title: The AG1478 tyrosine kinase inhibitor is an effective suppressor of leiomyoma cell growth.
abstract: BACKGROUND
  Uterine leiomyomas are the most common benign smooth muscle cell tumours in women. Formation of leiomyomas, still not completely understood, is viewed as a multistep process, with involvement of ovarian steroid hormones, cytokines and growth factors. Our study aimed to identify tyrosine kinase inhibitors as potential 'signal transduction therapeutics' for leiomyomas, underlying the effect of ovarian steroidal hormones.
  
  
  METHODS
  The selective epidermal growth factor (EGF) receptor blocker AG1478 was evaluated as a potential target, since EGF has been shown to mediate estrogen action and to play a crucial role in regulating leiomyoma growth. Paired cultures of leiomyoma and normal myometrium samples were established and the suppressive effect of AG1478 on the cells prior and subsequent to steroidal hormone treatment was examined: cell proliferation, recovery after treatment, cell cycle analysis and immunochemical analysis of relevant proteins.
  
  
  RESULTS
  Leiomyoma cell growth is effectively blocked by AG1478 and is unaffected by the presence of physiological concentrations of progesterone and estradiol. AG1478 (10 microM) completely suppressed proliferation and the cells did not recover after cessation of treatment.
  
  
  CONCLUSIONS
  The growth-arresting properties of AG1478, unaffected by ovarian steroidal hormones, identify it as a potential lead agent for the non-surgical management of uterine leiomyomas.
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah University Hospital, PO Box 12000, Jerusalem 91120, Israel. shush@cc.huji.ac.il
authors.forename: Asher
authors.initials: A
authors.lastname: Shushan
authors.forename: Nathan
authors.initials: N
authors.lastname: Rojansky
authors.forename: Neri
authors.initials: N
authors.lastname: Laufer
authors.forename: Benjamin Y
authors.initials: BY
authors.lastname: Klein
authors.forename: Zipora
authors.initials: Z
authors.lastname: Shlomai
authors.forename: Rubina
authors.initials: R
authors.lastname: Levitzki
authors.forename: Zipora
authors.initials: Z
authors.lastname: Hartzstark
authors.forename: Hannah
authors.initials: H
authors.lastname: Ben-Bassat
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000473:pathology*; D009215:Myometrium / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000009:adverse effects*; D011799:Quinazolines; D020032:Tyrphostins / Q000494:pharmacology*; D014594:Uterine Neoplasms / Q000473:pathology*
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D011374:Progesterone; D004958:Estradiol; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases