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The introduction to the Yamamoto paper, Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF) Dr. Yamamoto strongly encourages anyone interested in his work to carefully read this Introduction. The number of elderly breast cancer patients has increased significantly in the last few decades.1,2 It has been reported that more than 40% of newly-diagnosed breast cancer occurs in women age older than 65 years and that older women present more frequently with advanced disease.3 At least 50% of the patients die as a consequence of metastatic disease. Even in node-negative breast cancer patients, one third will have a distant recurrence within several years.4 Metastatic breast cancer patients are essentially incurable with standard therapy, and have a median survival duration of less than 2 years after documentation of metastases.4,5 While sensitive to initial treatment such as hormonal therapy, metastatic breast cancer virtually always progresses and responses are harder to obtain with subsequent regimens. Therapeutic approaches capable of tumoricidal to hormone-refractory and chemoresistant cancerous cells are limited to a certain immunotherapy without producing side effects. Inflammation of cancerous tissues induced by intratumor administration of BCG (Bacille Calmette Guerin) or other bacterial cells can result in regression of local as well as metastasized tumors, suggesting development of specific immunity against the tumors.6,7 However, inflammation in noncancerous normal tissues results in no significant effect on the tumors.7 Inflamed normal tissues release membranous lipid metabolites, lyso-phosphatidylcholine (lyso-Pc) and other lysophospholipids, that efficiently activate macrophages.8–11 Inflamed cancerous tissues release lipid metabolites, lysoalkylphospholipids and alkylglycerols, because cancerous tissues contain alkylphospholipids.11–14 Both lysoalkylphospholipids and alkylglycerols are at least 400 times more potent macrophage activating agents than lysophospholipids in terms of the minimal dosages required for optimal macrophage activation. 12–14 These observations suggest that highly activated macrophages are tumoricidal and also explain why inflammation in cancerous tissues cures the disease. In fact, highly activated macrophages have a potential to kill and eradicate cancer cells.15–18 Inflammation-derived macrophage activation is the principal macrophage activation process which requires serum vitamin D binding protein (known as Gc protein)19–24 and participation of B and T lymphocytes.9–14 Gc protein carries a trisaccharide composed of N-acetylgalactosamine with dibranched galactose and sialic acid termini.22–25 This oligosaccharide is hydrolyzed by the inducible membranous b-galactosidase (Bgli) of inflammationprimed (or lyso-Pc-treated) B cells to yield a macrophage proactivating factor. This in turn is hydrolyzed by the membranous Neu- 1 sialidase of T-cells to yield the macrophage activating factor (MAF)22–27 (Fig. 1a). Thus, Gc protein is the precursor for the principal MAF.22,27 However, the MAF precursor activity of cancer patient Gc protein is lost or reduced, because their serum Gc protein is deglycosylated by serum a-N- acetylgalactosaminidase (Nagalase) secreted from cancerous cells28–31 (Fig. 1b). Thus, serum Nagalase activity is proportional to tumor burden.29,32 Deglycosylated Gc protein cannot be converted to MAF, resulting in no macrophage activation. Since macrophage activation for phagocytosis and antigen presentation to B and T lymphocytes is the first indispensable step in humoral and cellular immunity development, lack of macrophage activation leads to immunosuppression. 28–31,33–36 Advanced cancer patient sera contain high Nagalase activity with a concomitant loss of the MAF precursor activity. Thus, lack of macrophage activation and severe immunosuppression in advanced cancer patients explain why they die with overwhelming infection (e.g., pneumonia).29 Stepwise treatment of purified Gc protein with immobilized bgalactosidase and sialidase generates probably the most potent MAF (termed GcMAF)23–27,32,37–39 ever discovered (Fig. 2), which produces no side effect in humans.30,32,38,40 Administration of 100 ng GcMAF per human results in the maximal level of macrophage activation which develop an enormous variation of receptors that recognize abnormality in malignant cell surface and kill cancerous cells.30,32,37,38 All malignant cells have abnormalities in their cell surface. A series of glycolipid, glycoprotein and mucin antigens have been identified and designated as tumor-associated antigen (TAA) on the cell surface of a wide variety of tumor cells.41–44 When human macrophages were treated in vitro with GcMAF (100 pg/ml) for 3 hr and a breast cancer cell line MCF-7 was added with effector/target ratio of 1.5, 60% and 86% of MCF-7 cells were killed in 4 hr and 18 hr incubation, respectively.38,40 When mice bearing a mammary adenocarcinoma (Ehrlich ascites tumor) were treated with 4 dministrations of 100 pg GcMAF, serum Nagalase activity decreased to the enzyme activity level of control healthy mice.32,37 These mice still carried a trace amount of ascites cells.37 We designated them as dormant cells because they were nonproliferating. Later we found that they are terminally differentiated osteoblast cells. Thus, GcMAF therapy eradicates Ehrlich ascites tumor cells. Although in recent years CA27.29, CA15-3 and carcinoembryonic antigen (CEA) have been diagnostic and prognostic indices for breast cancer,45,46 more precision of prognostic index is desirable for therapeutic efficacy of GcMAF for breast cancer. The MAF precursor activity and serum Nagalase activity have been used as diagnostic indices for a variety of cancer patients28–32,37,38 and as prognostic indices during radiation therapy,28,47,48 surgical resection of tumors29 and GcMAF therapy of tumor bearing mice.32,37,47
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