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PMID: 21555850 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts.

The Journal of clinical investigation ·Vol. 121 ·No. 6 ·2011-06-00 ·Pages 2383-90

Ni X, Zhang Y, Ribas J, Chowdhury WH, Castanares M, Zhang Z, Laiho M, DeWeese TL, Lupold SE

Abstract

Dose-escalated radiation therapy for localized prostate cancer (PCa) has a clear therapeutic benefit; however, escalated doses may also increase injury to noncancerous tissues. Radiosensitizing agents can improve ionizing radiation (IR) potency, but without targeted delivery, these agents will also sensitize surrounding normal tissues. Here we describe the development of prostate-targeted RNAi agents that selectively sensitized prostate-specific membrane antigen-positive (PSMA-positive) cells to IR. siRNA library screens identified DNA-activated protein kinase, catalytic polypeptide (DNAPK) as an ideal radiosensitization target. DNAPK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNAPK in PCa cells, xenografts, and human prostate tissues. Aptamer-targeted DNAPK shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. These findings support aptamer-shRNA chimeras as selective sensitizing agents for the improved treatment of high-risk localized PCa.

MeSH Terms
Adenocarcinoma/pathology,radiotherapy Animals Antigens, Surface/analysis Aptamers, Nucleotide/administration & dosage Cell Line DNA-Activated Protein Kinase/antagonists & inhibitors Glutamate Carboxypeptidase II/analysis Humans Male Mice Mice, Nude Molecular Targeted Therapy Nuclear Proteins/antagonists & inhibitors Prostatic Neoplasms/pathology,radiotherapy RNA Interference RNA, Small Interfering/administration & dosage,pharmacology Radiation Tolerance Radiation-Sensitizing Agents/administration & dosage,therapeutic use Tumor Stem Cell Assay Xenograft Model Antitumor Assays
Chemicals
Antigens, Surface Aptamers, Nucleotide Nuclear Proteins RNA, Small Interfering Radiation-Sensitizing Agents DNA-Activated Protein Kinase PRKDC protein, human FOLH1 protein, human Glutamate Carboxypeptidase II
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Ni Xiaohua
James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Zhang Yonggang
Ribas Judit
Chowdhury Wasim H
Castanares Mark
Zhang Zhewei
Laiho Marikki
DeWeese Theodore L
Lupold Shawn E
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI45109
Published
2011-06-00
Epub
2011-00-09
Pages
2383-90
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3104752
Subset
IM
Grants
NCI NIH HHS · P50 CA058236 · United States
NCI NIH HHS · 5P50CA058236-15 · United States
External Links
PubMed source DOI: 10.1172/JCI45109 PMC Full Text View journal details
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