Effects of oxygenation and pH on tumor cell response to alkylating chemotherapy

In the present investigations we evaluated the consequence of changing the cellular microenvironment on the treatment efficacy of the alkylating chemotherapeutic agent melphalan. Human A549 adenocarcinoma and mouse KHT/iv sarcoma cells were treated with melphalan under aerobic or hypoxic conditions at pH 6.6 or 7.4. Both low oxygenation and acidic pH individually were found to increase tumor cell killing by this chemotherapeutic agent. However, the magnitude of the enhanced toxic effect was greatest when hypoxic conditions and acidic pH were combined during treatment. For example, A549 cells treated with melphalan under hypoxic conditions at pH 6.6 were approximately 3 times more sensitive to this anticancer drug than were cells exposed in air at pH 7.4. Conditions of low oxygen and pH also increased the chemosensitization potential of the nitroimidazole misonidazole (MISO) when combined with this chemotherapeutic agent. Thus, when KHT/iv cells were treated with the combination of melphalan plus MISO, the resulting enhancement ratio increased from 1.8 to 2.5, when the pH maintained during the treatment was changed from physiologic (7.4) to acidic (6.6).