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Hydrogen Ion-mediated Enhancement of Cytotoxicity of Bis-Chloroethylating Drugs in Rat Mammary Carcinoma Cells in Vitro¹

Institut für Zellbiologie (Tumorforschung), Universität Essen (GH), Hufelandstrasse 55, D-4300 Essen 1 [E. J., K-H. G., M. F. R.]; Medizinische Universitätsklinik, Abteilung Innere Medizin II, Otfried-Müller-Strasse 10, D-7400 Tübingen [E. J.]; Biologisches Institut der Universität Stuttgart, Abteilung Biophysik, Pfaffenwaldring 57, D-7000 Stuttgart 80 [I. K., D. F. H.]; and Institut für Organische Chemie der Georg-August-Universität, Tammannstrasse 2, D-4300 Göttingen [L-F. T.]; Federal Republic of Germany

Aerobic glycolysis, a metabolic characteristic of malignant cells, can be exploited to increase the concentration of lactic acid selectively in tumor tissues in vivo by systemic administration of glucose (E. Jähde and M. F. Rajewsky, Cancer Res., 42: 1505–1512, 1982). To investigate whether a more acidic microenvironment can enhance the effectiveness of cytocidal drugs, we have analyzed the colony-forming capacity of M1R rat mammary carcinoma cells exposed to bis-chloroethylating agents in culture as a function of extracellular pH (pH_e). At pH_e 6.2 the cytotoxicity of 4-hydroperoxycyclophosphamide, as measured by inhibition of colony formation, was potentiated by a factor of 200 as compared to pH_e 7.4. Similar results were obtained with mafosfamide, nitrogen mustard, nornitrogen mustard, melphalan, and chlorambucil; not, however, with ifosfamide. As indicated by experiments using the ionophor nigericin for rapid equilibration of pH_e and intracellular pH (pH_i; measured with pH-sensitive microelectrodes), modulation of drug action by varying pH_e primarily resulted from the concomitant decrease in pH_i. The acidic microenvironment enhanced cytotoxicity most effectively during the phase of cellular drug uptake and monofunctional alkylation of DNA. DNA cross-link formation appeared to be less affected by pH, and lowering of pH_e during the phase of cross-link removal was only marginally effective.

¹ This investigation was supported by the Federal Ministry for Research and Technology, by BYK Gulden Fonds für Experimentelle Krebsforschung, by Grant 85.003.1 from the Wilhelm Sander-Stiftung, and by the Deutsche Forschungsgemeinschaft (Hu 204/9-4). Presented in preliminary form at the Annual Congress of the German Society of Hematology and Oncology, Tübingen, Federal Republic of Germany, October 5–8, 1986.

² To whom requests for reprints should be addressed, at Institut für Zellbiologie (Tumorforschung), Universität Essen (GH), Hufelandstrasse 55, D-4300 Essen 1, Federal Republic of Germany.

Received 9/27/88. Revised 2/17/89. Accepted 2/24/89.

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