|
|
 Previous Article | Table of Contents | Next Article 
Human lymphotoxin has at least equal antitumor activity in comparison to
human tumor necrosis factor but is less toxic in mice
Z Qin, LJ van Tits, WA Buurman and T Blankenstein
Max-Delbruck-Center of Molecular Medicine, Berlin, Germany.
Because of the severe toxicity of systemically applied tumor necrosis
factor (TNF) in cancer patients, considerable efforts have been made to
construct mutant TNF molecules, which retain antitumor activity, but
display less toxicity. We compared tumor suppression in relation to the
toxic effects of human TNF and human lymphotoxin (LT) in mice. The genes
for these two cytokines were expressed in Chinese hamster ovary (CHO)
cells. Intraperitoneal injection of parental and gene modified CHO cell
lines producing similar amounts of biologically active TNF or LT,
respectively, into nude mice showed that CHO-TNF cells killed the mice more
rapidly than parental cells, but that CHO-LT tumor bearing mice lived
significantly longer than mice injected with parental cells. Injection of
the cells subcutaneously into severe combined immunodeficiency (SCID) mice
allowed direct comparison of tumor suppression and toxic effects of the two
cytokines. Both TNF and LT produced by the tumor effectively suppressed
tumor growth by an indirect mechanism, LT being at least as effective as
TNF. However, mice bearing CHO-TNF cells either died rapidly or developed
cachexia, as shown by weight loss. In contrast, mice injected with CHO-LT
cells never rapidly died and became cachectic much later than CHO-TNF cell
injected animals, though serum levels of LT were higher than those of TNF.
Analysis of soluble forms of TNF receptors (TNF-R1 and TNF-R2) in sera of
tumor bearing mice showed that soluble TNF-R1 was downregulated in both
CHO-TNF and CHO-LT, in comparison with CHO-neo cell injected mice and to
normal SCID mice. The soluble form of TNF-R2 was induced by CHO cell lines.
In CHO-TNF cell injected SCID mice, serum levels were significantly
increased, whereas in mice injected with CHO-LT cells, serum levels of
soluble TNF-R2 were decreased. Together, our results show a higher
therapeutic index of LT compared with TNF.
Volume 85,
Issue 10,
pp. 2779-2785,
05/15/1995
Copyright © 1995 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
X. Zhao, M. Mohaupt, J. Jiang, S. Liu, B. Li, and Z. Qin
Tumor Necrosis Factor Receptor 2-Mediated Tumor Suppression Is Nitric Oxide Dependent and Involves Angiostasis
Cancer Res.,
May 1, 2007;
67(9):
4443 - 4450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Bongartz, A. J. Sutton, M. J. Sweeting, I. Buchan, E. L. Matteson, and V. Montori
Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials.
JAMA,
May 17, 2006;
295(19):
2275 - 2285.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Q. Li, C. S. T. Hii, M. Costabile, D. Goh, C. J. Der, and A. Ferrante
Regulation of Lymphotoxin Production by the p21ras-raf-MEK-ERK Cascade in PHA/PMA-Stimulated Jurkat Cells
J. Immunol.,
March 15, 1999;
162(6):
3316 - 3320.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
