Amino acid metabolism in human cancer cachexia

Cancer cachexia is a complex syndrome that occurs with variable incidence in patients with solid tumors and those with hematologic malignancies. It is associated with characteristic physical and laboratory findings, and at a more fundamental level, with significant abnormalities in carbohydrate, lipid, and protein metabolism. These alterations in intermediary metabolism are demonstrable early in the syndrome, even before the onset of weight loss, when the more characteristic features of cancer cachexia are evident. Progressive wasting of peripheral protein stores is a major feature of cancer cachexia and often one of the most graphic realities of malignancy for patients and their families. Unfortunately, significant problems with the animal models of cancer cachexia make conclusions derived from animal studies difficult to extrapolate to humans. Data from human studies indicate that human cancer cachexia is associated with minimal aberrations in circulating free amino acid concentrations; increased whole-body protein turnover, synthesis, and catabolism; reduced rates of skeletal muscle protein synthesis; and increased rates of hepatic protein synthesis. Whether or not these alterations represent pathologic responses or physiologic adaptation by the host to the presence of malignancy remains to be seen. Future investigations must focus on more careful evaluation of interorgan amino acid metabolism, investigation of skeletal muscle protein catabolic rates in cancer cachexia, and definition of the roles of altered hormonal and cytokine regulation of these processes. Such studies will more precisely define the level at which amino acid metabolism is altered significantly and, we hope, permit more specific therapeutic intervention designed to reverse the debilitating effects of cancer cachexia.