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. 1994 Sep 1;180(3):1059–1065. doi: 10.1084/jem.180.3.1059

Circadian dynamics of tumor necrosis factor alpha (cachectin) lethality

PMCID: PMC2191660  PMID: 8064225

Abstract

Recombinant human tumor necrosis factor-alpha (TNF-alpha) has demonstrable antitumor activity in transplantable murine tumor models and patients with cancer but is highly toxic to both animals and human beings. The narrow therapeutic index of TNF-alpha has limited its anticancer utility. Toxicity associated with many standard anticancer drugs is highly dependent upon the circadian timing of their administration. The effect of time of day of TNF-alpha administration on lethal toxicity was examined in 238 BALB/c female mice in two studies. Each mouse received a single intravenous injection of human TNF-alpha at one of six equispaced times within the first contiguous 24- h cycle. The probability of dying across all times of day of TNF-alpha treatment was not equal (p < 0.01) and varied up to ninefold. Significant time of day dependence of TNF-alpha toxicity was present over a full order of magnitude of TNF-alpha dose. The frequency of TNF- alpha-induced lethality was greatest and the time to death was most brief when TNF-alpha was administered just before awakening. The survival probability was highest when TNF-alpha was administered in the second half of the daily activity span corresponding roughly to late afternoon and evening hours for human beings. The optimization of TNF- alpha administration timing is a strategy that warrants further investigation for improving the toxic/therapeutic ratio of this important cytokine. From a more fundamental perspective, these data may be essential for achieving a fuller understanding of TNF-alpha in vivo biology.

