Hyperthermia and radiation in vivo: Effect of 2-deoxy-D-glucose

Abstract

Since hypoxic cells rely heavily on glucose metabolism for energy, 2-deoxy-D-glucose (2-DG), an inhibitor of anaerobic glycolysis, would be expected to increase tumor cell killing by heat and thus enhance the effect of concurrent radiation. In order to test this hypothesis two types of BALB/c mouse tumors, one induced by subcutaneous injection of 106 herpes virus Type 2-transformed (H238) cells and the other by injection of 1.6 × 105 1,2-dimethylhydrazine-transformed (#51) cells in the right thigh, were subjected to radiation, 2-DG, and heat used singly and in various combinations. Control mice were injected with saline. Three to four weeks after inoculation the mice were assigned to one of eight treatment groups (28 mice/group) so that average tumor volume/group before treatment would be equivalent. A single 2000 rad dose of radiation 3 hr prior to heat and 2-DG injected intraperitoneally at 1 g/kg 30 min before heating were given to some of the groups. Localized heat at 43.5 ± 0.1°C for 30 min, when used, was administered by means of a water bath. Rectal temperatures were kept below 39°C, whereas intratumor temperatures reached a maximum of 42°C. After treatment, tumor volume, mouse weight, and mortality were noted twice a week for four weeks. In both tumor models, mice receiving radiation plus heat, and radiation plus heat plus 2-DG, had significantly smaller tumors over the entire 4 to 28 day range after treatment than saline-injected control mice. In addition, in the H238 tumor model, addition of 2-DG to treatment with radiation and heat resulted in significantly smaller tumors at 25 days. 2-DG alone or in combination with heat (without radiation) resulted in significantly smaller H238 cell-induced tumors at day 28 post-treatment when compared to the saline controls. The H238 tumor-bearing mice experienced a significant (4.7%) loss in total body weight after heating. It could be that heating trauma produced dehydration and possibly also decreased caloric intake to an extent which could be measured in weight loss. This observation, however, was not made in the heated mice in the #51 tumor model.