One of the most significant medical advances in the past twenty years is the discovery of the hormones of the immune system known as cytokines.
The most famous of the cytokine are interleukins and the interferon’s, such as IL2 and gamma interferon, the other major cytokine group are the enkephalin and endorphins. The enkephalin and endorphins regulate not only the cells of the immune system but also the endocrine system keeping the two in balance. The balance is important to keeping the immune system healthy. Clinically, cytokines have been found to stimulate the immune system in the treatment of viral infections such as HIV/AIDS, hemorrhagic fever and hepatitis as well as a number of different types of cancer.
The immune system is the bodies defensive system against infectious organisms such as bacteria, viruses, fungi, parasites and most important – tumor cells. The immune system includes many different defense cells such as macrophages, T cells, Natural Killer (“NK”) cells, B cells and neutrophils. Cytokines are produced by the macrophages and the T cells and communicate with all of the cells in the immune system. T cells include a group of cells that are described as killer cells that destroy viruses and tumor cells.
Met-enkephalin, some times referred to as Opioid Growth Factor (OGF) have been studied by a number of scientists but the most published of these are Dr. Ian Zagon and his team from Pennsylvania State Medical Center at Hershey extensively in relationship to growth – especially in cancer and Dr. Nicholas Plotnikoff in conjunction with. Bihari and Dr. Ronald Herberman and Robert Good in the treatment of HIV/AIDS and cancer. Much of this research has been carried out in the USA, Belgium, Croatia and Germany.
Professor Ian S. Zagon and a research team, a, discovered that endogenous opioid peptides served as growth factors. In subsequent studies, these researchers found that one native opioid peptide – met-enkephalin (OGF/MENK) has been shown to regulate the growth of cancer cells.
The effect of OGF/MENK is to delay the replication of cells. The retarding of cell multiplication is often referred to as cytostatic (cyto = cellular growth, static = halt). Unlike chemotherapy, OGF/MENK does not directly destroy cancer cells and is not cytotoxic.
OGF/MENK has been shown to halt the growth of the cells and is thought to allow immunological mechanisms (e.g. macrophages, natural killer cells) to accomplish the task of destroying the cancerous cells.
OGF/MENK also appears to work as an adjunct to chemotherapy, when combined with traditional chemotherapy it shown to work in a more effective and less toxic manner.
Phase II clinical trials for the treatment of HIV/AIDS and cancer have shown that MENK/OFG provided evidence for the treatment of HIV/AIDS, as well as anti-cancer activity in Kaposi Sarcoma, Lung, Melanoma, Ovarian, Cervical, Head and Neck, Pancreatic, liver and renal cancer. MENK/OFG has been found to have immunostimulating and immuno-regulating effects. MENK/OFG has been used to treat several autoimmune conditions in human subjects, including Multiple Sclerosis, Uveitis, Behcet’s Syndrome, and Optic Neuritis.
Boosting NK cell levels is essential in helping to beat cancer. Studies have demonstrated that OGF significantly raises NK (Natural Killer) cell levels, although the mechanism by which this happens has not yet been fully clarified.
All the studies that have been carried out to date have consistently demonstrated the existence of OGF receptors in every type of malignancy that has been examined. Furthermore, in addition to the clinical trials there is anecdotal evidence of a variety of cancers, which respond to an OGF/MENK- boosting drug.
Studies in animals have clearly determined that the mechanism for this response is through OGF/OGFr interaction. It is therefore reasonable to assume that the responses to this OGF-increasing drug, which have been anecdotally reported in humans, are similarly mediated via OGF receptors.