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Selected References

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  1. Alexander R. B., Nelson W. G., Coffey D. S. Synergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II. Cancer Res. 1987 May 1;47(9):2403–2406. [PubMed] [Google Scholar]
  2. Arya S. K., Wong-Staal F., Gallo R. C. Dexamethasone-mediated inhibition of human T cell growth factor and gamma-interferon messenger RNA. J Immunol. 1984 Jul;133(1):273–276. [PubMed] [Google Scholar]
  3. Balkwill F. R., Lee A., Aldam G., Moodie E., Thomas J. A., Tavernier J., Fiers W. Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons. Cancer Res. 1986 Aug;46(8):3990–3993. [PubMed] [Google Scholar]
  4. Bernhagen J., Calandra T., Mitchell R. A., Martin S. B., Tracey K. J., Voelter W., Manogue K. R., Cerami A., Bucala R. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature. 1993 Oct 21;365(6448):756–759. doi: 10.1038/365756a0. [DOI] [PubMed] [Google Scholar]
  5. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  6. Beutler B., Cerami A. Cachectin, cachexia, and shock. Annu Rev Med. 1988;39:75–83. doi: 10.1146/annurev.me.39.020188.000451. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Beutler B., Krochin N., Milsark I. W., Luedke C., Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Creagan E. T., Kovach J. S., Moertel C. G., Frytak S., Kvols L. K. A phase I clinical trial of recombinant human tumor necrosis factor. Cancer. 1988 Dec 15;62(12):2467–2471. doi: 10.1002/1097-0142(19881215)62:12<2467::aid-cncr2820621202>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  12. Creasey A. A., Reynolds M. T., Laird W. Cures and partial regression of murine and human tumors by recombinant human tumor necrosis factor. Cancer Res. 1986 Nov;46(11):5687–5690. [PubMed] [Google Scholar]
  13. Creaven P. J., Plager J. E., Dupere S., Huben R. P., Takita H., Mittelman A., Proefrock A. Phase I clinical trial of recombinant human tumor necrosis factor. Cancer Chemother Pharmacol. 1987;20(2):137–144. doi: 10.1007/BF00253968. [DOI] [PubMed] [Google Scholar]
  14. Edwards C. K., 3rd, Yunger L. M., Lorence R. M., Dantzer R., Kelley K. W. The pituitary gland is required for protection against lethal effects of Salmonella typhimurium. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2274–2277. doi: 10.1073/pnas.88.6.2274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Elliott G. T., Welty D., Kuo Y. D. The D-galactosamine loaded mouse and its enhanced sensitivity to lipopolysaccharide and monophosphoryl lipid A: a role for superoxide. J Immunother (1991) 1991 Feb;10(1):69–74. doi: 10.1097/00002371-199102000-00010. [DOI] [PubMed] [Google Scholar]
  16. Feinberg B., Kurzrock R., Talpaz M., Blick M., Saks S., Gutterman J. U. A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients. J Clin Oncol. 1988 Aug;6(8):1328–1334. doi: 10.1200/JCO.1988.6.8.1328. [DOI] [PubMed] [Google Scholar]
  17. Gessani S., McCandless S., Baglioni C. The glucocorticoid dexamethasone inhibits synthesis of interferon by decreasing the level of its mRNA. J Biol Chem. 1988 Jun 5;263(16):7454–7457. [PubMed] [Google Scholar]
  18. HALBERG F., JOHNSON E. A., BROWN B. W., BITTNER J. J. Susceptibility rhythm to E. coli endotoxin and bioassay. Proc Soc Exp Biol Med. 1960 Jan;103:142–144. doi: 10.3181/00379727-103-25439. [DOI] [PubMed] [Google Scholar]
  19. Haranaka K., Satomi N., Sakurai A. Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice. Int J Cancer. 1984 Aug 15;34(2):263–267. doi: 10.1002/ijc.2910340219. [DOI] [PubMed] [Google Scholar]
  20. Hauser G. J., McIntosh J. K., Travis W. D., Rosenberg S. A. Manipulation of oxygen radical-scavenging capacity in mice alters host sensitivity to tumor necrosis factor toxicity but does not interfere with its antitumor efficacy. Cancer Res. 1990 Jun 15;50(12):3503–3508. [PubMed] [Google Scholar]
  21. Hori K., Suzuki M., Tanda S., Saito S., Shinozaki M., Zhang Q. H. Circadian variation of tumor blood flow in rat subcutaneous tumors and its alteration by angiotensin II-induced hypertension. Cancer Res. 1992 Feb 15;52(4):912–916. [PubMed] [Google Scholar]
  22. Hrushesky W. J., Bjarnason G. A. Circadian cancer therapy. J Clin Oncol. 1993 Jul;11(7):1403–1417. doi: 10.1200/JCO.1993.11.7.1403. [DOI] [PubMed] [Google Scholar]
  23. Kettelhut I. C., Fiers W., Goldberg A. L. The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4273–4277. doi: 10.1073/pnas.84.12.4273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Koren S., Fleischmann W. R., Jr Circadian variations in myelosuppressive activity of interferon-alpha in mice: identification of an optimal treatment time associated with reduced myelosuppressive activity. Exp Hematol. 1993 Apr;21(4):552–559. [PubMed] [Google Scholar]
  25. Koren S., Fleischmann W. R., Jr Optimal circadian timing reduces the myelosuppressive activity of recombinant murine interferon-gamma administered to mice. J Interferon Res. 1993 Jun;13(3):187–195. doi: 10.1089/jir.1993.13.187. [DOI] [PubMed] [Google Scholar]
  26. Koren S., Whorton E. B., Jr, Fleischmann W. R., Jr Circadian dependence of interferon antitumor activity in mice. J Natl Cancer Inst. 1993 Dec 1;85(23):1927–1932. doi: 10.1093/jnci/85.23.1927. [DOI] [PubMed] [Google Scholar]
  27. Lee S. W., Tsou A. P., Chan H., Thomas J., Petrie K., Eugui E. M., Allison A. C. Glucocorticoids selectively inhibit the transcription of the interleukin 1 beta gene and decrease the stability of interleukin 1 beta mRNA. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1204–1208. doi: 10.1073/pnas.85.4.1204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Levi F. A., Canon C., Blum J. P., Mechkouri M., Reinberg A., Mathe G. Circadian and/or circahemidian rhythms in nine lymphocyte-related variables from peripheral blood of healthy subjects. J Immunol. 1985 Jan;134(1):217–222. [PubMed] [Google Scholar]
  29. Nawroth P., Handley D., Matsueda G., De Waal R., Gerlach H., Blohm D., Stern D. Tumor necrosis factor/cachectin-induced intravascular fibrin formation in meth A fibrosarcomas. J Exp Med. 1988 Aug 1;168(2):637–647. doi: 10.1084/jem.168.2.637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Old L. J. Tumor necrosis factor. Sci Am. 1988 May;258(5):59-60, 69-75. doi: 10.1038/scientificamerican0588-59. [DOI] [PubMed] [Google Scholar]
  31. Parant M., Le Contel C., Parant F., Chedid L. Influence of endogenous glucocorticoid on endotoxin-induced production of circulating TNF-alpha. Lymphokine Cytokine Res. 1991 Aug;10(4):265–271. [PubMed] [Google Scholar]
  32. Sherman M. L., Spriggs D. R., Arthur K. A., Imamura K., Frei E., 3rd, Kufe D. W. Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism. J Clin Oncol. 1988 Feb;6(2):344–350. doi: 10.1200/JCO.1988.6.2.344. [DOI] [PubMed] [Google Scholar]
  33. Smaaland R., Laerum O. D., Sothern R. B., Sletvold O., Bjerknes R., Lote K. Colony-forming unit-granulocyte-macrophage and DNA synthesis of human bone marrow are circadian stage-dependent and show covariation. Blood. 1992 May 1;79(9):2281–2287. [PubMed] [Google Scholar]
  34. Sugarman B. J., Aggarwal B. B., Hass P. E., Figari I. S., Palladino M. A., Jr, Shepard H. M. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science. 1985 Nov 22;230(4728):943–945. doi: 10.1126/science.3933111. [DOI] [PubMed] [Google Scholar]
  35. Szabó C., Thiemermann C., Wu C. C., Perretti M., Vane J. R. Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):271–275. doi: 10.1073/pnas.91.1.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  37. Tsujimoto M., Okamura N., Adachi H. Dexamethasone inhibits the cytotoxic activity of tumor necrosis factor. Biochem Biophys Res Commun. 1988 May 31;153(1):109–115. doi: 10.1016/s0006-291x(88)81196-3. [DOI] [PubMed] [Google Scholar]
  38. UNGAR F., HALBERG F. Circadian rhythm in the in vitro response of mouse adrenal to adrenocorticotropic hormone. Science. 1962 Sep 28;137(3535):1058–1060. doi: 10.1126/science.137.3535.1058. [DOI] [PubMed] [Google Scholar]
  39. Zuckerman S. H., Shellhaas J., Butler L. D. Differential regulation of lipopolysaccharide-induced interleukin 1 and tumor necrosis factor synthesis: effects of endogenous and exogenous glucocorticoids and the role of the pituitary-adrenal axis. Eur J Immunol. 1989 Feb;19(2):301–305. doi: 10.1002/eji.1830190213. [DOI] [PubMed] [Google Scholar]

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