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pH Dependence of Mitomycin C-induced Cross-Linking Activity in EMT6 Tumor Cells

Departments of Pharmacology [K. A. K., J. D. M.] and Medicine [O. A., L. L.], The George Washington University School of Medicine, Washington, DC 20037

Mitomycin C (MC), a quinone-containing bioreductive alkylating agent, is cytotoxic to aerobic EMT6 tumor cells despite the fact that little bioactivation of MC occurs in EMT6 cell homogenates in the presence of O₂. Because spontaneous activation of MC at acidic pH has been reported in chemical systems, aerobic EMT6 tumor cells were incubated in serum-free 2-(N-morpholino)ethanesulfonic acid or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer at pH 5.7, 6.4, and 7.5 and exposed to MC for 2 h. As the extracellular pH was lowered, MC-induced DNA-DNA cross-linking, as measured by alkaline elution techniques, was enhanced. This effect was dose dependent at the three pH values tested. Measurement of intracellular pH by flow cytometric analysis indicated that the decrease in extracellular pH was paralleled by a fall in intracellular pH. The alteration of the extracellular pH had no effect on the colony-forming ability of control cells. The survival of cells treated with MC, however, was decreased as the pH was lowered. These data suggest that the intracellular and/or the extracellular pH is an important determinant of MC activity in aerobic EMT6 tumor cells.

¹ Recipient of Grant CA-36946 from the NIH and a Young Investigator Award from the Eli Lilly Co. To whom requests for reprints should be addressed.

² Recipient of Grant CA-32756 from the NIH.

Received 2/18/85. Revised 5/ 9/85. Accepted 5/10/85.

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