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LeadDiscovery Reports
siRNA blocking CXCR4 expression limits metastasis
RNA interference (RNAi), a
cellular mechanism in which double-stranded RNA triggers the silencing of the
corresponding cellular gene, has become a powerful tool for studying gene
function. Early studies depended on the exogenous administration of siRNA
which presents significant problems relating to drug delivery pharmacokinetics
and other issues. Since it has become possible to use DNA templates to express
siRNA endogenously the therapeutic potential of this technology has increased
considerably. For a full analysis of the therapeutic and commercial potential
of siRNA technology click here.
CXCR4 and its ligand SDF-1 (CXCL12) play pleiotropic roles in angiogenesis,
host immune response, homing and tumor metastasis. Recent data suggests that
chemokines and chemokine receptors might be involved in tissue preferential
metastasis of cancers. Considering the biological activity of CXCR4,
inhibiting its expression may be of considerable benefit in the treatment of
cancer. Further proof of concept is found in studies reporting that CXCR4
expression is significantly up-regulated in highly invasive human breast
cancer cells, and that organs to which breast cancer cells metastasize express
high levels of SDF-1. Most recently, and as highlighted in a recent edition of
our tracking service DailyUpdates, peptidic CXCR4 antagonists effectively
inhibited SDF-1-induced migration of human breast cancer cells. Furthermore,
slow release administration by subcutaneous injection reduced pulmonary
metastasis of breast cancer cells (Tamamura et al, 2003).
In their recent Cancer Research article, Chen et al target CXCR4 through siRNA
technology. This group first advanced this technology in general by designing
a vector in which gene expression could be induced, in this case by
doxycycline. Induction of siRNA targeted against CXCR4 expression in
metastatic MDA-MB-231 breast cancer cells prevented their migration towards
SDF-1 in an in vitro system. This study therefore not only shows that it is
possible to transfect cells with vectors that express siRNA in a controlled
fashion, but also confirms that CXCR4 represents a therapeutic target.
Extension of this technology could allow the specific and prolonged expression
of siRNA targeted against CXCR4 in the tumor environment, therefore
potentially a highly specific therapeutic strategy. On a broader basis, the
ability to inducible siRNA expression should improve this technology as both a
research and a therapeutic tool.
Entry date Wednesday, September 17, 2003
Adapted from Chen et al, Cancer Res. 2003 Aug 15;63(16):4801-4
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