STRATEGY TO REDUCE SIDE EFFECTS IN MODERN CANCER THERAPY
The occurrence of
severe side effects and the development of resistance are two of the biggest
problems facing modern cancer therapy. Even the latest, highly targeted cancer
drugs such as the tyrosine kinase inhibitors Tarceva(R) or Sutent(R) are
affected by these problems, which can ultimately lead to treatment having to be
stopped. The effect of this class of inhibitors is based on the specific
inhibition of proteins that are over-activated in cancer cells and which drive
abnormal cell growth. However, clinical practice has shown that, as a result of
the physiological functions of these proteins in healthy tissue, their
inhibition can cause severe side effects. As a result, there is an acute need
for strategies to restrict the effect of these highly promising new drugs more
selectively to the malignant tumour
The aim of the
research was to develop an improved tyrosine kinase inhibitor that is actually
inactive and which is only activated selectively in the malignant tissue. This
is intended to prevent damage to healthy tissue and therefore minimise side
effects for patients. As part of the paper published in the journal Angewandte
Chemie [Applied Chemistry], International
Edition, a new inhibitor has been successfully synthesised and
coordinated to cobalt(III). This leads to initial drug inactivation and, thus,
no activity under normal physiological conditions. Only in tumour tissue where,
due to the rapid growth, unusually low-oxygen conditions prevail, the inactive
cobalt(III) compound is reduced to cobalt(II) and as a result releases the
active drug. The tumour-selective effectiveness of this approach has been
demonstrated both in living cells and in tumor-bearing organisms.
The development of
this complex idea and strategy was made possible by the outstanding
interdisciplinary collaboration organised in the context of the
"Translational Cancer Therapy Research" platform led by Bernhard
Keppler, Dean of the Faculty of Chemistry at the University of Vienna, and
Walter Berger, Professor at the Medical University of Vienna. This research
platform promotes constant scientific exchange between synthetic chemists at
the University of Vienna and cancer researchers at the Medical University of
Vienna. It is only through these opportunities that the team of university assistants
Christian Kowol (University of Vienna) and Petra Heffeter (Medical University
of Vienna) has been able, based on two diploma theses (by Claudia
Karnthaler-Benbakka, MSc., and Diana Groza, MSc.), to produce these results.
The study was funded by the City of Vienna fund for "innovative
interdisciplinary cancer research," the Austrian Science Fund (FWF) and
COST CM1105. In view of the highly promising results, the new combination class
has been patented by the two universities and currently a partner for further
(clinical) development is searched.
So far there has
been no comparable strategy for reducing the (severe) side effects of tyrosine
kinase inhibitors. As a result, there is hope that, in future, the approach
presented here will improve the tolerance of the therapy and allow this
treatment to benefit patients who have previously had to discontinue it.
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