AJP - Regulatory, Integrative and Comparative Physiology, Vol 261, Issue 1 106-R116, Copyright © 1991 by American Physiological Society
Enhancement of tumor proteolysis by TNF-alpha: correlation of in vivo isotope estimates with growth
N. W. Istfan, P. R. Ling, G. L. Blackburn and B. R. Bistrian
Department of Medicine, New England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02215.
To evaluate the accuracy of in vivo estimates of protein synthesis and
breakdown, measurements of plasma and tissue leucine kinetics were made in
rat tumor tissues at different conditions of growth by use of constant
intravenous infusion of [14C]leucine. These measurements were made in
Yoshida sarcoma tumors on days 10 and 13 after implantation, with and
without tumor necrosis factor (TNF) infusion and on day 10 in Walker-256
carcinosarcoma. Expressed as micromoles of leucine per gram tissue, tumor
protein breakdown increased (P less than 0.01) from 0.32 +/- 0.02 to 0.52
+/- 0.09 (SE) mumol/h, with progress of the Yoshida sarcoma tumor between
days 10 and 13 after implantation. Similarly, TNF increased tumor
proteolysis on day 10 (0.43 +/- 0.03 mumol.h-1.g-1, P less than 0.05 vs.
day 10 control) but not on day 13 after implantation of the Yoshida tumor.
Estimates of growth derived from the difference between protein synthesis
and breakdown rates were not statistically different from those based on
actual tumor volume changes in both tumor models. However, estimates of
"whole body" protein metabolism (plasma leucine flux) were not affected
either by tumor aging or by treatment with TNF. This study shows that in
vivo estimates of tissue protein metabolism based on our [14C]leucine
constant infusion model closely reflect the growth characteristic of that
tissue. A cytotoxic perfusion-independent effect for intravenous TNF on
growing tumor tissue is demonstrable as increased protein breakdown.
Furthermore, the commonly used concept of whole body protein metabolism,
derived solely from tracer dilution in plasma, is an oversimplification.
