Gallium: fighting Iron-avid tumors

Summary 

A very interesting substance, safe with a very clear anticancer (and not only) mechanisms. It is easy to administrate since it can be administrated orally and it has been shown to kill cancer cells in humans. The only drawback is that it is a bit difficult to access it, but not impossible (since I already have it at home).

Due to its anti cancer mechanism. it sis relevant for all type of tumors that are strongly dependent on Iron availability, which is the case for many cancer cells.

The origin of the anti cancer properties of Gallium is related to the fact that Gallium is very similar to Iron so it can mimic Iron. Iron is highly required by the cancer cells for various processes such as the rapid cellular division (Iron is required for DNA synthesis). Because Gallium is similar to Iron, transferrin in the blood will bind Gallium (instead of Iron) and transfer that to the cancer cells which have large number of transferrin receptors. However, even if Gallium it is similar to Iron it is not functional, so that the cancer cells cannot proliferate.

Because of reasons explained in the “Mechanism” section, Gallium has also anti inflammatory properties which can be very relevant in rheumatoid arthritis, significantly inhibiting ankle swelling, joint inflammation, bone degradation, andmenlargement of the spleen and liver http://www.painmed.org/2013posters/poster110.pdf

Before the administration, performing a gallium-67 scan can help to identify the chance for effectiveness of this treatment. If tumors show up on the gallium-67 scan than there is a good chance for this treatment to be effective. However, we do not have access to gallium-67 scan and since the substance is not toxic we will probably added this next to other treatments and hope for effectiveness.

It has been already used in humans with success in e.g. liver cancer. In trials of oral Gallium  Maltolate, dramatic pain reduction has often been noted, though it has not been clear if this was strictly an analgesic effect or was primarily related to GaM’s anticancer activities http://www.painmed.org/2013posters/poster110.pdf

One of the major scientists behind the Gallium Maltolate related discoveries was/is Dr. Lawrence Bernstein. He has a very informative website here http://home.earthlink.net/~alixapharm/index.html Next to that, he patented  Gallium Maltolate for various applications and currently has his own products for topical applications against a long list of health issues: https://www.gallixa.com/AboutGallixa.html

Case reports 

Hepatocellular Carcinoma Detection by Gallium Scan and Subsequent Treatment by Gallium Maltolate: Rationale and Case Study http://home.earthlink.net/~alixapharm/GAMReferences/BernsteinEtAl2011HCC.pdf

Abstract: Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a non-functional mimic of ferric iron (Fe3+). Because Fe3+ is needed for ribonucleotide reductase activity—and thus DNA synthesis—gallium can inhibit DNA production and cell division. Diagnostic gallium scans have shown that hepatocellular carcinoma (HCC) is commonly avid for gallium. Furthermore, in vitro studies have found that gallium nitrate, and particularly gallium maltolate (GaM), have dose-dependent antiproliferative activity against HCC cell lines. Rationale thus exists to use GaM, an orally active compound that has been well tolerated in Phase I clinical trials, to treat patients whose HCC is gallium-avid in a gallium scan. Because gallium absorbed from orally administered GaM is bound predominately to serum transferrin, which travels to all tissues in the body, GaM has the potential to treat even distant metastases. A patient with advanced HCC (20  10 cm primary tumor, ascites around liver and spleen, resistant to sorafenib (Nexavar® )), whose cancer was highly gallium-avid in a 67Ga-scan, was treated with oral gallium maltolate at 1500 mg/day q.d. After four weeks of treatment, the patient had a large reduction in pain, with greatly increased mobility and quality of life, and significantly lowered serum bilirubin and inflammation-related liver enzymes. At eight weeks, CT scans showed apparent necrosis of the tumor.

Clinical Trial

Safety and Pharmacokinetics of Orally Administered Gallium Maltolate in Various Refractory Malignancies

Gallium maltolate is an orally bioavailable form of gallium. This is a safety, pharmacokinetic and preliminary efficacy study. The primary objective of the study is to assess the safety profile in patients after oral administration of different doses of gallium maltolate for up to six 42-day cycles (28 days of gallium maltolate, followed by 14 days off treatment). In addition, serum concentrations of gallium and associated pharmacokinetic variables will be measured. From this information, an optimal dose will be selected for assessment of anti-tumor efficacy. The study assesses the effects of oral administration of gallium maltolate on pain resulting from bony metastasis, on biochemical measures of bone turnover, and on disease progression and overall survival in patients with various refractory malignancies. Patients may receive up to 6 cycles of the investigational agent. https://clinicaltrials.gov/ct2/show/NCT00050687?term=Gallium+Maltolate&rank=1\

