engleski

The chronic administration of ion exchange inhibitors markedly suppress tumour growth in vivo

Introduction: The extracellular pH of solid tumours is approximately 0.5 pH units below pH of normal tissues. Previously we have demonstrated that the viability of tumour cells in acidic microenvironment in vitro depends on the activity of membrane exchangers which regulate intracellular pH (pHi). Two main pHi regulating transport mechanisms are Na+/H+ antiport and Na+-dependent HCO3-/Cl- exchanger. It is possible to inhibit Na+/H+ antiport by amiloride and its analogues as 5-N-ethyl-N-isopropyl amilorid (EIPA) and Na+-dependent HCO3-/Cl- exchanger by stilbene derivates e.g. 4, 4'-diisothiocyanostilben-2, 2'- disulphonic acid (DIDS). Our experiments have been designed to demonstrate the activity of ion exchange inhibitors against murine tumour in vivo when delivered by chronic intratumour (i.t.) administration. Methods: Tumour-bearing mice (carrying subcutaneous mastocytoma P815 for 20 days) were divided in three experimental groups and treated with DIDS, EIPA or DIDS and EIPA together. The antitumour effects of long-term (18 days) i.t. administration of EIPA and/or DIDS were expressed as mean tumour diameter ą SE (mm). Survival rates in experimental groups have been also followed. Results: In all three experimental groups it has been occurred significantly (p<0.05) lower tumours' growth than in control group. At the end of experiment, mean tumour diameters in experimental groups were twice as small as in control group. Surviving rates in all experimental groups have been significantly higher (DIDS-69%, EIPA-76%, DIDS and EIPA-87%) than in control group (18%) (p<0.05). Conclusions: DIDS and EIPA and their combination were equally effective in inhibition of growth of murine mastocytoma P815. Surviving rates of treated animals compared to control group were also significantly higher. These results have shown the ability to obtain anti-tumour effects and prolonged life in experimental animals using chronic administration of DIDS and/or EIPA. Our results also suggest that pharmacological inhibition of pH-regulating mechanisms might be an exploitable strategy for the therapy of solid tumour.

tumour; intracellular and extracellular pH; ion exchangers

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