Suppression of BCL2 by Antisense Oligonucleotides and Compensation by Non-Targeted Genes May Enhance Tumor Proliferation.

Antisense oligonucleotides have been used to target regulatory proteins in both in vivo and in vitro models of prostate cancer. Our previous studies showed that oligonucleotide-treated LNCaP prostate cancer cells compensate for diminished expression of B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2), an apoptosis inhibitor, by suppressing the expression of caspase-3 (an apoptosis promoter) while enhancing that of serine/threonine protein kinase (AKT1) (another apoptosis inhibitor). In addition, we found an enhanced expression of the androgen receptor (AR), its p300 and interleukin-6 (IL6) co-activators, polymerase transcription mediator (MED12), and growth-regulating signal transducer (STAT3).

Additional compensatory mechanisms altering antisense oligonucleotide suppression of BCL2: effects upon AKT1 and STAT3.

Antisense oligonucleotides have targeted regulatory proteins in both in vivo and in vitro prostate cancer models. We evaluated mono- and bispecific oligonucleotides which targeted and comparably suppressed B-cell lymphoma-2 BCL-2 (an apoptosis-inhibitory protein) expression in LNCaP cells. These oligonucleotides were administered with lipofectin as part of a nanoparticle delivery system.

Oligonucleotide suppression of bcl-2 in LNCaP cells is compensated by increased androgen sensitivity, p53 and oncogene activity, and suppressed caspase-3.

Antisense oligonucleotides (oligos) have been employed against prostate cancer models in both in vivo and in vitro systems. While most target growth factors or their receptors, other oligos are directed against inhibitors of apoptosis or mediators of androgen action. Those which suppress bcl-2 activity (in prostate cancer patients) have even reached clinical trials.

Increased expression of the androgen receptor with p300 and interleukin-6 coactivators compensate for oligonucleotide suppression of bcl-2: no increased CREB binding protein or interleukin-4 expression.

Background: Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth regulatory proteins. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis and mediators of androgen action. We previously evaluated a set of oligos which targeted and comparably suppressed the expression of the apoptosis inhibitor protein bcl-2.

No compensation in CD44 stem cell marker following BCL-2 suppression by antisense oligonucleotides.

Antisense oligonucleotides have previously been used to target regulatory proteins in prostate cancer models. We evaluated mono- and bispecific oligonucleotides which comparably suppressed expression of B-cell lymphoma-2 (BCL-2) in LNCaP cells. Cells compensated by suppressing caspase-3 (an apoptosis promoter), and enhancing the expression of androgen receptor and co-activating p300 and interleukin-6 (IL-6) proteins.

Review: description of the developmental patterns of epithelial cells and cancers originating from them will provide many sites for therapy.

Many types of cancers represent different forms of blocked differentiation, but the relationship with major, currently identified cancer driver mutational and epigenetic events is not well defined. Normal cellular differentiation depends upon hierarchically-organized sequences of control and synthetic events coupled with cellular proliferation. An ability to identify and possibly correct or otherwise modify defective cancer stem or daughter cell differentiation, or even non-malignant precursor cell differentiation occurring prior to the effect of oncogene and suppressor genomic activity should provide many new approaches to circumventing the oncogenic process.

No compensation in VEGF expression follows antisense suppression of BCL-2 activity.

Antisense oligonucleotides (oligos) have been employed against prostate cancer models targeting growth-regulatory proteins, and at least one oligo (against bcl-2) has reached clinical trial. We previously found that, in LNCaP cells, mono- and bispecific oligos, which comparably suppressed the expression of bcl-2, compensated with suppression of caspase-3 (apoptosis promoter) activity, and enhanced the expression of the androgen receptor (AR) and its p300 and IL-6 co-activators. In addition, prostate-specific membrane antigen (PSMA) and (possibly its regulator) interferon (IFN) were elevated.

Order-of-magnitude estimates of latency (time to appearance) and refill time of a cancer from a single cancer 'stem' cell compared by an exponential and a logistic equation.

Background/aim: The time required before a mass of cancer cells considered to have originated from a single malignantly transformed cancer 'stem' cell reaches a certain number has not been studied. Applications might include determination of the time the cell mass reaches a size that can be detected by X-rays or physical examination or modeling growth rates in vitro in order to compare with other models or established data.

Materials And Methods: We employed a simple logarithmic equation and a common logistic equation incorporating 'feedback' for unknown variables of cell birth, growth, division, and death that can be used to model cell proliferation.