Phase II Gallium Nitrate in Relapsed or Refractory Non-Hodgkin’s Lymphoma

Eligible patients will have low- or intermediate-grade Non-Hodgkin’s Lymphoma (NHL) that has progressed after standard chemotherapy. Patients will receive gallium nitrate 300 mg/m2/day by continuous IV infusion for 7 consecutive days using a portable infusion pump. Hospitalization is not required. Stable or responding patients will receive additional gallium nitrate infusions every 3 weeks until the time of disease progression, for a maximum total of 8 infusions, or 2 cycles after complete remission has been documented. http://www.druglib.com/trial/08/NCT00054808.html

Mechanism

The semimetallic element gallium has repeatedly shown antiproliferative and anti-inflammatory activities in preclinical and clinical studies [1]. These biological activities stem largely from the chemical similarities between Ga3+ and Fe3+ (ferric iron), which allow gallium to enter many of the biochemical pathways of ferric iron. Unlike ferric iron, however, gallium is unable to be reduced to the divalent state under physiologic conditions, and it thus cannot participate in redox reactions. These factors make gallium an irreducible, and therefore non-functional, biochemical mimic of ferric iron. http://home.earthlink.net/~alixapharm/GAM.html

For example, the iron transport protein transferrin can bind to Ga3+, which can then be taken up by rapidly multiplying cells that overexpress transferrin receptor—in particular, many types of cancer cells. Such cells require iron to synthesize DNA, because the enzyme ribonucleotide reductase requires ferric iron in its active site. Gallium, by acting as a non-functional competitive mimic of ferric iron, can act to inhibit DNA synthesis and thus cellular proliferation [1]. http://www.painmed.org/2013posters/poster110.pdf

The potent anti-inflammatory activity of gallium is due in part to its ability to selectively inhibit the activation and multiplication of T-helper type 1 (pro-inflammatory) cells, and also the secretion of proinflammatory cytokines from activated macrophages. Small molecules containing iron tend to be highly pro-inflammatory; it is likely that gallium enters these inflammatory pathways but, due to its lack of redox activity, suppresses inflammation [1]. http://www.painmed.org/2013posters/poster110.pdf

A little on Iron transport: “Iron proteins in breast cancer cells. Under physiologic conditions, iron is bound to transferrin (Tf) in the circulation and is incorporated into cells by transferrin receptor1 (TfR1)-mediated endocytosis of Tf-Fe complexes. The binding site of the wild-type hemochromatosis protein (wt HFE) partially overlaps with the Tf-binding site on TfR1 and can, thus, competitively inhibit Tf binding to its receptor. This regulatory effect of HFE on Tf-Fe-TfR binding is lost with the HFE C282Y mutation, as the latter is degraded within the cell and no longer associates with the TfR to interfere with its binding to Tf-Fe. The Tf-Fe-TfR complex translocates from the cell surface to an intracellular acidic endosome, where Fe(III) dissociates from Tf and is reduced to Fe(II) by STEAP3 (six-membrane epithelial antigen of the prostate 3) (not shown). Fe(II) exits the endosome through divalent metal transporter1 (DMT1, not shown) to a labile iron “pool.” From here, iron trafficks to different compartments (mitochondria, ribonucleotide reductase [RR], and others). Excess iron is stored in ferritin. Iron exits from the cell through cell membrane-based ferroportin. Ferroportin levels can be lowered by hepcidin, which binds to it and translocates it to the lysosome for degradation. Cytoplasmic iron regulatory proteins (IRPs) function as sensors of cellular iron status and regulate the synthesis of Tf receptors, ferritin, and ferroportin at the mRNA translational level by interactions with iron response elements (IREs) present in the untranslated regions of their respective mRNAs. Iron proteins known to be altered in breast cancer are marked with an asterisk (*) and include an increase in TfR and ferritin as well as a reduction in ferroportin levels. In addition, the C282Y HFE mutation may be associated with an increased risk of breast cancer development. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557436/figure/f1/

Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin’s lymphoma, while the thiosemicarbazone Triapine(®) has demonstrated activity against other tumors. http://www.ncbi.nlm.nih.gov/pubmed/22900955

