Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate.

The avid consumption of glucose with concomitant lactate production by malignant cells, even under aerobic conditions, is called the Warburg effect, or aerobic glycolysis. This metabolic state is a final common pathway that apparently serves various invasive purposes. As most invasive tumours display the Warburg effect, this has proven of great clinical importance in detecting malignancies with 18-fluorine 2-deoxyglucose positron emission tomography (FDG-PET) scans. However, using the Warburg effect to target malignancies has proven more difficult. Since hypoglycaemia has been shown to be tumouricidal for cancers that display the Warburg effect, various schemes to block glucose utilization have been investigated. But in vivo it is difficult to selectively target glucose utilization in malignant cells without harming normal cells. Cancer cells produce large amounts of lactate under the Warburg effect, without fully oxidizing it to CO(2). In contrast normal cells can completely oxidize lactate under aerobic conditions. Recent studies have demonstrated that vital organs such as the brain, heart, liver, kidneys and muscle are capable of oxidizing lactate as a fuel alternative to glucose. It has also been shown that during hypoglycaemia intravenous lactate can serve as a salvage fuel in man. Other clinical studies showed that patients can effectively metabolize large amounts of exogenous lactate. All this appears to reflect the recently recognized major physiological role of lactate as a glucose alternative. Consequently, lactate is the most logical candidate to serve as a salvage fuel when local or systemic hypoglycemia is induced. Thus, we hypothesize that the combination of hypoglycaemia induced by insulin and concomitant lactate administration will selectively suppress cancers manifesting the Warburg effect, since such cancers will have great difficulty in metabolizing lactate. This metabolic therapy could be modulated in many ways both in amplitude, in duration and in timing with respect to other therapies. The validated isolated limb perfusion (ILP) model for sarcoma appears an attractive model to evaluate local therapy with insulin and lactate and test its (adjuvant) tumouricidal effects in animals and man. Such effects could be evaluated with modern metabolic detection techniques such as FDG-PET and magnetic resonance imaging in local models both in animals and humans. Subsequently the systemic effects of hypoglycaemia combined with sodium lactate administration could be evaluated.