In LNCaP cells enhanced expression of both androgen receptor and costimulatory protein p300 compensate for antisense oligonucleotide suppression of bcl-2.

Background: Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth stimulatory gene products. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis and mediators of androgen action. In LNCaP cells we evaluated a set of oligos which targeted and comparably suppressed the expression of the apoptosis inhibitor protein bcl-2.

Compensatory and non-compensatory effects on protein expression following BCL-2 suppression by antisense oligonucleotides.

Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth regulatory proteins. In LNCaP cells, we evaluated both monospecific and bispecific oligos that targeted and comparably suppressed the expression of bcl-2, an apoptosis inhibitory protein. Cells compensated with both suppressed caspase-3 (an apoptosis promoter) activity, and an enhancement of both androgen receptor (AR) and p300 expression.

In LNCaP cells enhanced expression of the androgen receptor compensates for Bcl-2 suppression by antisense oligonucleotides.

Background And Methods: Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth stimulatory gene products. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis. In LNCaP cells we evaluated a set of oligos which targeted and comparably suppressed the expression of the apoptosis inhibitor protein Bcl-2.

Effects of BCL-2 suppression by antisense oligonucleotides on additional regulators of apoptosis compensatory change in non-targeted protein expression.

Antisense oligonucleotides (oligos) have been employed against prostate cancer in both in vivo and in vivo models. While most oligos contain a single mRNA binding site, our laboratory has developed bispecifics directed towards two. Previous work has determined that when oligos are used to suppress the expression of individual proteins in highly regulated physiologic processes, additional proteins can be affected.

Differentiated prostatic antigen expression in LNCaP cells following treatment with bispecific antisense oligonucleotides directed against BCL-2 and EGFR.

Antisense oligonucleotides (oligos) have been administered against in vivo and in vitro prostate cancer models employing LNCaP and PC-3 cell lines. While most oligos consist of a single mRNA binding site targeting a single gene product or those with sequence homology, our lab has developed bispecific oligos directed toward two unrelated proteins. In LNCaP cells, we initially identified bispecifics that increased the expression of prostate-specific membrane antigen (PSMA) while not affecting secreted prostate-specific antigen (PSA).

Bispecific oligonucleotides may induce interferon expression in LNCaP cells enhancing surface antigen expression: effect of intrastrand base pair complementarity.

Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models. Most oligos consist of a single mRNA binding site, targeting a single gene product or others sharing sequence homology. However, our lab has developed bispecifics directed towards two (including unrelated) proteins.

Does the prostate retain an endogenous antiviral defense system suggesting a past viral etiology for cancer?

Evidence of viral infection of the prostate is presented, and consists of viral isolation as well as antigen and genomic detection of integrated or episomal forms. Prior infection from "ancient" exogenous retroviruses is suggested by residual endogenous forms. The presence of an antiviral defense system based upon interferon induction has been suggested for the testes.

Bispecific antisense oligonucleotides have activity comparable to monospecifics in inhibiting expression of BCL-2 in LNCaP cells.

Antisense oligonucleotides (oligos) have been employed against prostate cancer models in both in vivo and in vitro systems. Most oligos employed by investigators include only a single mRNA-binding site, and target only a single gene. However, some target multiple genes which share sequence homology.

Bax expression remains unchanged following antisense treatment directed against BCL-2.

Antisense oligonucleotides (oligos) have been evaluated in both in vivo and in vitro prostate cancer models. Although most contain a single mRNA binding site, our laboratory has also evaluated bispecific types directed toward two proteins. This study evaluates the inhibition of in vitro propagating LNCaP cells employing mono- and bispecific oligos directed against bcl-2 [the second binding site was directed against the epidermal growth factor receptor (EGFR)].

Increased prostate-specific membrane antigen expression in LNCaP cells following treatment with bispecific antisense oligonucleotides directed against bcl-2 and EGFR.

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)].

Treatment of prostate and breast tumors employing mono- and bi-specific antisense oligonucleotides targeting apoptosis inhibitory proteins clusterin and bcl-2.

Antisense oligonucleotides (oligos) have demonstrated their efficacy in inhibiting the growth of prostate and breast tumor cells. Previous studies employed first generation, phosphorothioated, cDNA oligos synthesized complimentary to mRNA encoding transforming growth factor-alpha (TGF-alpha), epidermal growth factor receptor (EGFR), the anti-apoptosis protein bcl-2, and the androgen receptor (AR). In an effort to construct oligos with greater than one mRNA binding site, bi-specifics have been developed which target combinations of the above proteins, and these have been shown at least as effective as the mono-specific oligos from which their sequences were derived.

