Mikkelsen R B, Asher C, Hicks T
Biochem Pharmacol. 1985 Jul 15;34(14):2531-4. doi: 10.1016/0006-2952(85)90538-6.
The effects of extracellular pH (6.2 to 7.3) on uptake and cytotoxicity of the weak acid anti-tumor drug chlorambucil were investigated. Decreasing extracellular pH from 7.3 to 6.5 had a negligible effect on the intracellular pH of Chinese hamster V79 fibroblasts, thus resulting in the formation of a transmembrane pH gradient (intracellular alkaline). Addition of high concentrations of acetate or bicarbonate partially collapsed the pH gradient. Chlorambucil (pKa = 5.8) behaved as a weak acid with enhanced accumulation and cytotoxicity at extracellular pH less than 7.0. As predicted for a weak acid, partial collapse of the transmembrane pH gradient decreased both uptake and cell killing. Since the interstitial pH of micrometastases and solid tumors of many cancers is low relative to normal tissues, these results have potential implications for both in vitro drug testing and in vivo therapy.
研究了细胞外pH值（6.2至7.3）对弱酸抗肿瘤药物苯丁酸氮芥摄取和细胞毒性的影响。将细胞外pH值从7.3降至6.5对中国仓鼠V79成纤维细胞的细胞内pH值影响可忽略不计，从而导致跨膜pH梯度（细胞内呈碱性）的形成。添加高浓度的乙酸盐或碳酸氢盐会部分消除pH梯度。苯丁酸氮芥（pKa = 5.8）表现为弱酸，在细胞外pH值低于7.0时积累增强且细胞毒性增强。正如弱酸的预测结果，跨膜pH梯度的部分消除会降低摄取和细胞杀伤作用。由于许多癌症的微转移灶和实体瘤的间质pH值相对于正常组织较低，这些结果对体外药物测试和体内治疗均具有潜在意义。
