The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics

The extracellular pH is lower in tumor than in normal tissue, whereas their intracellular pH is similar, In this study, we show that the tumor-specifi c pH gradient may be exploited for the treatment of cancer by weak acid che motherapeutics, i,v,-injected glucose substantially decreased the electrode estimated extracellular pH in a xenografted human tumor while its intracel lular pH, evaluated by P-31 magnetic resonance spectroscopy, remained virtu ally unchanged. The resulting increase in the average cell pH gradient caus ed a parallel increase in tumor growth delay by the weak acid chlorambucil (CHL). Regardless of glucose administration, the effect of CHL was signific antly greater in tumors preirradiated with a large dose of ionizing radiati on. This suggests that CHL was especially pronounced in radioresistant hypo xic cells possessing a larger transmembrane pH gradient. These results indi cate that the naturally occurring cell pH gradient difference between tumor and normal tissue is a major and exploitable determinant of the uptake of weak acids in the complex tumor microenvironment, The use of such drugs may be especially effective in combination with radiation.