Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles.

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.

• Authors: Harikrishna Devalapally, Zhenfeng Duan, Michael V Seiden, Mansoor M Amiji
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 10 Pg. 3193-203 (May 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18483388 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Ceramides
• Polyesters
• Selective Estrogen Receptor Modulators
• Tamoxifen
• polycaprolactone
• Polyethylene Glycols
• Paclitaxel

Topics

• Adenocarcinoma (drug therapy, metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cell Line, Tumor
• Ceramides (metabolism)
• Cytoplasm (chemistry, drug effects)
• Drug Delivery Systems (methods)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• In Situ Nick-End Labeling
• Mice
• Mice, Nude
• Nanoparticles
• Ovarian Neoplasms (drug therapy, metabolism)
• Paclitaxel (administration & dosage)
• Polyesters
• Polyethylene Glycols
• Selective Estrogen Receptor Modulators (administration & dosage)
• Tamoxifen (administration & dosage)