727 ANTISENSE OLIGONUCLEOTIDE TARGETING INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR ENHANCES PACLITAXEL SENSITIVITY IN A PACLITAXEL- RESISTANT PROSTATE CANCER MODEL
Bibliographic record
Abstract
You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011727 ANTISENSE OLIGONUCLEOTIDE TARGETING INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR ENHANCES PACLITAXEL SENSITIVITY IN A PACLITAXEL- RESISTANT PROSTATE CANCER MODEL Junya Furukawa, Hideaki Miyake, Masato Fujisawa, Christopher Wraight, Brett Monia, Martin Gleave, and Michael Cox Junya FurukawaJunya Furukawa Kobe, Japan More articles by this author , Hideaki MiyakeHideaki Miyake Kobe, Japan More articles by this author , Masato FujisawaMasato Fujisawa Kobe, Japan More articles by this author , Christopher WraightChristopher Wraight Victoria, Australia More articles by this author , Brett MoniaBrett Monia Carlsbad, CA More articles by this author , Martin GleaveMartin Gleave Vancouver, Canada More articles by this author , and Michael CoxMichael Cox Vancouver, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1696AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Altered expression of insulin-like growth factor (IGF) axis components have been consistently found in prostate cancer (PCa) and associated with adaptive growth and survival signaling implicated in castrate-resistant disease (CRPC) progression. These activities are mediated by activation of the IGF-I receptor (IGF-IR). While CRPC patients treated with taxanes alone or in combination with estramustine phosphate or predonisone show a survival benefit, development of chemotherapeutic resistance eventually occurs. Therefore novel strategies targeting the molecular basis of androgen deprivation therapy and chemotherapy resistance are required. In this study, we establish paclitaxel-resistant androgen-independent PCa cells (PtxR PC3) and assess the potency and anti-cancer activity of a 2 EMOE-modified antisense oligonucleotide (ASO) targeting human IGF-IR, ATL1101, on PtxR PC3 cells in vitro and in vivo. METHODS PtxR PC3 cells were established by culturing in step-wise increased drug concentrations. IGF-IR mRNA and protein expression in ATL1101- and control oligonucleotides (ODN)-treated PtxR PC3 cells were measured by QT-PCR and immunoblotting. The effect of IGF-1R ASO and paclitaxel combination therapy on PtxR PC3 cell growth and apoptosis in vitro was examined by crystal violet assay and flow cytometry. In vitro combination index (CI) was calculated by Calcusyn® softoware. For in vivo xenograft studies, PtxR PC-3 cells were inoculated s.c. in the flanks of athymic nude mice and tumor volume kinetics were compared for mice treated with paclitaxel injected i.v. and either ATL1101 or control ODN injected i.p. RESULTS The IC50 for paclitaxel in PtxR PC3 was 15-fold higher than that in parental cells. PtxR PC3 also shows cross-resistance to docetaxel and mitoxantrone. We observed dose- and sequence-specific suppression of IGF-IR mRNA and protein expression in ATL1101-treated PtxR PC3 cells in vitro which correlated with decreased proliferation and increased apoptosis of PtxR PC3 cells. Combination of ATL1101 with paclitaxel showed CI values below 1 at the IC50, IC75, suggesting the drug interactions resulted in synergy. Compared to control ODN, ATL1101 significantly suppressed PtxR PC3 tumor growth as a combination therapy with paclitaxel in murine xenografts. CONCLUSIONS This study reports the first preclinical proof-of-principle data that this novel IGF-IR ASO suppresses growth of paclitaxel resistant PC tumors, synergistically enhancing paclitaxel sensitivity in vitro and in vivo. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e292 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Junya Furukawa Kobe, Japan More articles by this author Hideaki Miyake Kobe, Japan More articles by this author Masato Fujisawa Kobe, Japan More articles by this author Christopher Wraight Victoria, Australia More articles by this author Brett Monia Carlsbad, CA More articles by this author Martin Gleave Vancouver, Canada More articles by this author Michael Cox Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".