title: Inhalation delivery and anti-tumor activity of celecoxib in human orthotopic non-small cell lung cancer xenograft model.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, USA.
authors.forename: Suniket V
authors.initials: SV
authors.lastname: Fulzele
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Madhu Sudhan
authors.initials: MS
authors.lastname: Shaik
authors.forename: Tanise
authors.initials: T
authors.lastname: Jackson
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D000068579:Celecoxib; D015232:Dinoprostone / Q000378:metabolism; D000077143:Docetaxel; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous
chemical_list: D000336:Aerosols; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016209:Interleukin-8; D011720:Pyrazoles; D013449:Sulfonamides; D043823:Taxoids; D000077143:Docetaxel; D000068579:Celecoxib; D015232:Dinoprostone