The
development of ruthenium anticancer drugs
Two Pt(II)
compounds, commercially known as cisplatin and carboplatin (Figure 1),
developed in the early seventies, are currently the most widely used
anticancer agents. Today there is hardly any clinical regimen of
combination
chemotherapy that does not contain either cisplatin
or carboplatin.
Notwithstanding the
widespread applications of platinum anticancer drugs, there is still a
large
need for the development of novel metal-based compounds with
unprecedented
features.
The search for “non-classical” metal
antitumor drugs has since long stimulated investigations into the field
of non-platinum metal drugs. Non-platinum
active compounds are likely to have mechanism of action,
biodistribution and
toxicity which are different from those of platinum drugs and might
therefore
be active against human malignancies that are resistant, or have
acquired
resistance, to them. They might also show a reduced host toxicity.
Ruthenium
seems to be the most promising among the several metals investigated.
Since many
years our group has actively worked in the
field of inorganic antitumor drugs and has developed several Ru(II) and
Ru(III)
complexes with coordinated dimethylsulfoxide (dmso), which were shown
to
possess good antitumor and, above all, antimetastatic properties
against animal
models. Among these compounds a Ru(III) complex named NAMI-A,
[ImH][trans-RuCl4(dmso-S)(Im)]
(Im = imidazole) (Figure 2),
was selected because of its very good antimetastatic activity and on
October
1999 it was introduced into phase I clinical trials at the Netherland
Cancer
Institute of Amsterdam (NL). NAMI-A
(Figure 3) is one of the
very few non-platinum antitumor drugs, and the first ruthenium-based
compound,
to reach clinical phase trials.
Phase I
clinical trials have been completed in fall
2002 and we expect to start phase II trials soon.
It is important to stress that metastases of solid tumors represent the main reason of failure in cancer therapy. In fact, while surgery and/or radiotherapy may successfully cure the primary lesions, many human tumors develop distant metastases that bring almost invariably to death. Because of the scattered location of metastases, drug therapy appears to be the best choice and, from the therapeutic standpoint, the development of new compounds endowed with a specific antimetastatic activity is a topic of paramount importance.
We recently developed
new dimeric Ru(III) compounds of formula Na2[{trans-RuCl4(dmso-S)}2(m-L)], in
which L = heterocyclic bridging N-ligand (Figure
4). In such dimers, the coordinative environment of
each Ru(III) nucleus is very similar to that of NAMI-A.
The chemical behavior of the new Ru(III) dimers in
physiological solution was also investigated; preliminary in vivo
results
showed that some of them have an antimetastatic activity comparable to
that of NAMI-A at dosages that are 3.5 times
lower in terms of moles of Ru.
The interactions of the
active Ru complexes with their
likely biological targets, i.e. DNA and proteins (in particular
transferrin and
albumin) were investigated in collaboration with other groups. In
general, Ru(III) complexes bind DNA but
much more weakly than platinum complexes. Thus the structural and
conformational modifications produced on the DNA double helix are
significantly
smaller. Under physiological conditions, antitumor Ru(III) complexes
bind
tightly plasma proteins (albumin and transferrin), with a marked
preference for
surface imidazole groups; thus, very likely, protein binding of
ruthenium(III)
complexes has a large impact on the biodistribution, the
pharmacokinetics and
the mechanism of action of these experimental drugs.
In vitro and in
vivo pharmacological experiments have shown that NAMI-A
and other active ruthenium compounds are scarcely cytotoxic,
suggesting that their mechanism of action is very likely different from
that of
platinum drugs and might be unrelated to interactions with DNA. One
possibility
for explaining the activity of NAMI-A against disseminated tumors is
that it
interferes with NO methabolism in vivo. Nitric oxide is known to play
an
important role in many biological functions, and recently it was
demonstrated
to be involved as mediator in one tumor-induced angiogenic process,
which is a
key step in the formation of metastases. NO is also known to interact
in vivo
with iron proteins, thus ruthenium action might also occurr through an
iron-mimicking mechanism.
Within this general framework
we investigated the reactivity of basic Ru(II)- and
Ru(III)-chloride-dmso
complexes and of NAMI-A towards NO with the goal of producing
spectroscopically
and structurally well characterized models. These will be used as
reference
compounds in subsequent biomimetic studies in physiological conditions.
A
summary of our results in this field (refs 22, 23), including the
reactivity of
some of the new Ru-dmso nitrosyls towards heterocyclic nitrogen ligands
(N) is
reported in Figure 5. The spectroscopic and
X-ray
structural features for all the new complexes are consistent with the
{Ru(NO)}6
formulation, that is a diamagnetic Ru(II) nucleus bound to NO+.
Electrochemical measurements on the Ru-NO complexes showed that they
are all
redox active in DMF solutions and the site of reduction is the NO+
moiety. The reduced complexes are not stable and rapidly release the NO· radical.
Moreover,
spectroscopic studies indicated that in
physiological conditions the active Ru(III) compounds, both monomers
and
dimers, are easily and quantitatively reduced to Ru(II) species by
stoichiometric amounts of biological reducing agents, such as ascorbic
acid,
cysteine and glutathion. This important feature suggests that NAMI-A and the Ru(III)-dmso compounds
might indeed be reduced also in vivo to generate Ru(II) active species.
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A. Sessanta o Santi, S. Geremia,
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Schettino, M. Coluccia
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G. Mestroni, S. Geremia, M. Calligaris, E. Alessio
«Novel Ru(III) dimers [Na]2{[trans-RuCl4(Me2SO-S)]2(m-L)} and {[mer,cis-RuCl3(Me2SO-S)(Me2SO-O)]2(m-L)} (L =
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G. Sava, R. Gagliardi, A. Bergamo, E. Alessio, G. Mestroni
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E. Iengo, S. Zorzet, A. Bergamo, M. Coluccia, A. Boccarelli,
G. Sava «Antimetastatic properties
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Marzilli «Understanding Orientation
and
Dynamic Motion of Planar Heterocyclic N-Donor Ligands by Exploiting the
Symmetry Properties of Mixed-Ligand m-oxo Rhenium(V)
Dimers [ReOCl2(L)(L')]-O-[ReOCl2(L)(L')]:
a Combined X-ray Structural and Dynamic NMR Investigation.» Inorg.
Chem. 2000, 39, 294-303.
14) L. Messori,
P. Orioli, D. Vullo, E. Alessio, E. Iengo «A
spectroscopic study of the reaction of
NAMI, a novel ruthenium(III) anti-neoplastic complex, with bovine serum
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E. Alessio, F. Gonzalez-Vilchez, R.
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Salerno, E. Alessio, G. Mestroni, G. Sava
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Cocchietto, A. Sorc, B.
Gava, E. Alessio, E. Iengo, G. Sava
«Lack of in vitro cytotoxicity, associated to increased
G2-M cell
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