Open AccessJournal Article
Acid pH in Tumors and Its Potential for Therapeutic Exploitation
Ian F. Tannock,Daniela Rotin +1 more
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Measurement of pH in tissue has shown that the microenvironment in tumors is generally more acidic than in normal tissues, and 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.Abstract:
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-sensitive Na+-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 which lack 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 combination of 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 conventional anticancer drugs. Ionophores such as nigericin or CCCP cause acid loading of cells in culture and are toxic only at low pHc; 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.read more
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References
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Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ.
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Biological Applications of Ionophores
TL;DR: This paper describes the phytochemical properties of Ionophores, and some of the properties that matter most in the determination of good and bad Ionophore properties are listed.
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Cytoplasmic pH and free Mg2+ in lymphocytes.
TL;DR: Measurements have been made of cytoplasmic pH, (pHi) and free Mg2+ concentration, ( [Mg2 +]i), in pig and mouse lymphocytes, and Mitogenic concentrations of concanavalin A (Con A) had no measurable effect on pH in the first hour.
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