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Host Cathepsin D Response to Tumor in the Normal and Pepstatin-treated Mouse

Department of Pharmacology, Medical College of Georgia, Augusta, Georgia 30912

In view of the postulated role of cathepsin D in cachexia, investigations have been pursued on the host tissue response of cathepsin D activity in DBA/2 mice inoculated with 5 x 10⁵ L1210 tumor cells. The results confirmed previous investigators' findings of the increase in cathepsin D activity (specific activity) in liver and muscle of tumor bearers. In addition, it was found that this increase was a general response of the host since heart, kidney, lung, and spleen cathepsin D specific activity were also enhanced in tumor bearers. These increases ranged from an average of 10% for spleen to 100% for gastrocnemius muscle. This effect was age related in heart and kidney. As a working hypothesis, we propose the concept that tumor bearers release protease-enhancing factor(s) which trigger increase or enhancement of cathepsin D activity in host tissues by yet unknown mechanisms.

Pepstatin (60 mg/kg), a known inhibitor of cathepsin D in vitro, was shown to provide long-lasting inhibition (3 to 6 days) of cathepsin D in vivo in non-tumor bearers particularly in spleen, liver, kidney, lung, and heart. Evidence is provided from assays of cell fractions that this inhibition takes place at or in the lysosome. The duration of the effectiveness of pepstatin was altered in tumor bearers in that cathepsin D activity of heart, lung, and spleen had returned to near normal values in 48 hr following pepstatin injection. However, in muscle, liver, and kidney, significant inhibition (90%) still persisted in tumor bearers as it did in non-tumor bearers.

Pepstatin or related antiproteases may prove useful as "anticachexia" agents by decreasing proteolysis in muscle and other tissues.

¹ To whom requests for reprints should be addressed.

Received 7/22/82. Accepted 3/ 8/83.