Relationship between of blood flow, glucose metabolism, protein synthesis, glucose and ATP content in experimentally-induced glioma (RG12.2) of rat brain

Abstract

In experimental RG1 2.2 glioma of rat brain, local blood flow, glucose utilization, protein synthesis, glucose and ATP content were measured by means of triple tracer autoradiography and bioluminescence technique, respectively, to determine hemodynamic and metabolic thresholds for local tumor energy failure. Perfusion thresholds were estimated at tumor blood flow values of 69.0 +/- 0.1 ml/100 g/min (estimate +/- standard error) and of 69 +/- 7.1 ml/100 g/min for the beginning of the decline in regional ATP and glucose content, respectively. Metabolic thresholds were derived at tumor glucose utilization values of 70.6 +/- 8.3 mumol/100 g/min for reduced protein synthesis, of 55.0 +/- 0.2 mumol/100 g/min for the decrease in glucose content, and 34.7 +/- 4.7 mumol/100 g/min for decline in ATP content. Our results suggest that blood flow limits glucose supply to tumor tissue at much higher flow rates than in normal brain which, in turn, is associated with a decrease in tumor glucose utilization. A reduction and not an increase in tumor glucose availability could be a more appropriate strategy for the induction of energy failure in tumors.

Pixel-to-pixel correlation between images of absolute ATP concentrations and blood flow in tumours

“…Blood flow has been correlated with ATP on a relative scale in brain tumours by Mies et al (1990). Unlike in the current report, the authors were able to demonstrate a breakpoint below which ATP was decreasing with decreasing blood flow and above which ATP remained constant at increasing flow rates.…”

Role of glucose and ketone bodies in the metabolic control of experimental brain cancer

“…We suggest that the metabolic mechanism by which moderate DR inhibits CT-2A brain tumour growth involves a failure to utilise alternative energy substrates. Most tumours including primary brain tumours actively consume glucose and are largely dependent on glycolysis for energy (Warberg, 1956;Galarraga et al, 1986;Mies et al, 1990;Oudard et al, 1997;Roslin et al, 2003). Mitochondrial defects and an inability to metabolise ketone bodies are thought to be responsible for the dependence of tumour cells on glycolytic energy (Warberg, 1956;Fredericks and Ramsey, 1978;Pedersen, 1978;Tisdale and Brennan, 1983;Lichtor and Dohrmann, 1986;Oudard et al, 1997;John, 2001).…”

“…In contrast to glucose, ketone bodies bypass cytoplasmic glycolysis and directly enter the TCA cycle as acetyl CoA (Sato et al, 1995;Veech et al, 2001). Gliomas and most tumour cells, however, lack this metabolic versatility and are largely dependent on glycolytic energy (Fearon et al, 1988;Mies et al, 1990;Oudard et al, 1997;Aronen et al, 2000;Roslin et al, 2003). Defects in ketone body metabolism, the mitochondrial TCA cycle, and electron transport chain systems are thought to underlie the dependence of tumour cells on glycolytic energy (Warberg, 1956;Fredericks and Ramsey, 1978;Tisdale and Brennan, 1983;Lichtor and Dohrmann, 1986;John, 2001).…”

Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model

“…It is documented that human and experimental gliomas are dependent on glycolysis for energy (Mies et al, 1990;Ikezaki et al, 1992;Oudard et al, 1997), and that DR-induced caloric restriction reduces glycolytic energy and down-regulates glycolytic gene expression (Lee et al, 2000;Cao et al, 2001;Greene et al, 2001). Additionally, the DR-induced down regulation of glycolysis should also reduce the level of pyruvic acid, a glycolytic end product with angiogenic activity .…”