The following cancers have either been shown to have OGF receptors and/or have been anecdotally reported to respond to OGF and/or OGF- boosting mechanisms:
Breast Cancer Cervical Cancer
Rectal Cancer Gastric Cancer Glioblastoma
Head and Neck
Lymphocytic Liver Cancer
Lymphoma – B Cell and T Cell Malignant Melanoma Neuroblastoma
Renal Cell Carcinoma
Small Cell and Non-Small Cell Lung Cancer
In laboratory studies, Zagon and his team discovered that OGF/MENK, which is involved in suppression of pain in the nervous system, also controls the production of some cells, both healthy and abnormal. Pancreatic cancer cells have OGF receptors that, when bound with OGF, inhibit additional cancer cell growth. Because cancer cells reproduce so quickly, the body cannot produce enough OGF/MENK to bind all of the receptors, so cancer cell growth continues unimpeded.
Zagon’s laboratory work suggested that providing enough OGF/MENK in the body could bind the OGF receptors, inhibit cancer cell proliferation, and give the body’s own defenses time to battle the disease.
In Phase I and Phase II clinical study, sponsored by the National Institutes of Health, Zagon’s collaborator Jill Smith, M.D., professor of medicine, Penn State College of Medicine, enrolled 21 patients with advanced, inoperable, pancreatic cancer. In one group, OGF was administered intravenously in a saline solution over 30 minutes once per week.
In a second part of the study, 10 patients were treated with 250 ug/kg intravenous infusions of OGF/MENL, this time delivered over 45 minutes. Because the timing of drug delivery was extended, there were no incidents of toxicity. Six other patients were treated with 50 ug/kg OGF injections twice per day.
Results showed that, unlike the chemotherapeutic agents often used to treat pancreatic cancer, OGF/MENK did not cause white blood cell, platelet or iron counts to drop, and did not cause gastrointestinal problems. Nor were there side effects such as hair loss, nausea or loss of appetite.
Quality of life surveys administered before and during the study showed that patients had improved social interaction and alertness behavior, improved sleep and rest, mobility and communication. Pain and depression surveys showed a diminishment in pain scores at certain points during the therapy, and that OGF/MENK did not induce depression, but may have actually prevented the development of depression in the terminally ill patients.
“Although this study was not intended to examine tumor response or survival, our preliminary results showed two patients with spread of the cancer to the liver responded with loss of metastases, and survival was increased from 5.6 months under the typical treatment with gemcitabine, to 9.1 months with OGF,” Zagon said. “Some patients survived from 21 to 23 months.”
The combination of OGF and gemcitabine also repressed the growth of another pancreatic cancer cell line, PANC-1. MIA PaCa-2 cells transplanted into athymic mice received 10 mg/kg OGF daily, 120 mg/kg gemcitabine every 3 days; 10 mg/kg OGF daily and 120 mg/kg gemcitabine every 3rd day, or 0.1 ml of sterile saline daily.
Tumor incidence, and latency times to tumor appearance, of mice receiving combined therapy with OGF and gemcitabine, was significantly decreased from those of the control, OGF, and gemcitabine groups. Tumor volumes in the OGF, gemcitabine, and OGF/gemcitabine groups were markedly decreased from controls beginning on days 14, 12, and 8, respectively, after tumor cell inoculation. Tumor weight and tumor volume were reduced from control levels by 36–85% in the OGF and/or gemcitabine groups on day 45 (date of termination), and the group of mice exposed to a combination of OGF and gemcitabine had decreases in tumor size of 70% and 63% from the OGF or the gemcitabine alone groups, respectively. This preclinical evidence shows that combined chemotherapy (e.g. gemcitabine) and biotherapy (OGF) provides an enhanced therapeutic benefit for pancreatic cancer.
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Upregulation of OGFr and consequent stimulation of the OGF-OGFr system are important for the anti-proliferative effects of imidazoquinoline drugs like imiquimod and resiquimod, which are immune response modifiers with potent antiviral and antitumour effects, used as topical creams for the treatment of skin cancers and warts.
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OGF/MENK appears to be an extraordinarily promising agent in the therapy of cancer; both Phase I and Phase II studies have determined an excellent safety profile, which is practically unrivaled in the field of oncology therapeutics. Furthermore, OGF/MENK has been demonstrated to exert beneficial effects on the immune system especially for those undergoing chemotherapy.