Potentiation of DNA-adduct formation and cytotoxicity of platinum-containing drugs by low pH

Abstract

The low interstitial pH of tumor tissue is an important modulator of various anti-tumor modalities. In order to explore the optimal conditions for the potentiating action of low pH on the cytotoxic activities of cis- and carboplatin, we have investigated the temporal aspects of drug activity and pH modulation in L1210 murine leukemia cells in comparison with various other drugs. Extra- and intra-cellular pH of L1210 cells was modulated before, during and after drug exposure and survival of L1210 cells was determined. During short exposures, cytotoxicity of cisplatin and alkylating drugs was potentiated by conditions of low pH in the ranking order of: cisplatin, mitomycin C, melphalan and chlorambucil. Low pH had no effect on the cytotoxic activity of carboplatin and cytosine arabinoside and it inhibited the action of doxorubicin. During prolonged incubation at low pH, potentiation of cisplatin was increased and a more than 3-fold potentiation was induced in the case of carboplatin. Part of the latter effect was also manifested by 20 hr post-incubation in drug-free medium at low pH after a 4-hr exposure to carboplatin. Post-incubation did not increase the stimulating effect of low pH on the cytotoxic activity of melphalan and cisplatin. Acidification affected neither the uptake nor the extracellular hydrolysis of platinum-containing drugs. Under all circumstances, potentiation of platinum-containing drugs was accompanied by an increase in platinum-induced DNA modification, as detected by immunocytochemistry.