MUSCLE HYPERCATABOLISM DURING CANCER CACHEXIA IS NOT REVERSED BY THE GLUCOCORTICOID RECEPTOR ANTAGONIST RU38486

In rats into which a fast growing ascites hepatoma (Yoshida AH-130) ha d been transplanted, tumor growth elicited a marked loss of body weigh t and tissue waste, particularly of the skeletal muscle. This depletio n has been associated with enhanced rates of protein breakdown, mainly due to hyperactivation of the ATP-ubiquitin-dependent proteolytic sys tem [Llovera, M., Garcia-Martinez, C., Agell, N., Marzabal, M., Lopez- Soriano, F.J. and Argiles, J.M. (1994) FEBS Lett., 338, 311-318]. Prof ound alterations of the hormonal status and the production of tumor ne crosis factor have been involved in the development of such wasting sy ndrome [Tessitore, L., Costelli, P. and Baccino, F.M. (1993) Br. J. Ca ncer, 67, 15-23]. In the present study, the role of glucocorticoids in muscle hypercatabolism was investigated using the glucocorticoid rece ptor antagonist RU38486. The treatment with this drug was unable to in terfere with the development of cachexia in the AH-130 hosts with rega rd to tissue weight as well as to muscle protein turnover rates. As on e would expect, the RU38486 was also ineffective in lowering both the expression of ubiquitin mRNA and the degree of muscle protein ubiquiti nization in AH-130 bearers. These data allow us to exclude that glucoc orticoids play a direct crucial role in the development of cachexia in this tumor model.