Gallium has potent antiproliferative activity against cancer cells due to its ability to locally disrupt iron uptake and utilization.  It is highly targeted to cancer tissue within the body, as demonstrated by diagnostic gallium scans.  Orally administered gallium maltolate delivers gallium efficiently into the bloodstream, where it becomes bound to transferrin, the form in which gallium has the highest uptake by cancer cells.

INTRODUCTION Gallium is well known for its ability to concentrate in cancerous and infected tissues. This ability allows gallium scans (employing 67Ga) to detect a variety of cancers and infections. Recently, antiproliferative mechanisms for gallium have been elucidated. Knowledge of these mechanisms has led to the development of a therapeutic gallium compound—gallium maltolate—that is designed to maximize efficacy and minimize potential adverse effects.

CHEMISTRY Gallium maltolate, tris(3-hydroxy-2-methyl-4-pyronato) gallium, is a coordination complex consisting of a gallium atom surrounded by three maltolate ligands. Maltol is a naturally occurring compound that is commonly produced during the cooking of foods containing sugars: it is responsible for the aroma of cotton candy and contributes to the fragrance of cookies, cakes, and other baked goods. Maltol is also found in some fruits and is a widely used, FDA-approved food additive. Gallium maltolate is electrically neutral and moderately soluble in both water and lipids. It is stable over a pH range of approximately 5 through 8, a relatively large interval for a metal complex.

MECHANISM OF ACTION Chemically, gallium behaves remarkably like ferric iron (Fe3+); unlike ferric iron, however, it cannot be reduced to a divalent form under physiologic conditions. Gallium is thus able to compete with ferric iron, which is required for some enzymes to function, but it is not incorporated into hemoglobin or other molecules that contain ferrous iron (Fe2+).

Gallium administered orally as gallium maltolate appears to follow the normal uptake pathway used by iron. Absorption is primarily in the proximal duodenum, where gallium separates from the maltolate ligand and becomes bound to transferrin in the blood plasma. Transferrin, the primary transport protein for iron, has two iron-binding sites per molecule; these binding sites are also able to accommodate gallium ions. Only about a third of the binding sites are typically occupied by iron, so sites are readily available for gallium.

Proliferating cells have a high need for iron: in many cases, iron appears to be the limiting nutrient for cell division. The requirement for iron is due in large part to ferric iron’s position at the active site of ribonucleotide reductase (RR), an enzyme essential for DNA synthesis. To acquire iron, many multiplying cells, and particularly cancer cells, express on their surface a large amount of transferrin receptor, which binds to metal-saturated transferrin in the blood. The complex of metal-saturated transferrin and transferrin receptor is taken into the cell by endocytosis; the metal ions are then released, and the transferrin and transferrin receptor are transported out of the cell and recycled. If gallium is present on the transferrin instead of iron, it will compete with intracellular iron and prevent RR from becoming functional. The resulting inability of the cell to synthesize DNA will halt cell division and lead to apoptosis (programmed cell death).

A further anticancer mechanism relates to gallium’s ability to strongly inhibit bone resorption. Clinical and preclinical experience with gallium nitrate has demonstrated that gallium blocks the resorptive activity of osteoclasts, without being cytotoxic to these cells. This antiresorptive activity is thought to significantly inhibit metastasis to bone and the destruction of bone by tumors. Animal and in vitro data suggest that gallium can, in addition, actually stimulate the regrowth of damaged bone (anabolic activity).

The ability of gallium to selectively target neoplastic tissue, on which it exerts antiproliferative activity by a unique mechanism (competition with ferric iron), together with its ability to potently inhibit bone resorption, make gallium an attractive therapeutic agent.

CLINICAL EXPERIENCE Intravenous gallium nitrate, approved by the FDA in 1991 for the treatment of cancer related hypercalcemia, has been administered to over a thousand subjects, mostly cancer patients. Efficacy against several cancers, particularly lymphomas, multiple myeloma, metastatic prostate cancer, and urothelial carcinoma, has been observed. Administration of this compound is, however, limited due to its renal (kidney) toxicity. Intravenous gallium nitrate is eliminated predominantly by the kidneys (approximately 49-94% is excreted in the urine in 24 hours) and may transiently reach high concentrations in the renal tubules. In contrast, only about 2% of gallium orally administered as gallium maltolate is eliminated in the urine in 72 hours, and no sign of renal toxicity has been observed for this compound. As mentioned, gallium from oral gallium maltolate is nearly all protein-bound (to transferrin) in the blood plasma, whereas a high proportion of gallium from intravenous gallium nitrate appears to be present as the free gallate ion, [Ga(OH)4]ˉ. Gallate, being a small charged molecule, is rapidly excreted by the kidneys. It thus appears that oral gallium maltolate, by delivering gallium so that it becomes bound almost entirely to plasma transferrin, should be more efficacious with lower toxicity on a per dosage basis than intravenous gallium nitrate.

