Phosphonium salts exhibiting selective anti-carcinoma activity in vitro.

Tetraphenylphosphonium cation (TPP) and other phosphonium cations selectively inhibited the growth in vitro of human pancreatic carcinoma-derived cells (PaCa-2) and Ehrlich Lettre Ascites cells (ELA) when compared with untransformed monkey kidney epithelial cells (CV-1). In contrast, neither cisplatin nor cytosine arabinoside showed significant selectivity using these lines. Evidence is presented to support the conclusion that the carcinoma-selective antiproliferative activity of phosphonium salts is due to selective accumulation caused by the abnormally high membrane potentials in carcinoma cells. Inhibition of TPP uptake into PaCa-2 and ELA cells by potassium and (for PaCa-2) valinomycin demonstrates that higher membrane potentials account for the carcinoma-selective uptake and cytostatic selectivity of the cation. For TPP chloride and 16 other phosphonium chlorides with a variety of structures, selective inhibition of PaCa-2 growth relative to CV-1 was optimal for the eight falling in a narrow range of octanol/water partition coefficients (between 0.013 and 0.24). A similar optimal selectivity range was observed for ELA cells relative to CV-1. The relationship between partition coefficients and cytostatic selectivity suggests that the rates of diffusion across cytoplasmic and mitochondrial membranes are key factors in the structure/anticarcinoma selectivity relationship for delocalized phosphonium salts in vitro. The relationship could prove useful for the design of other carcinoma-selective delocalized cations.