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Cell Survival Genes, bcl2 & clusterin.
"Two molecules to get to know." Discussion of antisense technology.
(January 2003)
An important goal of current research in targeted therapy
is prolonging the duration of disease control produced by anti-androgen
therapy; i.e. preventing the progression of PC to independence from
androgen suppression. An associated goal is increasing PC sensitivity to
cell death inflicted by irradiation and chemotherapy. The cellular
proteins, Bcl2 and clusterin, are two important products of PC gene
expression that are anti-apoptotic, that is, they function to prevent cell
death that results from senescence and injury from irradiation and
chemotherapy. These are cell survival proteins. New research coming from
the work of Dr. Martin Gleave and his colleagues at the Vancouver, BC,
Prostate Center highlights the significant increase in the PC cell's
production of these proteins as a consequence of androgen deprivation.
Immunohistochemistry studies show that cellular content of clusterin, for
example, increases by 10X shortly after castration, and by 17X within 4
weeks after androgen withdrawal. Prostatectomy specimens showed that
clusterin was highly expressed in 80% of prostate cancer cells after
neoadjuvant hormone therapy, but was only in <20% of untreated specimens.
Bcl2 follows the same pattern of increase described for clusterin.
Antisense oligonucleotides (ASOs) are an emerging type of therapy that
target specific messenger RNA's for destruction, thereby preventing gene
expression. An ASO is a short stretch of synthetic DNA that is designed as
a type of "mirror image" to a selected stretch of messenger RNA (mRNA),
which instructs the cellular production of protein. ASOs have been
designed to silence the production of clusterin and Bcl2. ASOs diffuse
into cells and can bond ("hybridize") with their counterpart stretches of
mRNA and cancel the expression of that specific protein. (This is
appropriately termed Watson-Crick base pairing) Dr. Gleave et.al. and
other institutions have clearly shown that ASOs directed against clusterin
and Bcl2 significantly decrease the production of these cell survival
proteins in PC cells. In one study clusterin expression was decreased by
70% by an ASO, tumor regression occurred faster, and there was a delay in
recurrence of androgen insensitive PC cells. Other studies showed the ASOs
against Bcl2 increased effectiveness of Adriamycin, those against
clusterin increased cell sensitivity to Taxanes, and both increased cell
kill from irradiation. "Genasense" is a commercial ASO against Bcl2 and is
in early trials. Phase I and II studies for clusterin ASO are in progress
in Vancouver, BC. Initially, the ASOs will most likely be used in studies
combining them with conventional chemotherapy.
Bottom Line: ASO targeted therapy holds promise as a new approach
to PC treatment with potentially greater specificity and fewer side
effects
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