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