Inhalation Delivery and Anti-tumor Activity of Celecoxib in Human Orthotopic Non-Small Cell Lung Cancer Xenograft Model

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Abstract
Purpose To determine the in vivo anti-tumor effect of aerosolized Celecoxib (Cxb) in combination with i.v Docetaxel (Doc) and compare the anti-tumor effect with oral Cxb combined with i.v Doc in human orthotopic non-small cell lung cancer (NSCLC) xenograft model. Materials and Methods Female Nu/Nu mice were implanted with orthotopic tumors by injecting A549 cells into the lung parenchyma. Seven day after tumor implantation the mice were treated with aerosolized Cxb (30 min exposure/day, 5 mg/ml solution) + i.v Doc (10 mg/kg) and the effect was compared with oral Cxb (150 mg/kg/day) + i.v Doc (10 mg/kg), for 28 days. Small-animal nose only inhalation chamber (CH Technologies, Westwood, NJ) was utilized for aerosol exposure. Therapeutic activity of Cxb (aerosol/oral) + Doc was estimated by differences in lung weight, tumor area and animal body weight. Lung tumor samples isolated from mice were analyzed for (a) PGE2 levels by enzyme immunoassay (EIA) (b) expression of Fas and Factor VIII by immunohistochemistry (c) IL-8 expression using EIA kits and (d) mRNA expression for caspase-3 by Real-Time PCR. Results Mice treated with Cxb (aerosol/oral) + Doc showed significant reduction (P < 0.001) in lung weight and tumor area as compared to Cxb or Doc treatments. Cxb (aerosol/oral) + Doc showed increased apoptosis mediated via increased Fas and caspase-3 (P < 0.001) expression as compared to untreated control. Further, the combination treatment showed antiangiogenic effect as demonstrated by reduced expression of Factor VIII, IL-8 (P < 0.001) and PGE2 (P < 0.001) in lung tumors as compared to untreated control. Aerosolized Cxb at a significantly lower therapeutic dose (4.56 mg/kg/day) demonstrated comparable anti-tumor efficacy to orally administered Cxb (150 mg/kg/day). Conclusion Cxb was formulated and effectively delivered via aerosolization to treat orthotopic lung tumors in combination with i.v Doc. Cxb when administered by aerosol produced same therapeutic effect as oral Cxb, but at lower therapeutic dose and thus shows promise for the treatment of lung cancer.

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