Linked Life Data

10606283

Source:http://linkedlifedata.com/resource/pubmed/id/10606283

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6A Suppl
pubmed:dateCreated
2000-1-5
pubmed:abstractText
Bcl-2 expression is upregulated in prostate cancer cells after androgen withdrawal and is associated with the development of androgen independence and chemoresistance. Induction of apoptotic cell death after androgen ablation, or chemotherapy, may be enhanced through functional inhibition of bcl-2. In this report, we tested the effects of antisense bcl-2 oligodeoxynucleotides (ODN) with androgen ablation and taxane therapy on time to androgen-independent (Al) progression in the androgen-dependent Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with 500 nmol/L antisense bcl-2 ODN decreased bcl-2 mRNA by 85%, compared with treatment with 500 nmol/L mismatch control ODN. Although bcl-2 expression levels in Shionogi cells were not changed by docetaxel treatment, docetaxel treatment induced bcl-2 phosphorylation. Consequently, the formation of bcl-2/Bax heterodimer formation was inhibited in a dose-dependent manner. Treatment of Shionogi tumors in vitro with either 500 nmol/L antisense bcl-2 ODN or 10 nmol/L docetaxel alone did not induce apoptosis or reduce growth rates. However, combined treatment reduced the concentration that reduces cell viability by 50% (IC50) of docetaxel from 100 nmol/L to 10 nmol/L and induced characteristic apoptotic DNA laddering and cleavage of the poly(ADP-ribose)polymerase (PARP) protein. Adjuvant in vivo administration of antisense bcl-2 ODN and polymeric micellar paclitaxel after castration resulted in a significant delay in time to Al recurrence when compared with administration of either agent alone. Furthermore, combined treatment of mice bearing Al recurrent Shionogi tumors with antisense bcl-2 ODN and micellar paclitaxel synergistically induced tumor regression and growth inhibition when compared with treatment with either agent alone. These findings suggest that down-regulation of bcl-2 by antisense ODN chemosensitizes Al Shionogi tumors to taxanes, over and above the effects of taxane-induced phosphorylation of bcl-2. Antisense bcl-2 ODN combined with taxanes may be a novel approach to the treatment of both established and emerging Al disease.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0090-4295
pubmed:author
pubmed:issnType
Print
pubmed:volume
54
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
36-46
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10606283-Androgens, pubmed-meshheading:10606283-Animals, pubmed-meshheading:10606283-Antineoplastic Agents, Phytogenic, pubmed-meshheading:10606283-Blotting, Northern, pubmed-meshheading:10606283-Blotting, Western, pubmed-meshheading:10606283-DNA, Neoplasm, pubmed-meshheading:10606283-DNA Primers, pubmed-meshheading:10606283-Disease Progression, pubmed-meshheading:10606283-Dose-Response Relationship, Drug, pubmed-meshheading:10606283-Drug Therapy, Combination, pubmed-meshheading:10606283-Gene Targeting, pubmed-meshheading:10606283-Genes, bcl-2, pubmed-meshheading:10606283-Male, pubmed-meshheading:10606283-Mice, pubmed-meshheading:10606283-Oligodeoxyribonucleotides, Antisense, pubmed-meshheading:10606283-Paclitaxel, pubmed-meshheading:10606283-Prostatic Neoplasms, pubmed-meshheading:10606283-Proto-Oncogene Proteins c-bcl-2, pubmed-meshheading:10606283-RNA, Messenger, pubmed-meshheading:10606283-Taxoids
pubmed:year
1999
pubmed:articleTitle
Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides.
pubmed:affiliation
The Prostate Centre, Vancouver General Hospital, British Columbia, Canada.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't