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Chapter: Essentials of Inorganic Chemistry : The Boron Group - Group 13

Introduction, Chemistry, Pharmacology of gallium-based drugs, Gallium nitrate – multivalent use, Gallium 8-quinolinolate, Gallium maltolate, Toxicity and administration




Gallium has atomic number 31 in the periodic table of elements. It has a silvery-white colour with a melting point of only 29 C, which means that it melts when held in the hand. It has no known physiological role in the human body, but it can interact with cellular processes and proteins that are normally involved in iron metabolism.

Gallium tartrate has a long research history. Researchers showed in the 1930s that it could be used to treat syphilis in rabbits with no significant toxicity [6a]. In subsequent studies, it has been shown that gal-lium ions predominantly accumulate in the bone and therefore would be a good candidate for radiotherapy of bone cancer. Unfortunately, the radioactive isotope 72Ga has only a half-life of around 14 h, which is not long enough for effective radiotherapy. Nevertheless, current clinical developments involve the use of radioactive gallium isotopes as tumour imaging reagents (see Chapter 10), gallium nitrate in metabolic bone disease, hypercalcaemia and as anticancer drug, as well as up-to-date research in the area of chemotherapeutic applications.



Gallium exists as the trivalent cation Ga3+, and in aqueous solution it presents as a hydrated complex. Depend-ing on the pH, a variety of hydroxyl species are formed, some of which are insoluble, such as Ga(OH)3. At physiological pH, nearly no free Ga3+ is present and the hydroxyl species Ga(OH4) (gallate, the domi-nant species) and Ga(OH)3 are formed. Gallium hydroxide species are amphoteric, analogous to aluminium hydroxide compounds.

It is important to note that the stability of solutions containing gallium chloride or gallium nitrate for oral administration is affected by the pH. They might not be stable over extended periods and gallium hydroxide precipitates.


Pharmacology of gallium-based drugs

Ga3+ has an ionic radius and binding properties similar to those of Fe3+ (ferric iron). Unlike Fe3+, it cannot be reduced to its divalent state, which means that it follows a completely different redox chemistry compared to iron. The oxidation and reduction of iron is important in many biological processes, which therefore cannot be mimicked by gallium. One example includes the uptake of Fe2+ by the haeme group (see Chapter 8). As Ga3+ is not readily reduced to it +II state, it cannot bind to the haeme group.

Transferrin is an important transport protein that controls the level of free Fe2+ in the blood plasma. Free iron ions are toxic to most forms of life, and therefore transferrin binds Fe2+ and removes it from the blood. There is an excess of transferrin present in the blood, and it has been shown that Ga3+ can also bind to this glycoprotein but with a lower affinity than Fe3+. Once the binding capacity of gallium ions to transferrin is exceeded, it is believed to circulate as gallate [Ga(OH)4−] [6a].

The therapeutic action of Ga3+ is very much based on the pharmacological activity of Fe3+ which it mainly mimics. Ga3+ is transported via transferrin to areas of the body that require increased Fe3+ levels, including proliferating cancer cells . Ga3+ can interrupt the cell cycle and DNA synthesis by competing with iron for the active sites in essential enzymes . Ga3+ accumulates in the endosomes mediated by transferrin uptake and transported into the cytosol, where it can bind to the enzyme ribonucleotide reductase. Ribonucleotide reductase has been proposed as the main target for Ga3+. Binding to this enzyme will impair DNA replication and ultimately lead to apoptosis . In vitro studies have shown that Ga3+ can bind directly to DNA .


Gallium nitrate – multivalent use

In clinical trials, gallium nitrate has proved to be highly active as an antitumour agent especially against non-Hodgkin’s lymphoma and bladder cancer. The cytotoxic activity of gallium nitrate has been demonstrated as single agent and as part of combination therapy, for example, together with fluorouracil. Gallium nitrate shows a relatively low toxicity and does not produce myelosuppression, which is a significant advantage over other traditional anticancer agents. Furthermore, it does not appear to show any cross-resistance with conventional chemotherapeutic agents (Figure 4.8) .

