title: Interferon-alpha improves docetaxel antitumoral and antimetastatic efficiency in Lewis lung carcinoma bearing mice.
abstract: OBJECTIVE
  Interferon-alpha (IFN-α) was shown to reduce P-glycoprotein (P-gp) expression and activity in several tissues. The purpose of this study was to evaluate the impact of IFN-α pretreatment on the antitumoral and antimetastatic, Docetaxel (DTX, P-gp substrate), on Lewis Lung Cancer (3LL) bearing mice and to correlate it to DTX pharmacokinetics.
  
  
  METHODS
  Six groups of C57/Bl6 mice received subcutaneous (s.c.) 2.10(6) 3LL cells, then IFN-α 4MIU/kg for 7days, then received or did not receive i.v. or oral DTX (30mg/kg). Pharmacokinetic studies were done on a part of the mice: DTX concentrations were assessed in plasma and tumors, where AUC were estimated with the Bailer method, and half-lives and MRT were determined with a non-compartmental analysis. Tumor growth was assessed more than 21days: animals were then sacrificed and lung metastases number was counted. Kaplan-Meier analysis was made to analyze survival data during the survey period.
  
  
  RESULTS
  DTX i.v. associated with IFN-α significantly improved mouse survival (19.6±0.6days vs. 17.1±0.8days for control mice, p=0.047) with greater antimetastatic effects (87.5% reduction in the number of metastases compared to control mice). The effect on tumor growth was not modified within the IFN-α/DTX i.v. treated groups when compared to mice receiving DTX i.v. alone. The pharmacokinetic analysis showed an increase of DTX concentrations in tumors at 30min after DTX i.v. administration and an increase in the oral bioavailability of orally given DTX following an IFN-α treatment.
  
  
  CONCLUSIONS
  Our study established that IFN-α increases DTX uptake in tumors, improves its antitumoral efficiency and improves animals' survival.
authors.affiliation: Université Paris XI, Clinical Pharmacy Department (UPRES 4123), Faculty of Pharmacy 92296 Châtenay-Malabry, France. makrem.benreguiga@bjn.aphp.fr
authors.forename: Makrem
authors.initials: M
authors.lastname: Ben Reguiga
authors.forename: Celine
authors.initials: C
authors.lastname: Bouquet
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Laurence
authors.initials: L
authors.lastname: Bonhomme-Faivre
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000188:drug therapy; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D016898:Interferon-alpha; D043823:Taxoids; D000077143:Docetaxel