Skip to main content

Advertisement

SpringerLink
Log in

RETRACTED ARTICLE: Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

This article was retracted on 09 October 2014

A Letter to the Editors to this article was published on 24 July 2014

Abstract

Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized β-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 pg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells. As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32–50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

Gc:

Human vitamin D3 binding protein

GcMAF:

Enzymatically generated Gc-derived macrophage-activating factor

Nagalase:

α-N-acetylgalactosaminidase

References

  1. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 172:248–254

    Article  Google Scholar 

  2. Braun S, Pantel K (1999) Micrometastatic bone marrows involvement detection and prognostic significance. Med Oncol 16:154–165

    Article  PubMed  CAS  Google Scholar 

  3. Cohen AM, Shank B, Friedman MA (1989) Colorectal cancer. In: Devita VT Jr, Hellman S, Rosenberg SA (eds) Cancer, principle and practice of oncology, 3rd edn. J.B. Lippincott, Philadelphia, pp 895–964

    Google Scholar 

  4. DeCosse JJ, Tsioulias GJ, Jacobson JS (1994) Colorectal cancer: detection, treatment and rehabilitation. CA Cancer J Clin 44:27–42

    Article  PubMed  CAS  Google Scholar 

  5. Gleason DF (1977) The Veteran,s Administration Cooperative Urological Research Group: histological grading and clinical staging of prostate carcinoma. In: Tannenbaum M (ed) Urologic pathology: the prostate. Lea and Febiger, Philadelphia pp 171–198

    Google Scholar 

  6. Gold P, Freedman SQ (1965) Demonstration of tumor specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques. J Exp Med 121:439–462

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Homma S, Yamamoto N (1990) Activation process of macrophages after in vitro treatment of mouse lymphocytes with dodecylglycerol. Clin Exp Immunol 79:307–313

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Homma S, Yamamoto M, Yamamoto N (1993) Vitamin D binding protein (group-specific component, Gc) is the sole serum protein required for macrophage activation after treatment of peritoneal cells with lysophosphatidylcholine. Immunol Cell Biol 71:249–257

    Article  PubMed  CAS  Google Scholar 

  9. Kanda S, Mochizuki Y, Miyata Y, Kanetake H, Yamamoto N (2002) Vitamin D-binding protein-derived macrophage activating factor, GcMAF, has an antiangiogenic activity both in vivo and in vitro. J Natl Cancer Inst 94:1311–1319

    Article  PubMed  CAS  Google Scholar 

  10. Kisker O, Onizuka S, Becker CM, Fannon M, Flynn E, D’Amato R, Zetter B, Folkman J, Ray R, Swamy N, Pirie-Shepherd S (2003) Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice. Neoplasia 5:32–40

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Koga Y, Naraparaju VR, Yamamoto N (1999) Antitumor effects of vitamin D3-binding protein-derived macrophage activating factor on Ehrlich tumor bearing mice. Proc Soc Exp Biol Med 220:20–26

    Article  PubMed  CAS  Google Scholar 

  12. Koprowski H, Herlyn M, Steplewski Z, Sears HF (1981) Specific antigen in serum of patients with colon carcinoma. Science 212:53–55

    Article  PubMed  CAS  Google Scholar 

  13. Link RP, Perlman KL, Pierce EA, Schnoes HK, DeLuca HF (1986) Purification of human serum vitamin D-binding protein by 25-hydroxyvitamin D3-Sepharose chromatography. Anal Biochem 157:262–269

    Article  PubMed  CAS  Google Scholar 

  14. Maehara Y, Kohnoe S, Sugimachi K (1990) Chemosensitivity test for carcinoma of digestive organs. Semin Surg Oncol 6:42–47

    Article  PubMed  CAS  Google Scholar 

  15. Morton D, Eibler FR, Malmgren RA, Wood WC (1970) Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 68:158-164

    PubMed  CAS  Google Scholar 

  16. Naraparaju VR, Yamamoto N (1994) Roles of ß-galactosidase of B lymphocytes and sialidase of T lymphocytes in inflammation-primed activation of macrophages. Immunol Lett 43:143–148

    Article  PubMed  CAS  Google Scholar 

  17. Ngwenya BZ, Yamamoto N (1985) Activation of peritoneal macrophages by lysophosphatidylcholine. Biochim Biophys Acta 839:9-15