These studies have also shown that gallium nitrate is able to decrease serum calcium levels in patients with tumour-induced hypercalcaemia. Subsequently, several studies have been carried out comparing traditional bisphosphonate drugs with gallium nitrate in their ability to decrease the calcium levels that are elevated as a result of cancer. Based on the clinical efficacy, gallium nitrate injections (Ganite™) was granted approval by the FDA for the treatment of cancer-associated hypercalcaemia. Gallium nitrate is also believed to inhibit the bone turnover and therefore to decrease osteolysis, the active reabsorption of bone material, in patients with bone metastasis secondary to other cancers.


Gallium 8-quinolinolate

Gallium 8-quinolinolate is a hexacoordinated Ga3+ complex in which the central gallium atom is coordinated by three quinolinolate groups. It was developed as an orally available anticancer agent. It was successfully tested in vitro against lung cancer and in transplanted rats against Walker carcinosarcoma . Main side effects were detected in experiments on mice at doses of 125 mg/kg/day. These included leukopaenia and some fatalities. The highest concentrations Ga3+ were found in the bone, liver and spleen (Figure 4.9) [6a].

Preclinical studies have established the IC50 values for a single-agent activity in the lower micromolar range for a variety of cancer cell lines. These cell lines include human lung adenocarcinoma, where gal-lium 8-quinolinolate was shown to be 10 times more potent than gallium nitrate. Other cell lines include melanoma and ovarian, colon and breast cancer. The inhibitory effect appears to be dose dependent and not time dependent.

Gallium 8-quinolinolate entered phase I clinical trials under the drug name KP46 in 2004 in order to estab-lish its safety and toxicity profile. KP46 was orally administered as a tablet, containing 10–30%w/w. Dose up to 480 mg/m2 were given to patients with advanced solid malignant tumours. The drug was well tolerated and preliminary success was seen in patients with renal cell cancer.


Gallium maltolate

Gallium maltolate [tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III)] is a coordination complex con-taining a central Ga3+ ion and three maltolate (deprotonated maltol) groups. Clinical studies have shown that oral administration of gallium maltolate leads to significantly increased bioavailability compared to gal-lium chloride. The oral bioavailability is estimated to 25–57% in comparison to 2% for gallium chloride (Figure 4.10) .

Phase I clinical trials on healthy humans showed that doses were well tolerated up to 500 mg. Further-more, the results suggested the possibility of a once-per-day treatment option as a result of the half-life of the drug in the blood plasma (17–21 h). Orally administered gallium maltolate is excreted significantly more slowly via the kidneys than gallium nitrate injected intravenously. It has been proposed that rapid intra-venous administration leads to the formation of gallate, which is quickly cleared as a small molecule via the kidneys. In contrast, oral administration leads to a slow loading of the blood plasma, and Ga3+ is bound to transferrin. 

This may lead to a different mechanism of excretion, leading to a reduction in renal toxicity. Also, the transferrin-bound Ga3+ has the potential to be directly transported to the cancer cell without causing sig-nificant side effects. Therefore, an oral administration seems to be superior to parenteral administration .


Toxicity and administration

Gallium nitrate is usually administered as a continuous intravenous infusion (200 mg/m2 for 5 days) for the treatment of cancer-induced hypercalcaemia. This dose is well tolerated even by elderly patients. Higher doses are usually used in the treatment of cancer. Renal toxicities being the dose-limiting factor are normally seen when gallium nitrate is administered as a brief intravenous infusion. With the long-term regime as described above, diarrhoea is the most common side effect. Renal toxicity can normally be minimised by adequate hydration of the patient .

The advantage of gallium nitrate therapies is that platelet count and white blood cell counts are not sup-pressed, which means that no myelosuppression takes place, which represents a major advantage over con-ventional chemotherapeutic agents .

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