title: Daily administration of low molecular weight heparin increases Hepatocyte Growth Factor serum levels in gynaecological patients: pharmacokinetic parameters and clinical implications.
abstract: BACKGROUND
  Hepatocyte Growth Factor (HGF) enhances cytotoxicity of paclitaxel (PTX) and cisplatin (CDDP) in human ovarian cancer cells. Because of potential pitfalls of HGF exogenous administration, we investigated whether HGF serum concentration might be alternatively raised in vivo by administering low molecular weight heparin (LMWH).
  
  
  METHODS
  The main HGF pharmacokinetic parameters were evaluated following acute and chronic LMWH treatment. First, women, operated on for gynaecological tumors, were treated with a single dose of calcium nadroparin and studied for 12 hours. Next, women operated on for benign or malignant gynaecological tumors were treated daily with calcic nadroparin for one month. Subsequently, the biological activity of the measured HGF serum levels was tested in assays of ovarian cancer cell sensitization to drugs.
  
  
  RESULTS
  In the short-term treated group, median HGF AUCss, Cmax and Caverage were about four-fold that of the control group, whereas Cmin was three-fold. In the patients treated chronically median HGF serum levels rose about six-fold in the first week, and decreased but remained significantly higher after one month. The pharmacokinetic of nadroparin-dependent HGF increase were similar in the two groups. The HGF concentrations measured after both acute and chronic treatment were found to be effective in sensitising ovarian cancer cells to chemotherapeutics.
  
  
  CONCLUSIONS
  This study raises the possibility of using LMWH to increase HGF serum concentration and to take advantage of its biological activities. In particular, nadroparin might be used as a chemo-potentiating agent in epithelial cell ovarian carcinoma through its action on HGF serum concentration.
  
  
  BACKGROUND
  ClinicalTrials.gov ID: NCT01523652.
authors.affiliation: Unit of Gynecologic Oncology, Department of Gynecology and Obstetrics of the University of Torino at Azienda Ospedaliera Ordine Mauriziano, Largo Turati 62, Turin, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Surbone
authors.forename: Luca
authors.initials: L
authors.lastname: Fuso
authors.forename: Roberto
authors.initials: R
authors.lastname: Passera
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ferrero
authors.forename: Cristiana
authors.initials: C
authors.lastname: Marchese
authors.forename: Cosimo
authors.initials: C
authors.lastname: Martino
authors.forename: Annalisa
authors.initials: A
authors.lastname: Luchin
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
authors.forename: Paolo
authors.initials: P
authors.lastname: Zola
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005833:Genital Neoplasms, Female / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D017228:Hepatocyte Growth Factor / Q000097:blood* / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D017762:Nadroparin / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011446:Prospective Studies; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D006495:Heparin, Low-Molecular-Weight; D017762:Nadroparin; D017228:Hepatocyte Growth Factor; D002945:Cisplatin