title: The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study.
abstract: BACKGROUND
  Interleukin-6 (IL-6) is associated with prostate cancer morbidity. In several experimental models, IL-6 has been reported to have anti-apoptotic and pro-angiogenic effects. Siltuximab (CNTO 328) is a monoclonal anti-IL-6 antibody which has been successfully applied in several models representing prostate cancer. This study was designed to assess preliminary safety of siltuximab in patients with early prostate cancer.
  
  
  METHODS
  Twenty patients scheduled to undergo radical prostatectomy received either no drug or siltuximab (6 mg/kg, five patients per group with administration once, two times, and three times prior to surgery). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Expression of elements of IL-6 signaling pathways was analyzed in tumor tissue by immunohistochemistry. Gene analysis in tumor specimens was performed with the DASL array.
  
  
  RESULTS
  No adverse events related to siltuximab were observed. Patients treated with siltuximab presented with higher levels of proliferation and apoptosis markers. Following a single dose, serum concentrations of siltuximab declined in a biexponential manner. This study revealed a decrease in phosphorylation of Stat3 and p44/p42 mitogen-activated protein kinases. In addition, gene expression analyses indicate down-regulation of genes immediately downstream of the IL-6 signaling pathway and key enzymes of the androgen signaling pathway.
  
  
  CONCLUSIONS
  Preliminary safety of siltuximab is favorable. Future studies in which siltuximab could be combined with androgen-deprivation therapy and experimental therapies in advanced prostate cancer are justified.
authors.affiliation: Centocor Research & Development, Radnor, Pennsylvania, USA.
authors.forename: Jayaprakash
authors.initials: J
authors.lastname: Karkera
authors.forename: Hannes
authors.initials: H
authors.lastname: Steiner
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.forename: Viktor
authors.initials: V
authors.lastname: Skradski
authors.forename: Patrizia L
authors.initials: PL
authors.lastname: Moser
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.forename: Manjula
authors.initials: M
authors.lastname: Reddy
authors.forename: Thomas
authors.initials: T
authors.lastname: Puchalski
authors.forename: Karim
authors.initials: K
authors.lastname: Safer
authors.forename: Uma
authors.initials: U
authors.lastname: Prabhakar
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C504234:siltuximab