Dobrowsky E, Newell K, Tannock I F
Physics Division, Ontario Cancer Institute, Toronto, Canada.
Int J Radiat Oncol Biol Phys. 1991 Feb;20(2):275-9. doi: 10.1016/0360-3016(91)90104-c.
We have investigated the ability of the weak acids, lactate, succinate, and the monomethylester of succinate, to cause intracellular acidification of EMT-6 and MGH-U1 cells. Each of the three substances caused a decrease of intracellular pH (pHi) when the cell lines were exposed at low extracellular pH (pHe) in the range 6.0-6.5. Only monomethylsuccinate caused intracellular acidification at neutral pHe. The fall in pHi increased with increasing dose of each agent and with decreasing pHe. The pHi recovered to almost normal values after exposure of 30 minutes to 50 mM lactate, but there was little or no recovery of pHi in the presence of succinate or monomethylsuccinate. Succinate and its methylester were toxic to cells at low pHe (less than 6.5), and cell killing increased with exposure time and with dose of the agents used. Lactate did not cause cell death at low pHe, and none of the three substances exhibited any cytotoxicity at neutral pHe. Solid tumors are known to have an acidic microenvironment, and pHe may be particularly low in regions of hypoxia. Succinate and its monomethylester may have the potential to kill cells in acidic regions of tumors and might therefore enhance the effect of radiation.
我们研究了弱酸乳酸、琥珀酸及其单甲酯使EMT-6细胞和MGH-U1细胞发生细胞内酸化的能力。当细胞系暴露于6.0 - 6.5范围内的低细胞外pH值（pHe）时，这三种物质中的每一种都会导致细胞内pH值（pHi）下降。只有琥珀酸单甲酯在中性pHe时会引起细胞内酸化。pHi的下降随着每种试剂剂量的增加以及pHe的降低而增加。暴露于50 mM乳酸30分钟后，pHi恢复到几乎正常的值，但在琥珀酸或琥珀酸单甲酯存在的情况下，pHi几乎没有恢复。在低pHe（小于6.5）时，琥珀酸及其甲酯对细胞有毒，并且细胞杀伤随着暴露时间和所用试剂剂量的增加而增加。在低pHe时乳酸不会导致细胞死亡，并且这三种物质在中性pHe时均未表现出任何细胞毒性。已知实体瘤具有酸性微环境，并且在缺氧区域pHe可能特别低。琥珀酸及其单甲酯可能具有杀死肿瘤酸性区域细胞的潜力，因此可能增强放疗效果。
