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-specific pH gradient may be exploited for the treatment of cancer by weak acid chemotherapeutics. i.v.-injected glucose substantially decreased the electrode estimated extracellular pH in a xenografted human tumor while its intracellular pH, evaluated by (31)P magnetic resonance spectroscopy, remained virtually unchanged. The resulting increase in the average cell pH gradient caused a parallel increase in tumor growth delay by the weak acid chlorambucil (CHL). Regardless of glucose administration, the effect of CHL was significantly greater in tumors preirradiated with a large dose of ionizing radiation. This suggests that CHL was especially pronounced in radioresistant hypoxic cells possessing a larger transmembrane pH gradient. These results indicate 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.
Kozin
S V
SV
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Shkarin
P
P
Gerweck
L E
LE
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002699:Chlorambucil / Q000737:chemistry / Q000494:pharmacology*; D004357:Drug Synergism; D005110:Extracellular Space / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D002699:Chlorambucil; D005947:Glucose