    Article  PubMed  CAS  Google Scholar 

  18. Ngwenya BZ, Yamamoto N (1986) Effects of inflammation products on immune systems: lysophosphatidylcholine stimulates macrophages. Cancer Immunol Immunother 21:174–182

    Article  PubMed  CAS  Google Scholar 

  19. Ngwenya BZ, Yamamoto N (1990) Contribution of lysophosphatidylcholine treated nonadherent cells to mechanism of macrophage activation. Proc Soc Exp Biol Med 193:118–124

    Article  PubMed  CAS  Google Scholar 

  20. Olson RM, Perencevich NP, Malcolm AW, Chaffey JT, Wilson RE (1980) Pattern of recurrence following curative resection of adenocarinoma of the colon and rectum. Cancer 45:2969–2974

    Article  PubMed  CAS  Google Scholar 

  21. Rich T, Gunderson LL, Lew R, Galdibini JJ, Cohen AM, Donaldson G (1983) Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer 52:1317–1329

    Article  PubMed  CAS  Google Scholar 

  22. Yamamoto N, Ngwenya BZ (1987) Activation of macrophages by lysophospholipids, and ether derivatives of neutral lipids and phospholipids. Cancer Res 47:2008-2013

    PubMed  CAS  Google Scholar 

  23. Yamamoto N, Ngwenya BZ, Pieringer PA (1987) Activation of macrophages by ether analogues of lysophospholipids. Cancer Immunol Immunother 25:185–192

    Article  PubMed  CAS  Google Scholar 

  24. Yamamoto N, St. Claire DA, Homma S, Ngwenya BZ (1988) Activation of mouse macrophages by alkylglycerols, inflammation products of cancerous tissues. Cancer Res 48:6044–6049

    PubMed  CAS  Google Scholar 

  25. Yamamoto N, Homma S (1991) Vitamin D3 binding protein (group-specific component, Gc) is a precursor for the macrophage activating signal from lysophosphatidylcholine-treated lymphocytes. Proc Natl Acad Sci USA 88:8539–8543

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Yamamoto N, Homma S, Haddad JG, Kowalski MN (1991) Vitamin D3 binding protein required for in vitro activation of macrophages after dodecylglycerol treatment of mouse peritoneal cells. Immunol 74:420–424

    CAS  Google Scholar 

  27. Yamamoto N, Homma S, Millman I (1991) Identification of the serum factor required for in vitro activation of macrophages: role of vitamin D binding protein (group-specific component, Gc) in lysophospholipid activation of mouse peritoneal macrophages. J Immunol 147:273–280

    PubMed  CAS  Google Scholar 

  28. Yamamoto N (1993) In vitro enzymatic conversion of glycosylated human vitamin D binding protein to a potent macrophage activating factor. US Patent number: 5,177,002

  29. Yamamoto N, Kumashiro R (1993) Conversion of vitamin D3 binding protein (group-specific component) to a macrophage activating factor by the stepwise action of ß-galactosidase of B cells and sialidase of T cells. J Immunol 151:2794–2902

    PubMed  CAS  Google Scholar 

  30. Yamamoto N, Kumashiro R, Yamamoto M, Willett NP, Lindsay DD (1993) Regulation of inflammation-primed activation of macrophages by two serum factors, vitamin D3-binding protein and albumin. Infect Immun 61:5388–5891

    PubMed  CAS  PubMed Central  Google Scholar 

  31. Yamamoto N (1994) Macrophage activating factor from vitamin D binding protein. US Patent Number: 5,326,749

  32. Yamamoto N, Naraparaju VR, Srinivasula SM (1995) Structural modification of serum vitamin D3-binding protein and immunosuppression in HIV-infected patients. AIDS Res Human Retrovirus 11:1373–1378

    Article  CAS  Google Scholar 

  33. Yamamoto N (1996) Structural definition of a potent macrophage activating factor derived from vitamin D3 binding protein with adjuvant activity for antibody production. Mol Immunol 33:1157–1164

    Article  PubMed  CAS  Google Scholar 

  34. Yamamoto N, Naraparaju VR, Asbell SO (1996) Deglycosylation of serum vitamin D-binding protein and immunosuppression in cancer patients. Cancer Res 56:2827–2831