Gallium maltolate has been administered to healthy volunteers and to some late-stage cancer patients in Phase I clinical trials. It has been given at doses as high as 3,500 mg/day for 28-day cycles, with no dose-limiting toxicity or serious drug-related adverse effects. The compound has shown high oral bioavailability with an elimination half-life of approximately 17 to 21 hours. Anecdotal efficacy has been observed in patients with lymphoma, end-stage liver cancer (hepatocellular carcinoma), metastatic prostate cancer, metastatic colon cancer, and metastatic breast cancer.

As an example, a patient with inoperable, late-stage liver cancer, who had not responded to chemotherapy with sorafenib (Nexavar®), was administered a daily dose of oral gallium maltolate. Prior to gallium maltolate treatment, the patient had severe right abdominal pain, elevated serum bilirubin, anorexia, and could not perform most routine activities. A 67Ga scan showed avid gallium uptake by the 20 cm tumor. Within two weeks following the start of gallium maltolate treatment, the patient’s right abdominal pain had decreased substantially. Two months following the start of treatment, the patient had resumed most normal activities, serum bilirubin was well within the normal range, and a CT scan showed apparent necrosis and shrinkage of the tumor.

Gallium scan showing the neck and chest of a patient with Hodgkin’s lymphoma. Black regions in the image represent tumors, which had high gallium uptake. The surrounding healthy tissue had very low gallium uptake. [J Nucl Med Tech 28:221-232 (2000)]

SELECTED REFERENCES

Bernstein LR (1998) Mechanisms of therapeutic activity for gallium. Pharmacological Reviews 50:665-682.

Bernstein LR, Tanner T, Godfrey C, Noll B (2000) Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability. Metal Based Drugs 7:33-48.

Bernstein LR (2005) Therapeutic gallium compounds, in Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine, M. Gielen and E.R.T. Tiekink, Editors, p. 259-277.

Wiley, New York. Bernstein LR, van der Hoeven JJM, Boer RO (2011) Hepatocellular carcinoma detection by gallium scan and subsequent treatment by gallium maltolate: rationale and case study. Anti-Cancer Agents in Medicinal Chemistry 11:585-590.

Chitambar CR, Narasimhan J, Guy J, Sem DS, O’Brien WJ (1991) Inhibition of ribonucleotide reductase by gallium in murine leukemic L1210 cells. Cancer Research 51:6199-6201.

Chitambar CR, Purpi DP, Woodliff J, Yang M, Wereley JP (2007) Development of gallium compounds for treatment of lymphoma: gallium maltolate, a novel hydroxypyrone gallium compound, induces apoptosis and circumvents lymphoma cell resistance to gallium nitrate. Journal of Pharmacology and Experimental Therapeutics 322:1228-1236.

Chua MS, Bernstein LR, Li R, So SKS (2006) Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma. Anticancer Research 26:1739-1744.

Foster BJ, Clagett-Carr K, Hoth D, Leyland-Jones B (1986) Gallium nitrate: the second metal with clinical activity. Cancer Treatment Reports 70:1311-1319.

Niesvizky R (2003) Gallium nitrate in multiple myeloma: Prolonged survival in a cohort of patients with advanced-stage disease. Seminars in Oncology 30 (suppl 5):20-24.

Scher HI, Curley T, Geller N, Dershaw D, Chan E, Nisselbaum J, Alcock N, Hollander P, Yadoda A (1987) Gallium nitrate in prostatic cancer: evaluation of antitumor activity and effects on bone turnover. Cancer Treatment Reports 71:887-893.

Warrell RP Jr, Bockman RS (1989) Gallium in the treatment of hypercalcemia and bone metastasis, in DeVita, V.T., Hellman, S., Rosenberg, S.A., Editors, Important Advances in Oncology 1989, p. 205-220.

J.B. Lippincott, Philadelphia. Warrell RP Jr, Coonley CJ, Straus DJ, Young CW (1983) Treatment of patients with advanced malignant lymphoma using gallium nitrate administered as a seven-day continuous infusion. Cancer 51:1982-1987.