Multigene targeting of signal transduction pathways for the treatment of breast and prostate tumors: comparison between combination therapies employing bispecific oligonucleotides with either Rapamycin or Paclitaxel.

Previous studies have demonstrated that monospecific antisense oligonucleotides (oligos) directed against mRNA encoding proteins associated with tumor growth, death, and survival are efficacious against breast and prostate tumors. Targeted proteins, associated with different signal transduction pathways, have included transforming growth factor-alpha [TGF-alpha (MR(1))], its binding site the epidermal growth factor receptor [EGFR (MR(2))] sharing sequence homology to the breast cancer prognostic marker Her-2/neu, an apoptosis inhibiting protein [bcl-2 (MR(4))], and the androgen receptor [AR (MR(5))]. In attempts to enhance antisense therapy, recent reports describe how two of the binding sites mentioned above can be sequentially placed within a single complementary (bispecific) strand and administered either in the presence or absence of additional therapeutic agents.

Treatment of MCF-7 breast cancer cells employing mono- and bispecific antisense oligonucleotides having binding specificity toward proteins associated with autocrine regulated growth and BCL-2.

Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha) (MR1) and its binding site, the epidermal growth factor receptor (EGFR) (MR2), are efficacious against the UACC 897 breast, PC-3 and LNCaP prostate, and T98G glioblastoma tumor lines in both in vitro and in vivo studies. Oligos against the anti-apoptosis protein bcl-2 (MR4) are also efficient against PC-3 and LNCaP tumors in similar in vitro experiments. To enhance activity, and also to introduce a derivative type of multifunctional oligo into this field, "bispecifics" were constructed containing two truncated complementary DNA sequences (from either MR1 or MR2) designed to bind targeted mRNA about their respective AUG initiation codons, and/or a similar sequence adjacent to the AUG site of mRNA encoding bcl-2.

Combination chemotherapy employing bispecific antisense oligonucleotides having binding sites directed against an autocrine regulated growth pathway and bcl-2 for the treatment of prostate tumors.

In previous studies we demonstrated that antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha [MR1]), its binding site the epidermal growth factor receptor (EGFR [MR2]), and the anti-apoptosis protein bcl-2 (MR4) are efficacious against prostate tumors. In recent reports we also describe how two of these mRNA directed binding sites can be synthesized sequentially within a single linear complementary strand and administered either in the presence or absence of additional therapeutic agents. In these continuing experiments "bispecific" oligo pairs were further evaluated in the presence or absence of Cytoxan, Taxol, or DES.

Bispecific antisense oligonucleotides having binding sites directed against an autocrine regulated growth pathway and bcl-2 for the treatment of prostate tumors.

Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha) (MR1) and its binding site, the epidermal growth factor receptor (EGFR) (MR2), are efficacious against PC-3 and LNCaP prostate tumors. To enhance activity and aid in simultaneous delivery, "bispecific" 39-mer oligos were constructed containing portions of both MR1 and MR2 sequences. The first pair contained truncated sequences recognizing TGF-alpha and EGFR mRNA binding sites, about their respective AUG initiation codons.

Targeting of biotinylated oligonucleotides to prostate tumors with antibody-based delivery vehicles.

Specific delivery of therapeutic agents to tumor sites remains a problem and requires a nontoxic carrier able to bind a specific tumor cell marker. Although antibodies have been utilized as protein carriers for different types of drugs, they have not been employed for delivery of antisense oligonucleotides (ODNs). In this study, we modified monoclonal antibodies to target biotinylated ODNs to prostatic tumors which express prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA).

Synthesis of branched antisense oligonucleotides having multiple specificities. Treatment of hormone insensitive prostate cancer.

Antisense oligonucleotides (oligos) directed against transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR), have demonstrated in vitro and in vivo efficacy against both the PC-3 and LNCaP prostate tumor models. In an attempt to increase the efficiency of these oligos a new type of antisense compound called a bispecific oligo has been evaluated in vitro both alone and in combination with traditional chemotherapeutic agents. These bispecifics, which were first proposed in this journal in 2004, include binding sites for both TGF-alpha and EGFR along the same stretch of complementary DNA.