Combined tissue oxygen tension measurement and positron emission tomography studies on glucose utilization in oncogene-transformed cell line tumour xenografts in nude mice

Abstract

Glucose utilization studies using high resolution positron emission tomography and tissue oxygenation measurements using microelectrode techniques were carried out in nude mice bearing oncogene-transformed (Rat1pEJ6.6 and REFpneoMYCrasEpool) cell line tumours and a non-transformed (Rat1) cell line tumour to determine the correlation between glucose utilization, tissue oxygenation and tumour growth rate. Control measurements were performed in the subcutis of tumour-free animals. Accelerated growth rates were observed in both ras-transformed cell lines with tumour doubling times of 2.5-4 days while Rat1 tumours had a doubling time of 28 days. Since rapid growth rates necessitate elevated consumption of oxygen and nutrients, severe tumour hypoxia was observed in tumours from both ras-transformed cell lines; median pO2 being 1-5 mmHg (tumour sizes ca. 400 mm3). Size-matched Rat1 tumours exhibited a median pO2 value of 12 mmHg corresponding to the slow growth rate. Comparing both ras-transformed cell lines, Rat1pEJ6.6 tumours had a more adequate vascularization than REFpneoMYCrasEpool tumours indicated by a better tissue oxygenation (5 mmHg versus 1 mmHg) and higher glucose metabolic rates (13.4 +/- 2.2 mumol/min/100 cm3 versus 9.7 +/- 1.3 mumol/min/100 cm3). At advanced growth stages, a reduction of tissue oxygen levels is obtained which is accompanied by a 30% elevation of glucose metabolic rate. The data presented here demonstrate for the first time an impact of well defined oncogenic alterations on the therapeutically relevant parameters of the micromilieu of malignant tumours.