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Vol. 60, Issue 6, 1296-1307, December 2001
(Isis 3521) and Antisense bcl-2 (G3139)
Phosphorothioate Oligodeoxynucleotides: Relationship to the Decreased
Viability of T24 Bladder and PC3 Prostate Cancer Cells
Departments of Medicine (L.B., S.B., A.L.H., C.A.S.) and
Pharmacology (C.A.S.), Columbia University, New York, New York;
Department of Biochemistry and School of Hygiene and Public Health
(P.M.), Johns Hopkins University, Baltimore, Maryland;
Department of Bioorganic Chemistry (A.M., P.G.), Centre of Molecular
and Macromolecular Studies, Polish Academy of Sciences, Lodz, Poland;
and Division of Therapeutic Proteins (S.L.B., A.W., A.G.), Food and
Drug Administration, Bethesda, Maryland
Isis 3521 and G3139 are 20- and 18-mer phosphorothioate
oligonucleotides, respectively, targeted to the protein kinase C
(PKC)-
and bcl-2 mRNAs. Treatment of T24 bladder and PC3
prostate carcinoma cells with full-length and 3'-truncation mutants of
Isis 3521 causes down-regulation of PKC- protein and mRNA. However,
at the level of a 15-mer and shorter, down-regulation of mRNA
expression is no longer observed. Further, no diminution in cellular
viability, as measured by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl
tetrazolium bromide assay, in response to increasing concentrations of
paclitaxel, can be observed for these shorter oligomers. These
observations not only indicate that PKC- protein expression can be
down-regulated by both RNase H-dependent and -independent mechanisms
but also that down-regulation of PKC- is insufficient by itself to
"chemosensitize" cells. G3139, which down-regulates bcl-2 protein
and mRNA expression, also down-regulates PKC- protein and mRNA
expression but not that of PKC-
I, -
, or -
. However, the
down-regulation of PKC- and bcl-2 are not linked. When the carrier
Eufectin 5 is employed, only bcl-2 is down-regulated in both T24 and
PC3 cells at 50 nM oligonucleotide concentration. At 100 nM, both bcl-2
and PKC- expression are down-regulated, and only at this
concentration can "chemosensitization" to paclitaxel and
carboplatin be observed. In contrast, the down-regulation of bcl-2
seems to be linked with that of RelA (p65). However, this too is also
not sufficient for chemosensitization, even though it leads to the loss
of expression of genes under the putative control of nuclear
factor-
B and to detachment of the cells from plastic surfaces. These
results underscore the complexity of the intracellular requirements for
the initiation of chemosensitization to anti-neoplastic agents.
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