Overview of Macrophage Activating Factor and the Nagalase Assay – Potential for Control of Micrometastatic or Early Primary Cancer

Macrophage activating factor (GcMAF) functions physiologically to boost the superoxide-generating, phagocytic, and cancerocidal capacities of macrophages; it is generated from vitamin D binding protein by lymphocyte beta-galactosidase and sialidase activities up-regulated by inflammation. Many and possibly most cancers secrete an N-acetylgalactosaminidase – a.k.a. nagalase – that prevents the synthesis of and also degrades GcMAF, protecting the cancer from macrophage-orchestrated destruction. Yamamoto, who discovered these phenomena, has presented evidence that elevated serum nagalase is a virtually universal feature of cancer, and that nagalase can be used to monitor cancer status when cancer is in a microscopic metastatic form. He further proposes that intramuscular injections of pre-formed GcMAF can aid cancer control by compensating for the immunosuppressive activity of nagalase and boosting macrophage activity within tumors. In clinical trials enrolling breast, prostate, and colorectal cancer patients who had achieved remission after therapy, but who were presumed to harbor microscopic metastatic disease owing to elevated serum nagalase levels, he found that weekly administration of GcMAF was associated with a gradual monotonic decline in serum nagalase; the normal range was achieved within 24-48 weeks, and these patients were reported to be alive and clinically cancer free a number of years later. Hence, it is proposed that GcMAF administration can be employed to “mop up” residual cancer cells after effective extirpative therapy; concurrent monitoring of nagalase can provide evidence that the GcMAF is working effectively, and insure that it is administered for a sufficient time to effect a cure. If this model is correct, adjuvant use of GcMAF has the potential to make surgery, chemotherapy, and radiotherapy notably more curative than they are at present. GcMAF may also have the potential to slow the spread of more advanced cancers, and it has strong anti-angiogenic activity if injected daily. Conceivably, the routine monitoring of serum nagalase could aid early detection of cancer. Although these prospects are exciting, much further research is needed to verify the utility of nagalase as a cancer marker and to confirm the efficacy of GcMAF as adjuvant therapy, in a range of cancers. The use of GcMAF in conjunction with agents that promote a pro-inflammatory M1 phenotype in tumorassociated macrophages merits evaluation as an immunotherapeutic strategy. Although GcMAF is not currently available as an investigational drug, patients can order and self-administer it, and their doctors can monitor their progress. Macrophage Activating Factor Boosts the Cytotoxic Capacity of Macrophages Yamamoto and colleagues have presented evidence that, within inflamed tissues, vitamin D-binding globulin (a.k.a. Gc protein, a member of the albumin family secreted by the liver) becomes structurally altered, giving rise to a “macrophage activating factor” – GcMAF – that rapidly and potently boosts the superoxide-generating and phagocytic capacity of macrophages. 2 In vitro, exposure of macrophages to 100 pg/ml GcMAF is reported to boost their generation of superoxide by about 9-fold, with a 2-fold increase seen at 0.1 pg/ml. The increase in antibody-dependent phagocytic capacity, reflects, at least in