Safety

Orally administered gallium maltolate has been very well tolerated in Phase I clinical trials, even at high repeated doses, with no renal or other dose-limiting toxicity. The absence of renal toxicity is due to the fact that gallium from orally administered gallium maltolate becomes almost entirely protein-bound (which is the low-toxicity and therapeutically efficacious form), whereas gallium from intravenously administered gallium nitrate remains mostly non-protein-bound (the renally toxic and rapidly excreted form). http://home.earthlink.net/~alixapharm/GAM.html

In human cancer clinical trials, GaM has been well tolerated, with no dose-limiting or other serious toxities observed at oral doses of up to 3500 mg/day for repeated 28-day cycles [2]. In these trials of oral GaM, dramatic pain reduction has often been noted, though it has not been clear if this was strictly an analgesic effect or was primarily related to GaM’s anticancer activities http://www.painmed.org/2013posters/poster110.pdf

Although not specifically reported, I believe that the risk is potentially induced anemia so I would have an eye on that during the Gallium administration: Evidence that gallium actually produces cellular iron deficiency in vivo was presented in clinical studies that showed that red blood cells from patients receiving gallium nitrate contained increased levels of zinc protoporhyrin, a marker of iron deficiency [75], and that anemia in patients being treated with gallium chloride may be due to gallium-induced iron deficiency [76]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574811/

Pharmacokinetics

Gallium maltolate, tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium (GaM), is an orally active gallium compound for therapeutic use. It is moderately soluble in water (10.7+0.9 mg/mL at 25C) with an octanol partition coefficient of 0.41+0.08. The molecule is electrically neutral in aqueous solution at neutral pH; a dilute aqueous solution (2.5×10 – M) showed little dissociation at pH 5.5-8.0. Single crystal X-ray diffraction analysis found the GaM molecule to consist of three maltolate ligands bidentately bound to a central gallium atom in a propeller-like arrangement, with one of the ligands disordered in two possible orientations. The compound is orthorhombic, space group Pbca, unit cell a 16.675(3), b 12.034(2), c 18.435(2) A at 158K. GaM was administered to healthy human volunteers at single doses of 100, 200, 300, and 500 mg (three subjects per dose). GaM was very well tolerated. Oral absorption of Ga into plasma was fairly rapid (absorption half life 0.8-2.0h), with a central compartment excretion half life of 17-21h. Absorption appeared dose proportional over the dosage range studied. Estimated oral gallium bioavailability was approximately 25-57%, based on comparison with published data on intravenous gallium nitrate. Urinary Ga excretion following oral GaM administration was approximately 2% of the administered dose over 72h, in contrast to 49-94% urinary Ga excretion over 24h following i.v. gallium nitrate administration. We suggest that oral administration of GaM results in nearly all plasma gallium being bound to transferrin, whereas i.v. administration of gallium nitrate results in formation of considerable plasma gallate [Ga(OH)4-], which is rapidly excreted in the urine. These data support the continued investigation of GaM as an orally active therapeutic gallium compound.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2365198/pdf/MBD-07-033.pdf

Preparation and administration

During gallium administration, for an increase effectiveness of the treatment, avoid iron-rich foods and any supplement that contains iron. Also avoid Iron chellation.

1.5 grams taken one hour before breakfast. During the first administration days, a higher dose (3g/day) can be administrated.

Note that 3.5g/day are not showing any form of toxicity based on phase one clinical trial: http://www.painmed.org/2013posters/poster110.pdf

(From the case report: Treatment of the patient was started a week after the gallium scans were performed. GaM was administered at a dose of 1500 mg per day, taken before breakfast, in two gelatin capsules each containing 750 mg GaM with no excipients. Four weeks after the start of GaM treatment, assays of liver condition showed improvement: serum bilirubin (total) dropped from 27.5 to 13.7 μmol/L (normal: 2-20 μmol/L) (Fig. 4) and serum alanine aminotransferase (ALT) dropped from 47 to 22 IU/L (normal: 0-45 IU/L) (Fig. 5). The patient reported that her right abdominal pain was nearly gone, and she could lie and sleep on her right side. http://home.earthlink.net/~alixapharm/GAMReferences/BernsteinEtAl2011HCC.pdf)

Source

There are various forms of Gallium, such as Gallium nitrate (brand name Ganite) which is a drug used to treat symptomatic hypercalcemia secondary to cancer. However, this has to be administrated IV and may lead to some side effects and it is not the preferred Gallium version https://en.wikipedia.org/wiki/Gallium_nitrate

The preferred Gallium version is Gallium maltolate (GaM). This is a water soluble form of Gallium that can be administrated orally with no toxicity according to the above references.

