Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells

Traditional chemotherapies, aimed at DNA replication in rapidly dividing ce lls, have achieved only limited success in the treatment of carcinomas due largely to their lack of specificity for cells of tumorigenic origin. It is important, therefore, to investigate treatment strategies aimed at novel c ellular targets that are sufficiently different between normal cells and ca ncer cells so as to provide a basis for selective tumor cell killing. Deloc alized lipophilic cations (DLCs) are concentrated by cells and into mitocho ndria in response to negative inside transmembrane potentials. The higher p lasma and/or mitochondrial membrane potentials of carcinoma cells compared to normal epithelial cells account for the selective accumulation of DLCs i n carcinoma mitochondria. Since most DLCs are toxic to mitochondria at high concentrations, their selective accumulation in carcinoma mitochondria and consequent mitochondrial toxicity provide a basis for selective carcinoma cell killing. Several of these compounds have already displayed some degree of efficacy as chemotherapeutic agents in vitro and in vivo. The effective ness of DLCs can also be enhanced by their use in photochemotherapy or comb ination drug therapy. Discovery of the biochemical differences that account for the higher membrane potentials in carcinoma cells is expected to lead to the design of new DLCs targeted specifically to those differences, resul ting in even greater selectivity and efficacy for tumor cell killing. (C) 2 001 Elsevier Science B.V. All rights reserved.