Skip to main content
SpringerLink
Log in

Down-regulation of tumor necrosis factor expression by pentoxifylline in cancer patients: A pilot study

  • Short communication
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The wasting syndrome (cachexia) characterized by anorexia, malaise, and weight loss is observed in many patients with cancer or chronic infection. The excessive levels of tumor necrosis factor-α (TNF)/cachectin reported in 50% of cancer patients exhibiting clinically active disease may therefore mediate, at least in part, the cachexia associated with malignancy. Pentoxifylline, a substituted methylxanthine approved for treatment of intermittent claudication, has been shown in preclinical studies to down-regulate TNF RNA expression as well as TNF activity. We report that pentoxifylline suppressed TNF RNA levels on all three occasions in patients with initially elevated levels of TNF RNA. Pentoxifylline did not suppress TNF RNA to subnormal levels in all five patients with initially normal TNF RNA levels. Four patients reported an increased sense of well-being, improved appetite and ability to perform the activities of daily living. Two of these five patients with normal TNF levels each had a weight gain of more than 5% after 3 weeks of pentoxifylline therapy suggesting that, although TNF may be important in the pathogenesis of cancer cachexia, other anorexia-producing cytokines that are potentially affected by pentoxifylline may also be involved. No severe adverse effects were observed. Taken together these findings suggest that pentoxifylline can down-regulate TNF expression and improve the sense of well-being in cancer patients. A larger study with a randomized, double-blind, placebo-controlled design and more sophisticated estimates of quality of life will be needed to confirm these observations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Aderka D, Engelmann H, Hornik V, Skornick Y, Levo Y, Wallach D, Kushtai G (1991) Increased serum levels of soluble receptors for tumor necrosis factor in cancer patients. Cancer Res 51: 5602–5607

    PubMed  Google Scholar 

  2. Balkwill F, Burke F, Talbot D, Tavernier J, Osborne R, Naylor S, Durbin H, Fiers W (1987) Evidence for tumor necrosis factor/cachectin production in cancer. Lancet II: 1229–1232

    Google Scholar 

  3. Bauer KA, ten Cate H, Barzegar S, Spriggs DR, Sherman ML, Rosenberg RD (1989) Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans. Blood 74: 165–172

    PubMed  Google Scholar 

  4. Beutler B, Cerami A (1987) Cachectin: more than a tumor necrosis factor. N Engl J Med 316: 379–385

    PubMed  Google Scholar 

  5. Beutler BA, Milsark IW, Cerami A (1985) Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunol 135: 3972–3977

    PubMed  Google Scholar 

  6. Boogaerts M (1988) In vivo and in vitro modulation of normal and diseased human neutrophil function by pentoxifylline. In: Mandell GL, Novick WJ (eds) Proceedings of a Symposium: Pentoxifylline and leukocyte function, Somerville, N. J. Hoechst-Roussel Pharmaceuticals, pp 165–174

    Google Scholar 

  7. Chirgwin JM, Pryzybyla AE, MacDonald RJ, Rutter WJ (1979) Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18: 5294–5299

    PubMed  Google Scholar 

  8. Cleveland DW, Lopata MA, MacDonald RJ, Cowan NJ, Rutter WJ, Kirschner MW (1980) Number and evolutionary conservation of α-and β-tubulin and cytoplasmic β- and γ-actin genes using specific cloned DNA probes. Cell 20: 95–105

    PubMed  Google Scholar 

  9. Dezube BJ, Fridovich-Keil JL, Bouvard I, Lange RF, Pardee AB (1990) Pentoxifylline and wellbeing in patients with cancer. Lancet 335: 662

    Google Scholar 

  10. Dezube BJ, Pardee AB, Beckett LA, Ahlers CM, Ecto L, Allen-Ryan J, Anisowicz A, Sager R, Crumpacker CS (1992) Cytokine dysregulation in AIDS: the in vivo overexpression of mRNA of tumor necrosis factor-α and its correlation with that of the inflammatory cytokine GRO. J Acquir Immune Defic Syndr (in press)

  11. Dezube BJ, Pardee AB, Chapman B, Beckett L, Korvick J, Ahlers CM, Ecto L, Chatis P, Crumpacker CS and ACTB 160 team (1992) Pentoxifylline (Trental) decrases tumor necrosis factor (TNF) and HIV replication in patients with AIDS (abstract MoB 0019). Proceedings VIII International Conference on AIDS, (Amsterdam, The Netherlands)

  12. Duh EJ, Maury WJ, Folks TM, Fauci AS, Rabson AB (1989) Tumor necrosis factor α activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kB sites in the long terminal repeat. Proc Natl Acad Sci USA 86: 5974–5978

