Abstract
Eighteen patients with advanced cancer have been treated intravenously with human recombinant tumour necrosis factor (rhTNF). The drug produced febrile reactions at all doses although these were preventable by steroids and indomethacin. Doses at or above 9 x 10(5) units (400 micrograms)m-2 were associated with hypotension, abnormal liver enzymes, leucopenia and mild renal impairment in a substantial proportion of patients. RhTNF was cleared from plasma with a half life of approximately 20 minutes but non-linear pharmacokinetics lymphoma, improvements in their tumours were recorded. RhTNF was noted to produce rapid increases in serum C-reactive protein concentrations. Endogenous TNF levels were not found to be elevated in 72 cancer patients. TNF deserves further therapeutic evaluation and these observations support its biological importance as an endogenous pyrogen, mediator of acute phase protein responses, and a mediator of endotoxic shock.
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- Aderka D., Fisher S., Levo Y., Holtmann H., Hahn T., Wallach D. Cachectin/tumour-necrosis-factor production by cancer patients. Lancet. 1985 Nov 23;2(8465):1190–1190. doi: 10.1016/s0140-6736(85)92713-8. [DOI] [PubMed] [Google Scholar]
- Aggarwal B. B., Eessalu T. E., Hass P. E. Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature. 1985 Dec 19;318(6047):665–667. doi: 10.1038/318665a0. [DOI] [PubMed] [Google Scholar]
- Bertolini D. R., Nedwin G. E., Bringman T. S., Smith D. D., Mundy G. R. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986 Feb 6;319(6053):516–518. doi: 10.1038/319516a0. [DOI] [PubMed] [Google Scholar]
- Beutler B., Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987 Feb 12;316(7):379–385. doi: 10.1056/NEJM198702123160705. [DOI] [PubMed] [Google Scholar]
- Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
- Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cooper E. H., Stone J. Acute phase reactant proteins in cancer. Adv Cancer Res. 1979;30:1–44. doi: 10.1016/s0065-230x(08)60893-3. [DOI] [PubMed] [Google Scholar]
- Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fransen L., Van der Heyden J., Ruysschaert R., Fiers W. Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol. 1986 Apr;22(4):419–426. doi: 10.1016/0277-5379(86)90107-0. [DOI] [PubMed] [Google Scholar]
- Kull F. C., Jr, Jacobs S., Cuatrecasas P. Cellular receptor for 125I-labeled tumor necrosis factor: specific binding, affinity labeling, and relationship to sensitivity. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5756–5760. doi: 10.1073/pnas.82.17.5756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matthews N. Tumour-necrosis factor from the rabbit. II. Production by monocytes. Br J Cancer. 1978 Aug;38(2):310–315. doi: 10.1038/bjc.1978.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matthews N., Watkins J. F. Tumour-necrosis factor from the rabbit. I. Mode of action, specificity and physicochemical properties. Br J Cancer. 1978 Aug;38(2):302–309. doi: 10.1038/bjc.1978.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mestan J., Digel W., Mittnacht S., Hillen H., Blohm D., Möller A., Jacobsen H., Kirchner H. Antiviral effects of recombinant tumour necrosis factor in vitro. 1986 Oct 30-Nov 5Nature. 323(6091):816–819. doi: 10.1038/323816a0. [DOI] [PubMed] [Google Scholar]
- Nedwin G. E., Naylor S. L., Sakaguchi A. Y., Smith D., Jarrett-Nedwin J., Pennica D., Goeddel D. V., Gray P. W. Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985 Sep 11;13(17):6361–6373. doi: 10.1093/nar/13.17.6361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Old L. J. Tumor necrosis factor (TNF). Science. 1985 Nov 8;230(4726):630–632. doi: 10.1126/science.2413547. [DOI] [PubMed] [Google Scholar]
- Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
- Playfair J. H., de Souza J. B., Taverne J. Endotoxin induced 'tumour-necrosis serum' kills a subpopulation of normal lymphocytes in vitro. Clin Exp Immunol. 1982 Mar;47(3):753–755. [PMC free article] [PubMed] [Google Scholar]
- Rubin B. Y., Anderson S. L., Sullivan S. A., Williamson B. D., Carswell E. A., Old L. J. High affinity binding of 125I-labeled human tumor necrosis factor (LuKII) to specific cell surface receptors. J Exp Med. 1985 Sep 1;162(3):1099–1104. doi: 10.1084/jem.162.3.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sato N., Goto T., Haranaka K., Satomi N., Nariuchi H., Mano-Hirano Y., Sawasaki Y. Actions of tumor necrosis factor on cultured vascular endothelial cells: morphologic modulation, growth inhibition, and cytotoxicity. J Natl Cancer Inst. 1986 Jun;76(6):1113–1121. [PubMed] [Google Scholar]
- Scuderi P., Sterling K. E., Lam K. S., Finley P. R., Ryan K. J., Ray C. G., Petersen E., Slymen D. J., Salmon S. E. Raised serum levels of tumour necrosis factor in parasitic infections. Lancet. 1986 Dec 13;2(8520):1364–1365. doi: 10.1016/s0140-6736(86)92007-6. [DOI] [PubMed] [Google Scholar]
- Shirai T., Yamaguchi H., Ito H., Todd C. W., Wallace R. B. Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. 1985 Feb 28-Mar 6Nature. 313(6005):803–806. doi: 10.1038/313803a0. [DOI] [PubMed] [Google Scholar]
- Taverne J., Dockrell H. M., Playfair J. H. Endotoxin-induced serum factor kills malarial parasites in vitro. Infect Immun. 1981 Jul;33(1):83–89. doi: 10.1128/iai.33.1.83-89.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taverne J., Matthews N., Depledge P., Playfair J. H. Malarial parasites and tumour cells are killed by the same component of tumour necrosis serum. Clin Exp Immunol. 1984 Aug;57(2):293–300. [PMC free article] [PubMed] [Google Scholar]
- Vilcek J., Palombella V. J., Henriksen-DeStefano D., Swenson C., Feinman R., Hirai M., Tsujimoto M. Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors. J Exp Med. 1986 Mar 1;163(3):632–643. doi: 10.1084/jem.163.3.632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Waage A., Halstensen A., Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987 Feb 14;1(8529):355–357. doi: 10.1016/s0140-6736(87)91728-4. [DOI] [PubMed] [Google Scholar]
- Wang A. M., Creasey A. A., Ladner M. B., Lin L. S., Strickler J., Van Arsdell J. N., Yamamoto R., Mark D. F. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149–154. doi: 10.1126/science.3856324. [DOI] [PubMed] [Google Scholar]
- Wong G. H., Goeddel D. V. Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons. 1986 Oct 30-Nov 5Nature. 323(6091):819–822. doi: 10.1038/323819a0. [DOI] [PubMed] [Google Scholar]