The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells

The accumulation and toxicity of the weak base doxorubicin has been investi gated as a function of extracellular pH, intracellular pH and the cellular pH gradient in cells previously cultured under normal (pH 7.4) and low-pH ( 6.8) conditions. Low-pH-adapted cells exhibit transmembrane pH gradients wh ich substantially differ from normal cells at the same extracellular pH. No relationship was obtained between intracellular pH and the uptake or toxic ity of doxorubicin in the two cell types. In contrast, doxorubicin accumula tion and toxicity increased with increasing extracellular pH in both normal and low-pH-adapted cells. However. at the same extracellular pH, drug cyto toxicity was more pronounced in normal than in low-pH-adapted cells. The di fference in doxorubicin accumulation and cytotoxicity at the same extracell ular pH was found to be dependent on the difference in the transmembrane pH gradient of the two cell types. As the cellular pH gradient differs betwee n tumour and normal tissue. this observation suggests a basis for enhancing cellular drug uptake in either tissue type.