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Protocols for
combining "Taxotere" with antisense agents inhibiting bc12 and cluster in
gene expression. (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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