Reduction of intracellular pH as a strategy to enhance the pH-dependent cytotoxic effects of melphalan for human breast cancer cells.

The microenvironment within solid tumors is slightly acidic, and manipulation of this extracellular acidity to cause intracellular acidification might be used to increase selective antitumor effects of some anticancer drugs. Potential mechanisms include inhibition of repair of DNA damage and inhibition of repopulation of tumor cells between successive courses of chemotherapy. Here, we evaluate the influence of extracellular pH (pHe) and of two agents that lead to intracellular acidification (cariporide and S3705) on toxicity of melphalan for two human breast cancer cell lines (MDA-MB231 and MCF7). Both the total number and number of colony-forming cells were evaluated during and after three sequential weekly drug treatments. Our results indicate the following: (a) Slow or absent repopulation after the first course of treatment that is influenced minimally by pHe. (b) Rapid repopulation after the second course of treatment that may be inhibited at low pHe. (c) Effects of low pHe following treatment with melphalan to increase cell kill. (d) Small effects of incubation in cariporide and S3705 at low pHe to increase the net cell kill after treatment with melphalan. Although these results add to evidence that manipulation of intracellular pH within the acidic environment of solid tumors can influence the effects of chemotherapy, they are too small and inconsistent to warrant clinical evaluation.