Solid tumors often contain regions of necrosis and have a high rate of cell death; they are also known to contain regions of hypoxia and acidity. Previous work in the applicant's laboratory has shown: (i) that hopoxia and acid extracellular pH (pHe) may interact to cause rapid death of cells; (ii) mechanisms that lead to cell death under these conditions include inhibition of ion exchangers in the cell membrane which function to regulate interacellular pH (pHi); (iii) variant cells derived from the MGH-U1 human bladder cancer cell line which lack the Na+/H+ exchanger do not generate tumors or spheroids, or generate a few tumors after long latency which contain revertant cells; and (iv) inhibitors of pHi regulation may kill cells selectively under acid conditions in culture. Two major mechanisms are known to regulate pHi in mammalian cells under acid conditions: the Na+/H+ antiport and the Na+-dependent HCO3-/C1-exchanger. The current aims will test the hypothesis that these mechanisms which regulate pHi are essential for cells to survive and proliferate in solid tumors. The proton sucide technique will be used to generate variant cells which lack Na+/H+ exchange from two murine tumor lines, and one leukemic cell line. These variant cell lines (and appropriate controls) will be characterized, and assessed for generation of experimental tumors or leukemia. Novel methods for generation of variant cells which lack the Na+-dependent Cl-/HCO3- exchanger are proposed. These variants will also be characterized and studied for growth of tumors and spheroids. The proposed experiments will assess requirements for tumor growth of the two major mechanisms which regulate pHi under acid conditions. If tumor growth is impaired the inclusion of a leukemic cell line will further test the hypothesis that this is due to the acid milieu which develops in solid tumors. If one or both of the ion exchange mechanisms is essential for survival of tumor cells, it would accelerate the development of new anticancer agents which could inhibit such mechanisms in vivo. The acid conditions in tumors as compared to normal tissues should provide specificity for such drugs.
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