Tumor pH: Implications for treatment and novel drug design

Although limited data exist, electrode-measured pH values of human tumors and adjacent normal tissues, which are concurrently obtained by the same investigator in the same patient, consistently show that the electrode pH (believed to represent tissue extracellular pH primarily) is substantially and consistently lower in tumor than in normal tissue. In contrast, the 31P-magnetic resonance spectroscopy-estimated intracellular pH is essentially identical or slightly more basic in tumor compared with normal tissue. As a consequence, the cellular pH gradient is substantially reduced or reversed in these tissues. This difference provides an exploitable avenue for the treatment of cancer. The extent to which drugs exhibiting weakly acid or basic properties are ionized depends on their ionization potential (pKa) and the pH of their milieu. Weakly acidic drugs that are lipid soluble in their nonionized state diffuse freely across the cell membrane and on entering a relatively basic intracellular compartment become trapped and accumulate within the cell. This may lead to substantial (10-fold or more) differences in the intracellular-to-extracellular drug distribution between tumor and normal tissue for cytotoxics, hypoxic cell sensitizers, or other drugs exhibiting appropriate pKa. Experimental in vitro evaluation of these predictions confirms both the predicted pH gradient-dependent changes in cellular drug accumulation and toxicity.