GLUCOSE METABOLISM AND HYDRAZINE IN CANCER CACHEXIA

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Weight loss commonly accompanies cancer and is associated with a poor clinical outcome. Caloric provision alone has been largely unsuccessful in altering this prognosis. We and others have demonstrated increased whole body glucose production rates and glucose intolerance in patients with advanced cancer compared to age-matched controls. We have also shown in a randomized trial that hydrazine sulfate, a known inhibitor of gluconeogenesis in animals, favorably influences the abnormal glucose metabolism in weight losing cancer patients as well. In our studies, improvement in glucose metabolism was associated with weight maintenance in patients given short term hydrazine treatment. In the proposed studies, the ability of hydrazine sulfate to influence the poor clinical outcome and nutritional status of patients with advanced non-small cell lung cancer and adenocarcinoma of the colon will be assessed in two prospective, double-blind, placebo-controlled, randomized clinical trials. All patients will be initially studied under metabolic ward conditions to quantitate metabolic, nutritional and clinical parameters. Glucose production and glucose recycling using combined UC-14 and 6H-3 glucose infusions as well as glucose counter-regulatory hormones will be determined. Insulin sensitivity alteration associated with hydrazine sulfate will be defined using the Bergman minimal model and hyperinsulinemic euglycemic clamp techniques. Resting energy expenditure will be assessed. Body composition (unsing anthropometrics, H-3 water determination and CT scanning) and tumor mass will be measured. Patients will then receive defined chemotherapy treatment for colon and non-small cell lung cancer with or without the addition of daily oral hydrazine. All inpatient testing procedures will be repeated after 4 and 12 weeks of therapy. Changes in nutritional status, energy expenditure and clinical outcome will be correlated with metabolic changes associated with hydrazine use. As a result, the ability of hydrazine sulfate to influence nutritional and clinical outcome by reversing abnormalities in glucose metabolism will be assessed in two cancer patient populations.