Continuing: Biology of cachexia.

I would like to comment briefly on the issue raised by Dr. Wheeler (1) with reference to the review by Tisdale (2) on the use of hydrazine sulfate for the treatment of patients with cancer cachexia. The point, in my opinion, is not whether or not hydrazine sulfate was effective in the clinical trials reported by the authors but whether its use in that context was appropriate. We know, in fact, that 1) cancer patients have an increased glucose synthesis from lactate, alanine, and glycerol and 2) energy metabolism of human cancer cells mainly relies on glucose (3–6). Hydrazine sulfate is a gluconeogenic blocking agent that selectively starves tumor cells by interrupting the cycle of tumor energy gain and host energy deprivation at the enzymatic level of phosphoenol pyruvate-carboxykinase, thus preventing glucose formation from lactate and amino acids. It seems obvious that if patients have a regular diet (as in the reported clinical trials), the intake of glucose with the diet is enough to maintain the energy metabolism of the cancer cells and to decrease or at least partially compensate the host for the shift of energy from the host tissue to the cancer cells due to the increased gluconeogenesis. It is not surprising that, in such conditions, hydrazine sulfate proved to be ineffective. The efficacy of hydrazine sulfate should be tested when patients are given a complete but otherwise glucose-free diet (consequently, tumor energy metabolism is only supported by the endogenous production of glucose). This nutritional approach may be taken because the brain, which is the main consumer of glucose (110–145 g/24 hours) switches to ketone body utilization after a short period of starvation. Moreover, the brain is able to directly use glycerol, whereas the tumor tissue cannot due to the very low activity of glycerokinase. This approach is the hypothesis that we are currently testing, with good preliminary results with respect to tolerance and feasibility of an intravenous complete glucose-free nutritional regimen plus hydrazine sulfate (7).