Effect of glucose-mediated pH reduction and cyclophosphamide on oxygenation of transplanted rat tumors

Glucose-mediated reduction of tumor pH is under investigation as a means to improve the therapeutic index of anticancer agents. An improvement of glucose supply to tumors is, however, likely to influence various metabolic and pathophysiological parameters apart from pH which, in turn, could modulate H+ ion-mediated effects. As a first step to identify changes in these parameter, we have investigated the effect of glucose-mediated pH reduction on oxygenation of malignant tissues either per se or in combination with a pH-sensitive drug, cyclophosphamide.

H+ ion and oxygen-sensitive semi-microelectrodes were used to measure pH and pO2 in transplanted TV1A and AH13r rat tumors at normoglycemia and following high-dose intravenous glucose infusion.

In both tumors analyzed, pH reduction was accompanied by a decrease in pO2. In TV1A tumors, for example, the mean (median) pO2 decreased from 8.2 mm Hg (3.7 mm Hg) to 3.9 mm Hg (1.7 mm Hg) at 2 hr and 2.9 mm Hg (1.9 mm Hg) at 24 hr, respectively, after raising the plasma glucose concentration to 25 +/- 2 mmol/l. At the same time points, the mean pH had declined from 6.89 to 6.29 and 6.24, respectively. The class of pO2 readings < 5 mm Hg increased from a pretreatment value of 65% to approximately 90% at 24 hr. In contrast, cyclophosphamide treatment resulted in improved oxygenation of AH13r tumors, an effect first observed at 24 hr after drug administration. When both modalities were combined, cyclophosphamide partly prevented the acidosis-associated decrease in oxygen partial pressure.

The results of this study indicate that, within the context of the therapeutic approach used, cytotoxic agents should be employed which are more active against hypoxic than against well-oxygenated cells. In particular, glucose-mediated reduction of oxygen partial pressure in malignant tissues may be exploited to increase the fraction of hypoxic cells prior to administration of drugs activated in hypoxic cells by reductive metabolism (bioreductive agents).