    PubMed  CAS  Google Scholar 

  35. Yamamoto N (1997) Diagnostic and prognostic indices for cancer and AIDS. US Patent Number: 5,620,846

  36. Yamamoto N, Naraparaju VR (1997) Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer Res 57:2187–2191

    PubMed  CAS  Google Scholar 

  37. Yamamoto N, Naraparaju VR, Urade M (1997) Prognostic utility of serum a-N-acetylgalactosaminidase and immunosuppression resulted from deglycosylation of serum Gc protein in oral cancer patients. Cancer Res 57:295–299

    PubMed  CAS  Google Scholar 

  38. Yamamoto N (1998) Vitamin D and the immune system. In: Delves PJ, Roitt I (eds) Encyclopedia of immunology, 2nd edn. Academic, London, pp 2494–2499

    Chapter  Google Scholar 

  39. Yamamoto N (1998) Diagnostic and prognostic ELISA assays of serum or plasma a-N-acetylgalactosaminidase for cancer. US Patent number: 5,712,104

  40. Yamamoto N, Naraparaju VR (1998) Structurally well-defined macrophage activating factor derived from vitamin D3-binding protein has a potent adjuvant activity for immunization. Immunol Cell Biol 76:237–244

    Article  PubMed  CAS  Google Scholar 

  41. Yamamoto N (2002) Preparation of potent macrophage activating factors derived from cloned vitamin D binding protein and its domain and their therapeutic usage for cancer, HIV-infection and osteopetrosis. US Patent no. 6,410,269

  42. Yamamoto N, Ueda M (2004) Eradication of HIV by treatment of HIV-infected/AIDS patients with vitamin D-binding protein (Gc protein)-derived macrophage activating factor (GcMAF). Immunology 2000. Medmond Ltd, Bolonia, pp 197–200

    Google Scholar 

  43. Yamamoto N, Ueda M (2004) Therapeutic efficacy of vitamin D-binding protein (Gc protein)-derived macrophage activating factor (GcMAF) for prostate and breast cancers. Immunology 2000. Medmond Ltd, Bolonia, pp 201–204

    Google Scholar 

  44. Yamamoto N, Urade M (2005) Pathogenic significance of a-N-acetylgalactosaminidase found in the hemagglutinin of influenza virus. Microbes Infect 7:674–681

    Article  PubMed  CAS  Google Scholar 

  45. Yamamoto N (2006) Pathogenic significance of a-N-acetylgalactosaminidase found in the envelope glycoprotein gp160 of human immunodeficiency virus type 1. AIDS Res Human Retrovirus 22:262–271

    Article  CAS  Google Scholar 

  46. Yamamoto N, Suyama H, Yamamoto N-Y, Ushijima N (2008) Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Int J Cancer 122:461–467

    Article  PubMed  CAS  Google Scholar 

  47. Zbar B, Tanaka T (1971) Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis. Science 172:271-273

    Article  PubMed  CAS  Google Scholar 

  48. Zhang S, Zhang HS, Cordon-Cardo C, Ragupathi G, Livingston PO (1998) Selection of tumor antigens as targets for immune attack using immunohistochemistry. III. Protein antigen. Clin Cancer Res 4:2669–2676

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This investigation was supported in part by US Public Health Service Grant AI-32140 and Elsa U. Pardee Foundation Grant to N. Y.

Author information

Authors and Affiliations

  1. Division of Cancer Immunology and Molecular Immunology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA, 19126, USA

    Nobuto Yamamoto & Nobuyuki Yamamoto

  2. Nagasaki Immunotherapy Research Group, Yokoh, Nagasaki, Japan

    Hirofumi Suyama

  3. Yokoyama Gastroenterology Hospital, Nagoya, Japan

    Hiroaki Nakazato

  4. Nakagawa Hospital, Fukuoka City, 811-1345, Japan

    Yoshihiko Koga

  5. Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, 1040, 66th Ave, Philadelphia, PA, 19126-3305, USA

    Nobuto Yamamoto

Authors
  1. Nobuto Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirofumi Suyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroaki Nakazato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nobuyuki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshihiko Koga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nobuto Yamamoto.

Additional information

This article has been retracted by the journal's co-Editors-in-Chief in conjunction with the publisher (Springer) due to irregularities in the Institutional Review Board documentation.

About this article

Cite this article

Yamamoto, N., Suyama, H., Nakazato, H. et al. RETRACTED ARTICLE: Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF. Cancer Immunol Immunother 57, 1007–1016 (2008). https://doi.org/10.1007/s00262-007-0431-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-007-0431-z

Keywords

Search

Navigation