By Ian F. Tannock2 and Daniela Rotin3
Departments of Medicine and Medical Biophysics, Ontario Cancer Institute and University of Toronto, Toronto, Ontario, Canada M4X 1K9
Measurement of pH in tissue has shown that the microenvironment in tumors is generally more acidic than in normal tissues. Major mechanisms which lead to tumor acidity probably include the production of lactic acid and hydrolysis of ATP in hypoxic regions of tumors.
Further reduction in pH may be achieved in some tumors by administration of glucose (±insulin) and by drugs such as hydralazine which modify the relative blood flow to tumors and normal tissues.
Cells have evolved mechanisms for regulating their intracellular pH. The amiloride-sensitive Na+/H+ antiport and the DIDS-sensitiveNa+-dependent HCO3–/Cl– exchanger appear to be the major mechanisms for regulating pHi under conditions of acid loading, although additional mechanisms may contribute to acid extrusion.
Mitogen-induced initiation of proliferation in some cells is preceded by cytoplasmic alkalinization, usually triggered by stimulation of Na+/H+ exchange; proliferation of other cells can be induced without prior alkalinization. Mutant cells whichlack Na+/H+ exchange activity have reduced or absent ability to generate solid tumors; a plausible explanation is the failure of such mutant cells to withstand acidic conditions that are generated during tumor growth.
Studies in tissue culture have demonstrated that the combinationof hypoxia and acid pHe is toxic to mammalian cells, whereas short exposures to either factor alone are not very toxic. This interaction may contribute to cell death and necrosis in solid tumors. Acidic pH may influence the outcome of tumor therapy.There are rather small effects of pHe on the response of cells to ionizing radiation but acute exposure to acid pHe causes a marked increase in response to hyperthermia; this effect is decreased in cells that are adapted to low pHe. Acidity may have varying effects on the response of cells to conventionalanti cancer drugs. Ionophores such as nigericin or CCCP causea cid loading of cells in culture and are toxic only at low pHe;this toxicity is enhanced by agents such as amiloride or DIDS which impair mechanisms involved in regulation of pHi. It is suggested that acid conditions in tumors might allow the development of new and relatively specific types of therapy which are directed against mechanisms which regulate pHi under acid conditions.
1 Experimental work described in this paper was supported by the Medical Research Council of Canada.
2 To whom requests for reprints should be addressed.
3 MRC Research Fellow; supported previously by a National Cancer Institute of Canada Studentship. Present address: Department of Cell Biology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1K