Antisense oligonucleotides have been employed against in vivo and in vitro
prostate cancer models. While most oligos consist of a single
mRNA binding site, targeting a single gene product or others sharing sequence homology, our laboratory has developed bispecific oligos directed toward even unrelated
proteins. This study evaluates the inhibition of in vitro propagating LNCaP cells employing mono- and bispecific oligos directed against bcl-2 [the second bispecific binding site was directed against the
epidermal growth factor receptor (EGFR)]. Employing RT-PCR, the expression of non-targeted
proteins encoded by
mRNA for prostate-specific membrane
antigen (PSMA) and
prostate-specific antigen (PSA) were subsequently evaluated. When LNCaP prostate
tumor cells were incubated with bispecific oligos (directed against bcl-2 and EGFR) and compared to
lipofectin-containing controls significant growth inhibition resulted. In subsequent experiments, the levels of
mRNA encoding PSMA were unexpectedly found to be elevated following treatment with the bispecific oligos but not with the monospecific directed solely against bcl-2. No differences were detected in
mRNA levels encoding PSA following treatment with either mono- or bispecific oligos. Previously, we suggested that cell growth inhibition produced by some bispecifics could be attributed to complementary double-stranded regions formed by intra-strand base pairs. Double-stranded
nucleic acids are known inducers of
interferon, which promote expression of cell surface HLA type
antigens. If induced, perhaps this
cytokine also enhances PSMA expression, making prostate
tumor cells a more recognizable target for cytotoxic T cells.