Platinum-based drugs (in particular
cisplatin and oxaliplatin) have marked cancer
chemotherapy for the last 40 years. Beside their
indisputable activity, these drugs share with
almost any other chemotherapy drug a significant
host toxicity and the possibility to induce
resistance in cancer cells. These two aspects
have been and still are the main targets for
the development of new platinum-based drugs
capable of replacing cisplatin and its analogues
with new compounds more active and capable of
circumventing tumour resistance and/or exibiting
a lower toxicity.
The current approaches, in the preclinical development
of new platinum-based drugs, pursue theese targets:
| i) |
circumvent resistance; |
| ii) |
to include activity on refractary tumours; |
| iii) |
to improve pharmacokinetics, particularly
in orally administrable drugs.
|
These goals are pursued with compounds directed
to G-G rich DNA regions (in telomers for example),
or with compounds suitable for activation by small
pH differences (usually lower in solid tumour
masses) or by intracellular components such as
the GSH-GSSG system (anyhow invariably directed
to guanines of cellular DNA).
The evaluation of the status of the art in EU,
in which the COST D20 (2000-2006) project is specifically
oriented on “Metal Compounds in the Treatment
of Cancer and Viral Diseases” and, more generally,
in the world, as results from the recent Symposium
on Platinum Compounds in Cancer Chemotherapy,
held at NY, USA, on October 2003, gives us a picture
with few differences: mainly, it appears that
in EU there is a slightly more interest
| i) |
to study also compounds with
metals different from platinum; |
| ii) |
to include more “imaginative” structures
and |
iii) |
to evaluate some pharmacological besides
the usual chemotherapy mechanism.
|
|
WHAT
IS A POSSIBLE FUTURE? |
Although, there is an apparently
general refractoriness of the “platinum
club” to study compounds active on targets
different from DNA bases, it is time to capitalize
the enormous knowledge on metal compounds in
the context of the significant advancements
on the biology of tumour cells.
Germane to this subject, for example, is the
possibility to study “metals”:
| 1) |
targeted to cytoskeleton molecules,
including adhesion cell membrane and extracellular
matrix components; |
| 2) |
controlling the pro-angiogenic activities
of cancer cells; |
| 3) |
active on signalling pathways regulating
molecules; |
| 4) |
or on caspase activation in caspase-deficient
cells; |
| 5) |
or even on metastatic cells or on single
tumour cell phenotypes.
|
LINFA, with the activation of the project
MADE
(MetAl
compounDs
in the postgenomic Era),
forces the idea that these compounds may change
the actual view of cancer treatment: from
“cytotoxic, irreversibly active”, chemotherapics
to “pharmacologically active” drugs.
The goal is to obtain compounds
| i) |
active at the physiological
regulation of cell behaviour with loss of
the “malignant” phenotype, |
| ii) |
endowed with selective recognition of
cancer cells (reduced or null side-effects),
that will allow |
| iii) |
the individual tumour type treatment.
|
This strategy can be pursued:
| a) |
giving chemists a number of
“biological labs” with expertise
in cell biology and cancer growth; |
| b) |
supporting the use of “metals”
that do not necessarily show strong DNA-interaction; |
| c) |
selecting “biological tests”
predictive of activity on malignant cells; |
| d) |
including contacts with “Pharma Co”
to allow rising of patents; |
| e) |
studying “surrogate” endpoints
to ascertain drug efficacy.
|
LINFA
and MADE
choose Ruthenium and offer full collaboration
to those who will share this challenge.
LINFA
and MADE
will stimulate joint research programs on Ruthenium-based
compounds targeted to cell cycle, signalling
transduction and adhesion molecules. The research
programs will extend the knowledge on the pharmacological
effects of “sulfoxide-rutheniums” to
other compounds and will lead training courses
for young scientists in conjunction with major
institutions in EU.
On-line
resources of related articles
Hits
on anticancer metall-based compound discovery |