Topical gallium maltolate (Gallixa®) http://www.gallixa.com/BuyGallixa.html

Gallium maltolate powder http://www.nanomanindustries.com/store/p2/Gallium_Maltolate.html

Synergy and Antagonism

Avoid Iron chelators, possibly even Artemisinin and Baicalein.

Gallium compounds can synergistically increase the cytotoxicity of hydroxyurea, fludarabine, IFN-α, gemcitabine, bortezomib, paclitaxel and cisplatin http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574811/

References

Iron-targeting antitumor activity of gallium compounds and novel insights into triapine(®)-metal complexes http://www.ncbi.nlm.nih.gov/pubmed/22900955

SIGNIFICANCE: Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents.

RECENT ADVANCES: Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin’s lymphoma, while the thiosemicarbazone Triapine(®) has demonstrated activity against other tumors.

CRITICAL ISSUES: Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed.

FUTURE DIRECTIONS: The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it.

Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma http://www.ncbi.nlm.nih.gov/pubmed/16827101

BACKGROUND: Hepatocellular carcinoma (HCC) is a particularly lethal cancer with few treatment options. Since gallium is known to accumulate specifically in HCC tumors but not in non-tumor liver, we investigated two gallium compounds, gallium nitrate (GaN) and gallium maltolate (GaM), as potential new agents for treating HCC.

MATERIALS AND METHODS: The anti-proliferative and apoptotic activities of GaN and GaM were assessed in vitro using four HCC cell lines. HCC gene expression data was analyzed to provide a mechanistic rationale for using gallium in the treatment of HCC.

RESULTS: Both compounds showed dose-dependent antiproliferative activity in all four HCC cell lines after 6-day drug exposure (IC50 values range from 60-250 microM for gallium nitrate and 25-35 microM for gallium maltolate). Gallium maltolate at 30 microM additionally induced apoptosis after 6 days. HCC gene expression data showed significantly elevated expression of the M2 subunit of ribonucleotide reductase, which is a target for the antiproliferative activity of gallium.

CONCLUSION: These data support clinical testing of gallium maltolate, an orally active compound, in the treatment of HCC.

Gallium-containing anticancer compounds http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574811/

There is an ever pressing need to develop new drugs for the treatment of cancer. Gallium nitrate, a group IIIa metal salt, inhibits the proliferation of tumor cells in vitro and in vivo and has shown activity against non-Hodgkin’s lymphoma and bladder cancer in clinical trials. Gallium can function as an iron mimetic and perturb iron-dependent proliferation and other iron-related processes in tumor cells. Gallium nitrate lacks crossresistance with conventional chemotherapeutic drugs and is not myelosuppressive; it can be used when other drugs have failed or when the blood count is low. Given the therapeutic potential of gallium, newer generations of gallium compounds are now in various phases of preclinical and clinical development. These compounds hold the promise of greater anti-tumor activity against a broader spectrum of cancers. The development of gallium compounds for cancer treatment and their mechanisms of action will be discussed.
Article was written by http://www1.mcw.edu/Hematology-Oncology/faculty/Christopher-Chitambar-MD-FACP.htm

Repurposing of galliumbased drugs for antibacterial therapy http://www.researchgate.net/profile/Francesco_Imperi/publication/260212220_Repurposing_of_gallium-based_drugs_for_antibacterial_therapy/links/0f317534cdbac2f47d000000.pdf

Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391038/

Bacterial infection remains one of the leading causes of death worldwide, and the options for treating such infections are decreasing, due the rise of antibiotic-resistant bacteria. The pharmaceutical industry has produced few new types of antibiotics in more than a decade. Researchers are taking several approaches toward developing new classes of antibiotics, including (1) focusing on new targets and processes, such as bacterial cell–cell communication that upregulates virulence; (2) designing inhibitors of bacterial resistance, such as blockers of multidrug efflux pumps; and (3) using alternative antimicrobials such as bacteriophages. In addition, the strategy of finding new uses for existing drugs is beginning to produce results: antibacterial properties have been discovered for existing anticancer, antifungal, anthelmintic, and anti-inflammatory drugs. In this review, we discuss the antimicrobial properties of gallium compounds, 5-fluorouracil, ciclopirox, diflunisal, and some other FDA-approved drugs and argue that their repurposing for the treatment of bacterial infections, including those that are multidrug resistant, is a feasible strategy.

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This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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