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Increase in Thermosensitivity of Tumor Cells by Lowering Intracellular pH¹

University of Minnesota Medical School, Department of Therapeutic Radiology-Radiation Oncology, Minneapolis, Minnesota 55455 [C. W. S., J. C. L., R. J. G., C. M. M.], and Nacogdoches, Texas 75963-1548 [E. J. C.]

We previously reported that the thermosensitivity of tumor cells can be increased when the intracellular pH is lowered by inhibiting Na⁺/H⁺ exchange through the plasma membrane with amiloride (3,5-diamino-6-chloro-N-(diamino methylene)pyrazinecarboxamide) or its analogues and HCO₃^-/Cl^- exchange with 4,4-diiothiocyanato-stilbene-2,2'-disulfonic acid. In this study, we investigated the effects of (3-amino-6-chloro-5-(1-homopiperidyl)-N-(diaminomethylene)pyrazine-carboxamide) (HMA), an analogue of amiloride and a potent inhibitor of Na⁺/H⁺ exchange, and R(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]acetic acid [B-3(+)], a potent inhibitor of HCO₃^-/Cl^- exchange, on the thermosensitivity of SCK tumor cells in vitro. We observed that 10 µM of HMA could effectively increase the cell death by heating at 43°C in pH 6.6 medium but not in pH 7.5 medium. The B-3(+) at 50 µM alone had no effect on the thermosensitivity of cells, but it increased the thermosensitizing effect of HMA in acidic medium. Our results strongly suggested that a combination of HMA and B-3(+) may preferentially thermosensitize tumors in vivo since the interstitial environment in tumors is acidic relative to that in normal tissues.

¹ This work was supported by National Cancer Institute grants CA13353 and CA44114.

² To whom requests for reprints should be addressed, at University of Minnesota Medical School. 424 Harvard Street S.E., Box 494 UMHC, Minneapolis, MN 55455.

Received 11/ 9/92. Accepted 1/27/93.

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