Dose-effect relationships for glucose-induced tumour acidification and its erythrocyte flux

Abstract

Preclinical investigations were performed with glucose administration in WAG/Rij rats carrying the rhabdomyosarcoma BA1112 in two sites per animal: one in the subcutis of the flank (for pH measurements in the tumour tissue) and one in the transparent “sandwich” chamber for measuring the erythrocyte flux in the tumour tissue as an indication for changes in tumour blood flow. A glucose solution (20%) was slowly infused intravenously in a range of dose levels, similar to those reported for inducing long-term hyperglycaemia in man. The eventual aim of such investigations is to sensitise tumours for hyperthermic treatment. This approach is not new, but the present experiments were performed with the aim to explore the level of the minimal amount of glucose which would nonetheless yield a likely therapeutic effect. Endpoints in this study were the blood glucose level and pH and the relative erythrocyte flux in the tumour tissue. Obviously, as one would expect, many significant changes in the various parameters were found as a response to administration of glucose. However, the changes in the blood glucose level, the induced decrease in tumour pH and the influence of the tumour volume did not show a well-defined relationship which was reliable enough to predict the exact influence of the various parameters on the magnitude of the desired changes in individual animals and/or tumours. This was probably caused by interfering differences in physiological feedback mechanisms. Nonetheless, the data indicate that the optimal effect was not obtained with the highest treatment level, but with moderate doses of glucose, i.e. 2.4–3 g.kg/h which induced a satisfactory tumour acidification of 0.25 pH units. This may turn out to a clinically useful pH drop for enhancing the cytotoxic effect of hyperthermia. The erythrocyte flux through the tumour tissue does not appear to be influenced to a sizeable extent by such a treatment.