Warrell RP Jr, Lovett D, Dilmanian FA, Schneider R, Heelan RT (1993) Low-dose gallium nitrate for prevention of osteolysis in myeloma: results of a pilot randomized study. Journal of Clinical Oncology 11:2443-2450. Prepared by Lawrence R. Bernstein, October 2013 LawrenceRBernstein@gmail.com Tel.: 650-324-3344

 Mycoplasma is the smallest free-living organism known on the planet. It is neither a bacteria nor a virus. The primary difference is that mycoplasma does not have a cell wall; instead they have a pliable, jelly-fish like membrane. That allows them to take different shapes which makes it very difficult to identify them. They are literally invisible to the immune system. Unlike other pathogens, they can move through the body invading cells in different tissues, playing “hide and seek” with the immune system.

 The first connection between mycoplasma and rheumatic disease was made in 1939 by Drs. Swift and Brown.  In 1950’ one specific strand of mycoplasma was identified in pneumonia, pharyngitis and asthma. By 1970’ more mycoplasma species were identified and linked to disorders of blood, skin, joints, central nervous system, liver, pancreas and cardiovascular.

 According to Dr. Lida Holmes Mattman, the author of the book “Cell Wall Deficient Forms: Stealth Pathogens”:

             “Cell wall deficient forms easily move between groups of cells and fuse together to facilitate “genetic experiments” within the body”, frequently triggering or exacerbating numerous types of illness and disease.

 Drs. Baseman and Tully, in their article “Mycoplasmas: Sophisticated, Reemerging and Burdened by Their Notoriety” (published in the 1997 the National Center for Infectious Diseases, Centers for Disease Control and Prevention’s journal, Emerging Infectious Diseases) stated:

             “Nonetheless, mycoplasmas by themselves can cause acute and chronic diseases at multiple sites with wide-ranging complications and have been implicated as cofactors in disease. Recently, mycoplasmas have been linked as a cofactor to AIDS pathogenesis and to malignant transformation, chromosomal aberrations, the Gulf War Syndrome, and other unexplained and complex illnesses, including chronic fatigue syndrome, Crohn’s disease, and various arthritides.”

 Now it is known that mycoplasma is linked to such diseases as:

Arthritis and RA, Gulf War Syndrome, Fibromyalgia, Chronic Fatigue Syndrome, Lupus, AIDS/HIV, ALS, Psoriasis and Scleroderma, Crohn’s disease and IBS, Hashimoto’s and Grave’s disease, Cancer, Pneumonia, Asthma, Upper and Lower Respiratory Disease, Urogenital Infections and Diseases, Multiple Sclerosis, Diabetes, Endocrine Disorders, Autism, Parkinson’s  and other autoimmune diseases. (See references below)

 People who suffer from these conditions usually have more than one pathogen in their blood, which complicates the case and makes it more difficult to treat. Those pathogens include Candida Albicans, fungus, various parasites, etc. However, there are natural treatment options like high quality Olive Leaf Extract, Colloidal Silver, Cat’s Claw (especially Samento) that allow to safely eliminate pathogens from the blood and other supplements to support the immune system during the process.

 Through studying blood under dark field microscope, we are able to identify these pathogens in the individual’s blood and then, put together a customized protocol of treatment options that would also minimize the effects of Herxheimer’s reaction.

 P. S. While I was doing research for this article, going through numerous publications, I came across this very interesting information from Dr. Garth Nicolson, microbiologist, who discovered mycoplasma in … vaccines! Please watch this short video:

 Deadly Mycoplasma in Vaccines

References:

 “Cell Wall Deficient Forms: Stealth Pathogens”, book by Lida H. Mattman
http://www.rain-tree.com/myco.htm
http://www.immed.org/illness/autoimmune_illness_research.html
http://www.arthritistrust.org/Articles/Autoimmune%20Diseases%20Caused%20by%20Mycoplasmas.pdf
http://www.rense.com/general18/mcc.htm
http://www.roadback.org/index.cfm/fuseaction/studies.display/display_id/107.html

 My daughter sent me this amazing and fun lecture by Dr. Michael Holick of Boston University. It has been around for a couple of years now, and yet, among my friends and clients almost nobody has heard of it. In this lecture Dr. Holick is talking to the students of UC San Diego about vitamin D deficiency and what it means for us. Yes, even for us in San Diego!!! I’ve watched it many times, in parts, making notes and finding answers to all my questions.  It is not your regular “boring” lecture by all means! Very entertaining and full of vital information – you will not be sorry for your time!

Here it is! The D-lightfull story of vitamin D: