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 primarily represent tissue extracellular pH) is substantially and consistently lower in tumor than in normal tissue. In contrast, the 31P-magnetic resonance spectroscopy estimated that intracellular pH is essentially identical or slightly more basic in tumor compared to normal tissue. As a consequence, the cellular pH gradient is substantially reduced or reversed in tumor compared to normal tissue: in normal tissue the extracellular pH is relatively basic, and in tumor tissue the magnitude of the pH gradient is reduced or reversed. This difference provides an exploitable avenue for the treatment of cancer. The extent to which drugs exhibiting weakly acid or basic properties are ionized is strongly dependent on the pH of their milieu. Weakly acidic drugs which are relatively lipid soluble in their nonionized state may diffuse freely across the cell membrane and, upon entering a relatively basic intracellular compartment, become trapped and accumulate within a cell, leading to substantial differences in the intracellular/extracellular drug distribution between tumor and normal tissue for drugs exhibiting appropriate pKas.
↵1 Supported by National Cancer Institute Grant CA22860.
↵2 To whom requests for reprints should be addressed, at Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, COX 302, Boston, MA 02114-2617. Phone: (617) 726-8145; Fax: (617) 726-8145.
- Received October 20, 1995.
- Accepted January 25, 1996.
- ©1996 American Association for Cancer Research.