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PI‐18
Author(s) -
Ho E.,
Vassileva V.,
LimSoo P.,
Allen C.,
PiquetteMiller M.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.039
Subject(s) - in vivo , paclitaxel , in vitro , p glycoprotein , pharmacology , pi , chemistry , glycoprotein , medicine , biochemistry , biology , chemotherapy , microbiology and biotechnology , multiple drug resistance , antibiotics
BACKGROUND While ovarian tumors initially appear responsive to chemotherapy, most patients relapse with drug resistant disease. We hypothesized that sustained, local delivery of paclitaxel (PTX) could impact chemo‐responsiveness of ovarian tumors by controlling the expression of P‐glycoprotein (Pgp)/MDR1. METHODS Sustained and intermittent administration of PTX using free‐PTX or a novel sustained PTX implant system was examined in vitro in SKOV‐3 cells and in vivo in an intraperitoneal human ovarian xenograft murine model implanted ip with the sustained release formulation. MDR1/Pgp expression was examined by RT‐PCR, flow cytometry and immunohistochemistry. RESULTS Equivalent dosing of free‐PTX by either sustained or intermittent treatments (5–250 ng/ml) induced MDR1 mRNA levels by 3–4 fold in SKOV‐3 cells ( P <0.05) without altering Pgp protein levels. On the other hand, similar treatments with PTX‐implants did not induce MDR1 or Pgp expression in vitro . Likewise, we did not detect significant changes in the in vivo expression of MDR1/Pgp in xenografts obtained from mice treated for 14 days with sustained PTX‐implants which delivered doses of 2.4–240 mg/kg/day of PTX. Basal MDR1/Pgp levels were seen in the highest treatment group. CONCLUSIONS Overall, localized and sustained administration of PTX does not aggravate MDR1 development thereby demonstrating potential as a novel treatment strategy for ovarian cancer. Clinical Pharmacology & Therapeutics (2005) 79 , P11–P11; doi: 10.1016/j.clpt.2005.12.039