    PubMed  Google Scholar 

  13. Fazely F, Dezube BJ, Allen-Ryan J, Pardee AB, Ruprecht RM (1991) Pentoxifylline (Trental) decreases the replication of the human immunodeficiency virus type 1 in human peripheral blood mononuclear cells and in cultured T cells. Blood 77: 1653–1656

    PubMed  Google Scholar 

  14. Lahdevirta J, Maury CPJ, Teppo A-M, Repo H (1988) Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85: 289–291

    PubMed  Google Scholar 

  15. Lilly CM, Sandhu JS, Ishizaka A, Harada H, Yonemaru M, Larrick JW, Shi T-X, O'Hanley PT, Raffin TA (1989) Pentoxifylline prevents tumor necrosis factor-induced lung injury. Am Rev Respir Dis 139: 1361–1368

    PubMed  Google Scholar 

  16. Lowry SF, Moldawer LL (1990) Tumor necrosis factor and other cytokines in the pathogenesis of cancer cachexia. Principles and Practice of Oncology Updates 4: 1–12

    Google Scholar 

  17. Noel P, Nelson S, Bokulic R, Bagby G, Lippton H, Lipscomb G, Summer W (1990) Pentoxifylline inhibits lipopolysaccharide-induced serum tumor necrosis factor and mortality. Life Sci 47: 1023–1029

    PubMed  Google Scholar 

  18. Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, Wolfe A, Socher SH (1987) Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 50: 555–563

    PubMed  Google Scholar 

  19. Poli G, Kinter A, Justement JS, Kehrl JH, Bressler P, Stanley S, Fauci AS (1990) Tumor necrosis factor α functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proc Natl Acad Sci USA 87: 782–785

    PubMed  Google Scholar 

  20. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning. A laboratory manual. Cold Spring Harbor Laboratory, New York

    Google Scholar 

  21. Schade UF (1990) Pentoxifylline increases survival in murine endotoxin shock and decreases formation of tumor necrosis factor. Circ Shock 31: 171–181

    PubMed  Google Scholar 

  22. Sherman ML, Spriggs DR, Arthur KA, Imamura K, Frei III E, Kufe DW (1988) 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 6: 344–350

    PubMed  Google Scholar 

  23. Strieter RM, Remick DG, Ward PA, Spengler RN, Lynch III JP, Larrick J, Kunkel SL (1988) Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun 155: 1230–1236

    PubMed  Google Scholar 

  24. Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF (1985) Molecular cloning of the complementary DNA for human tumor necrosis factor. Science 228: 149–154

    PubMed  Google Scholar 

  25. Ward A, Clissold SP (1987) Pentoxifylline: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 34: 50–97

    PubMed  Google Scholar 

  26. Zabel P, Schonharting MM, Wolter DT, Schade UF (1989) Oxpentifylline in endotoxaemia. Lancet II: 1474–1477

    Google Scholar 

  27. Zheng H, Crowley JJ, Chan JC, Hoffman H, Hatherill JR, Ishizaka A, Raffin TA (1990) Attenuation of tumor necrosis factor-induced endothelial cytotoxicity and neutrophil chemiluminescence. Am Rev Respir Dis 142: 1073–1078

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cell Growth and Regulation, Department of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, D810a, 02115, Boston, MA, USA

    Bruce J. Dezube, Judith L. Fridovich-Keil, Judy Allen-Ryan & Arthur B. Pardee

  2. Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, 02115, Boston, MA, USA

    Bruce J. Dezube & Matthew L. Sherman

  3. Division of Medical Oncology, Department of Medicine, Beth Israel Hospital, Harvard Medical School, 02215, Boston, MA, USA

    Bruce J. Dezube

Authors
  1. Bruce J. Dezube
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew L. Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Judith L. Fridovich-Keil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Judy Allen-Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arthur B. Pardee
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This study was supported in part by a grant from Hoechst-Roussel Pharmaceuticals Inc., Somerville, N. J. to Dr. Dezube and by a fellowship from Aid for Cancer Research of Boston, Mass., to Dr. Fridovich-Keil. Part of this work has been presented at a workshop: Pentoxifylline, leukocytes and cytokines, held in Scottsdale, Arizona, 8–10 March 1991

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dezube, B.J., Sherman, M.L., Fridovich-Keil, J.L. et al. Down-regulation of tumor necrosis factor expression by pentoxifylline in cancer patients: A pilot study. Cancer Immunol Immunother 36, 57–60 (1993). https://doi.org/10.1007/BF01789132

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01789132

Key words

Search

Navigation