Studies with mouse
tumors have shown that the effectiveness of certain chemotherapeutic agents can be enhanced if they are used in appropriate combination with an
anti-hypertensive drug such as
hydralazine. This results in reduced
tumor blood flow with, among other things, a consequent decrease in oxygenation and increase in acidity in the
tumor tissue. The purpose of the present work was to determine to what extent
hypoxia and low pH are involved in the mechanism of this effect for
chlorambucil. V79-WNRE cells were exposed to various
drug concentrations under aerobic or hypoxic conditions, pH 6.4 or 7.4. Measurements of cell survival following 1 hr exposure at 37 degrees C showed that pH 6.4 produced a large potentiation of cell killing by
chlorambucil (ER = 4 approx.);
hypoxia, on the other hand, had little effect. The potentiation was shown to be greatest for pH values below 7.0. HPLC measurements of
drug uptake were made since it was anticipated that
chlorambucil, a weak
acid, might tend to accumulate in cells under conditions of low extracellular pH. It was found that at an extracellular pH of 6.4 the ratio of the intracellular (Ci) and extracellular (Ce)
drug concentrations was increased 4.5 and 3.6 fold for aerobic and hypoxic conditions, respectively. This probably explains most, if not all, of the cell killing potentiation observed at low pH.