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Modulation of Drug Resistance in Ovarian Adenocarcinoma by Enhancing Intracellular Ceramide Using Tamoxifen-Loaded Biodegradable Polymeric Nanoparticles
- Source :
- Clinical Cancer Research. 14:3193-3203
- Publication Year :
- 2008
- Publisher :
- American Association for Cancer Research (AACR), 2008.
-
Abstract
- Purpose: To modulate intracellular ceramide levels and lower the apoptotic threshold in multidrug-resistant ovarian adenocarcinoma, we have examined the efficacy and preliminary safety of tamoxifen coadministration with paclitaxel in biodegradable poly(ethylene oxide)–modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles.Experimental Design: In vitro cytotoxicity and proapoptotic activity of paclitaxel and tamoxifen, either as single agent or in combination, was examined in wild-type (SKOV3) and MDR-1–positive (SKOV3TR) human ovarian adenocarcinoma cells. Subcutaneous SKOV3 and SKOV3TR xenografts were established in female nu/nu mice, and this model was used to evaluate the antitumor efficacy and preliminary safety. Paclitaxel (20 mg/kg) and tamoxifen (70 mg/kg) were administered i.v. either as a single agent or in combination in aqueous solution and in PEO-PCL nanoparticles.Results: In vitro cytotoxicity results showed that administration of paclitaxel and tamoxifen in combination lowered the IC50 of paclitaxel by 10-fold in SKOV3 cells and by >3-fold in SKOV3TR cells. The combination paclitaxel/tamoxifen co-therapy showed even more pronounced effect when administered in nanoparticle formulations. Upon i.v. administration of paclitaxel/tamoxifen combination in PEO-PCL nanoparticle formulations, significant enhancement in antitumor efficacy was observed. Furthermore, the combination paclitaxel/tamoxifen therapy did not induce any acute toxicity as measured by body weight changes, blood cell counts, and hepatotoxicity.Conclusions: The results of this study show that combination of paclitaxel and tamoxifen in biodegradable PEO-PCL nanoparticles can serve as an effective clinically translatable strategy to overcome multidrug resistance in ovarian cancer.
- Subjects :
- Selective Estrogen Receptor Modulators
Cytoplasm
Cancer Research
Ceramide
Paclitaxel
endocrine system diseases
Polyesters
Mice, Nude
Adenocarcinoma
Pharmacology
Ceramides
Polyethylene Glycols
Mice
chemistry.chemical_compound
Drug Delivery Systems
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
In Situ Nick-End Labeling
medicine
Animals
Humans
Ovarian Neoplasms
Chemistry
medicine.disease
Drug Resistance, Multiple
Acute toxicity
Multiple drug resistance
Tamoxifen
Oncology
Drug Resistance, Neoplasm
Cell culture
Apoptosis
Nanoparticles
Female
Ovarian cancer
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....270f69d05f6904d0d606481d1d1dd7aa