Biomedical Engineering Reference
In-Depth Information
FIGURE 10.13
A Ru containing anticancer drug, KP1019. Ruthenium (green) is coordinated to two indazole
molecules and four chloride ions (orange).
It should be noted that most platinum containing agents bind to proteins rather than DNA and
that the degree of platinum cytotoxicity cannot be explained by inhibition of DNA synthesis alone.
Thus, other mechanisms such as direct binding and damage of proteins or other biomolecules may
also be of signii cance in triggering apoptosis or necrosis. Currently, research is focused on the
development of platinum (and ruthenium) anticancer drugs with other targets than DNA and on
combination therapies.
In the last few years, the search for effective anticancer compounds based on other metal centers
than Pt has been intensii ed and particularly anticancer drugs based on ruthenium are making
progress in clinical trials. Two ruthenium-based anticancer drugs, NAMI-A (Imidazolium
trans
-
[tetrachloro(DMSO)(imidazole)ruthenate(III)] and KP1019 (Indazolium
trans
-[tetrachlorobis
(1H-indazole)ruthenate-(III); cf. Figure 10.13], are scheduled to enter phase 2 trials in the near future.
Both NAMI-A and KP1019 are prodrugs that have Ru present in the +3 oxidation state and
are activated by reduction. The “activation by reduction” mechanism may contribute to the lower
toxicity of Ru(III) compounds compared with Pt-based anticancer compounds. However, the
lower toxicity may also be due to its ability to mimic iron in the binding to biological molecules
such as albumin and transferrin. Binding of ruthenium to transferrin allows for effective uptake of
Ru-based drugs into cancer cells, as transferrin receptors are generally overexpressed in rapidly
dividing cells.
The i rst Ru-based a nt ica ncer d r ugs were desig ned to t a rget DNA, si m ila rly to cisplat i n. However,
NAMI-A and KP1019 belong to a newer generation of Ru-based drugs that do not target primary
tumors and DNA, but instead target metastases cells and proteins. A recent approach is design of
Ru-drugs with multiple modes of activity by combining Ru with an active targeted ligand. Some
examples are the Ru-SERMs complexes (selective estrogen receptor modulators) that target
both hormone-dependent and -independent breast tumors and RAPTA complexes designed to
inhibit Glutathione-
S
-Transferases (GST), a cytosolic detoxii cation enzyme associated with drug
resistance.
10.6.5 C
OPPER
, S
ILVER
,
AND
G
OLD
Copper and iron constitute the most important redox active transition metals in bioinorganic
chemistry, and they seem to complement each other. Both copper and iron proteins are involved in
oxygen transport and charge transfer. But while the iron containing proteins and enzymes always
are found intracellularly, copper proteins and enzymes mainly operate outside the cells.
In humans most copper is found in the brain, the heart, and the liver. The high metabolic rate of
these organs requires relative large concentrations of copper containing enzymes, some of which
