell Lines1

Ethacrynic acid and piriprost (6,9-deepoxy-6,9-(phenylimino)-A''8prostaglandin I,) have been shown to potentiate the cytotoxic activity of chlorambucil in rat and human tumor cell lines. Walker 256 rat breast carcinoma cells (WS), with acquired resistance to nitrogen mustards (WR), and two human colon carcinoma cell lines, HT 29 and BE, were sensitized to chlorambucil when either ethacrynic acid or piriprost was administered at the same time as the alkylating agent. Both as single agents and in combination with chlorambucil, there was inhibition of glutathione 5-transferase activity as measured with l-chloro-2,4-dinitrobenzene as a substrate. A depletion in intracellular glutathione was also evident following ethacrynic acid alone or in combination with chloram bucil. Thus, diuretic plant phenols or prostaglandin analogues may have potential therapeutic utility in combination with alkylating agents.