Tannock I F, Rotin D
Department of Medicine, Ontario Cancer Institute, Toronto, Canada.
Cancer Res. 1989 Aug 15;49(16):4373-84.
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.
组织中pH值的测量表明，肿瘤中的微环境通常比正常组织更酸。导致肿瘤酸性的主要机制可能包括肿瘤缺氧区域中乳酸的产生和ATP的水解。在某些肿瘤中，通过给予葡萄糖（±胰岛素）以及使用如肼屈嗪等药物来改变肿瘤和正常组织的相对血流量，可进一步降低pH值。细胞已进化出调节细胞内pH值的机制。在酸负荷条件下，氨氯地平敏感的Na⁺/H⁺逆向转运体和DIDS敏感的Na⁺依赖性HCO₃⁻/Cl⁻交换体似乎是调节细胞内pH值的主要机制，尽管可能还有其他机制有助于酸的排出。在某些细胞中，有丝分裂原诱导的增殖起始之前会发生细胞质碱化，通常由Na⁺/H⁺交换的刺激引发；其他细胞的增殖可以在没有预先碱化的情况下被诱导。缺乏Na⁺/H⁺交换活性的突变细胞产生实体瘤的能力降低或丧失；一个合理的解释是，此类突变细胞无法承受肿瘤生长过程中产生的酸性条件。组织培养研究表明，缺氧和酸性细胞外pH值的组合对哺乳动物细胞有毒，而单独短时间暴露于任何一个因素都没有很强的毒性。这种相互作用可能导致实体瘤中的细胞死亡和坏死。酸性pH值可能会影响肿瘤治疗的结果。细胞外pH值对细胞对电离辐射的反应影响较小，但急性暴露于酸性细胞外pH值会导致对热疗的反应显著增加；在适应低细胞外pH值的细胞中，这种效应会减弱。酸性可能对细胞对传统抗癌药物的反应产生不同影响。尼日利亚菌素或CCCP等离子载体可导致培养细胞的酸负荷，并且仅在低细胞内pH值时有毒；氨氯地平或DIDS等药物会损害参与调节细胞内pH值的机制，从而增强这种毒性。有人提出，肿瘤中的酸性条件可能允许开发针对酸性条件下调节细胞内pH值机制的新型且相对特异的治疗方法。
