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, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Human vitamin D3 binding protein
Enzymatically generated Gc-derived macrophage-activating factor
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
Braun S, Pantel K (1999) Micrometastatic bone marrows involvement detection and prognostic significance. Med Oncol 16:154–165
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
DeCosse JJ, Tsioulias GJ, Jacobson JS (1994) Colorectal cancer: detection, treatment and rehabilitation. CA Cancer J Clin 44:27–42
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
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
Homma S, Yamamoto N (1990) Activation process of macrophages after in vitro treatment of mouse lymphocytes with dodecylglycerol. Clin Exp Immunol 79:307–313
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
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
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
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
Koprowski H, Herlyn M, Steplewski Z, Sears HF (1981) Specific antigen in serum of patients with colon carcinoma. Science 212:53–55
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
Maehara Y, Kohnoe S, Sugimachi K (1990) Chemosensitivity test for carcinoma of digestive organs. Semin Surg Oncol 6:42–47
Morton D, Eibler FR, Malmgren RA, Wood WC (1970) Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 68:158-164
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
Ngwenya BZ, Yamamoto N (1985) Activation of peritoneal macrophages by lysophosphatidylcholine. Biochim Biophys Acta 839:9-15
Ngwenya BZ, Yamamoto N (1986) Effects of inflammation products on immune systems: lysophosphatidylcholine stimulates macrophages. Cancer Immunol Immunother 21:174–182
Ngwenya BZ, Yamamoto N (1990) Contribution of lysophosphatidylcholine treated nonadherent cells to mechanism of macrophage activation. Proc Soc Exp Biol Med 193:118–124
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
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
Yamamoto N, Ngwenya BZ (1987) Activation of macrophages by lysophospholipids, and ether derivatives of neutral lipids and phospholipids. Cancer Res 47:2008-2013
Yamamoto N, Ngwenya BZ, Pieringer PA (1987) Activation of macrophages by ether analogues of lysophospholipids. Cancer Immunol Immunother 25:185–192
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
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
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
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
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
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
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
Yamamoto N (1994) Macrophage activating factor from vitamin D binding protein. US Patent Number: 5,326,749
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
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
Yamamoto N, Naraparaju VR, Asbell SO (1996) Deglycosylation of serum vitamin D-binding protein and immunosuppression in cancer patients. Cancer Res 56:2827–2831
Yamamoto N (1997) Diagnostic and prognostic indices for cancer and AIDS. US Patent Number: 5,620,846
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
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
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
Yamamoto N (1998) Diagnostic and prognostic ELISA assays of serum or plasma a-N-acetylgalactosaminidase for cancer. US Patent number: 5,712,104
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
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
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
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
Yamamoto N, Urade M (2005) Pathogenic significance of a-N-acetylgalactosaminidase found in the hemagglutinin of influenza virus. Microbes Infect 7:674–681
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
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
Zbar B, Tanaka T (1971) Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis. Science 172:271-273
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
This investigation was supported in part by US Public Health Service Grant AI-32140 and Elsa U. Pardee Foundation Grant to N. Y.
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
- Colorectal cancer
- Macrophage-activating factor