Kinetics of soluble TNF-receptors and soluble adhesion molecules ICAM-1, E-selectin and VCAM-1 under systemic rhTNF alpha therapy.
Cytostatic as well as cytotoxic effects of tumour necrosis factor alpha (TNF-alpha) therapy have been shown in vitro and in experimental in vivo models. Nevertheless, the mechanism of anti-tumour activity in humans in vivo remains unclear. To determine the role of the vascular lining endothelial cells as important mediators of several immunological interactions, we investigated changes in the levels of the soluble endothelial cell adhesion molecules intercellular adhesion molecule 1, E-selectin and vascular cell adhesion molecule 1 as well as of soluble TNF receptors I and II during systemic therapy with recombinant human rhTNF-alpha (rhTNF-alpha). All tests were performed by enzyme-linked immunosorbent assays (ELISAs). The clinical efficacy of the intravenous rhTNF-alpha therapy was poor. Only one patient with isolated intraarterial limb perfusion had a delayed, marked, but only temporary necrosis of tumour cells. In contrast, we found a marked, significant and (during therapy) undulating augmented increase in the levels of soluble adhesion molecules as well as of the soluble TNF receptors. Taken together, these data support the hypothesis that a sufficient tumour-specific cellular immunity is required to achieve a clinically apparent efficacy of systemic rhTNF-alpha therapy in addition to cytokine-dependent inducible activation mechanisms. In this context, the vascular lining endothelial cells might play an important role as mediators of the complex immunological antitumoral activity.
Boehme
M W
MW
Department of Internal Medicine IV, University of Heidelberg, Germany.
Waldherr
R
R
Kist
A
A
Riedl
S
S
Walter-Kirst
R
R
Kempeni
J
J
Raeth
U
U
D000328:Adult; D000368:Aged; D004359:Drug Therapy, Combination; D019040:E-Selectin / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects* / Q000378:metabolism; D007370:Interferon Type I / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000187:drug effects*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects* / Q000378:metabolism
D019040:E-Selectin; D007370:Interferon Type I; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1