title: Adenovirus-mediated calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer: bifunctional therapeutic effects on peritoneal cell layer and cancer cells.
abstract: OBJECTIVE
  Calponin h1 (CNh1), one of the family of actin-binding proteins, stabilizes the filaments of actin and modulates various cellular biological phenotypes. Recent studies revealed the close correlation between the invasive tumor spread and the reduced expression of CNh1 and alpha-smooth muscle actin in the surrounding stromal cells. The purpose of this study is to evaluate the efficacy of i.p. CNh1 gene therapy against peritoneal dissemination of ovarian cancer.
  
  
  METHODS
  We used an adenoviral vector to induce the CNh1 gene into peritoneal cells and ovarian cancer cells as a means of enhancing or inducing the expression of alpha-smooth muscle actin as well as CNh1. The efficacy of gene transfer was examined by in vitro cell culture and in vivo animal experiments.
  
  
  RESULTS
  The formation of longer and thicker actin fibers was observed in each transfected cell line, and the localization of these fibers coincided with that of externally transducted CNh1. With respect to changes in cell behavior, the CNh1-transfected peritoneal cells acquired an ability to resist ovarian cancer-induced shrinkage in cell shape; thus, cancer cell invasion through the monolayer of peritoneal cells was inhibited. In addition, CNh1-transfected ovarian cancer cells showed suppressed anchorage-independent growth and invasiveness, the latter of which accompanied impaired cell motility. The concomitant CNh1 transfection into both peritoneal cells and ovarian cancer cells produced an additive inhibitory effect with respect to cancer cell invasion through the peritoneal cell monolayer. By in vivo experiments designed to treat nude mice that had been i.p. inoculated with ovarian cancer cells, we found that the i.p. injected CNh1 adenovirus successfully blocked cancer-induced morphologic changes in peritoneal cell surface and significantly prolonged the survival time of tumor-bearing mice. Moreover, CNh1 adenovirus could successfully enhance the therapeutic effect of an anticancer drug without increase in side effects.
  
  
  CONCLUSIONS
  Thus, CNh1 gene therapy against peritoneal dissemination of ovarian cancer is bifunctionally effective (i.e., through inhibitory effects on the infected peritoneal cell layers that suppress cancer invasion and through direct antitumor effects against invasion and growth properties of cancer cells).
authors.affiliation: Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Ogura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Ueoka
authors.forename: Kaoru
authors.initials: K
authors.lastname: Okugawa
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kato
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirakawa
authors.forename: Shigenari
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Norio
authors.initials: N
authors.lastname: Wake
authors.forename: Hitoo
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000628:therapy*; D010529:Peritoneal Cavity / Q000166:cytology; D010534:Peritoneal Neoplasms / Q000628:therapy*; D014162:Transfection; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays; D000096985:Calponins
chemical_list: D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D000096985:Calponins