pH regulating therapy for hepatocellular carcinoma

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Measurements of intracellular pH (pHi) have shown no significant difference in mean pHi (almost 7.2) between solid tumors and normal tissues. Two membranous ion pumps (N+/H+ antiport and Na+- dependentHCO3-/Cl- exchanger) contribute to the regulation of pHi. This study was planned to clarify the anti-tumor effect of inhibiting agents against the two ion exchangers. Human hepatocellular carcinoma (HCC) was selected as a target tumor since the extracellular pH (pHe) of the tumor has potential to be more acidic by transcatheter arterioembolization (TAE) that is one of the most effective therapy for HCC. Under in-vitro assay using human HCC cell lines, Exposure to EIPA : 5-(N-ethyl-N-isopropyl) amiloride (an inhibitor of N+/H+ antiport) and DIDS : 4,4-diisothiocyanstibene 2,2- disulfonic acid (an inhibitor of Na+-dependentHCO3-/Cl- exchanger) at pHe 6.6 caused 100-fold cell killing compared with pHe 7.2. The cytotoxicity was enhanced about 10-fold under the hypoxic condition. In vivo assay using nude mice bearing human HCC tumors at the left hind leg, the administration of these inhibiting agents at the maximal dose that no animal death occurred led to significant reduction of the tumor size with massive necrotic area. Cells from non-necrotic tissues of the tumor treated with the inhibiting agents were cultured in vitro and showed the tolerance to the pH regulating therapy compared with their wild type cells. The establishment of the HCC models on the liver of small animals was not achieved because of the technical problem, therefore the combination effects of those pH regulating therapy and TAE have not been estimated.