title: Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells.
abstract: OBJECTIVE
  To explore the activity of dasatinib alone and in combination with paclitaxel and carboplatin in ovarian cancer cells and to determine if dasatinib activity can be predicted based on evaluation of the SRC pathway.
  
  
  METHODS
  Microarray analysis was performed for IGROV1, OVCAR3, A2780 and SKOV3 ovarian cancer cells and the status of the genomic SRC signature pathway was determined. Cells were treated with carboplatin, paclitaxel and dasatinib individually and in combination. Pre- and post-treatment phospho-SRC (pSRC) and SRC protein expression was determined. Dose-response curves were constructed, and drug interaction was assessed by the Combination Index (CI) method.
  
  
  RESULTS
  SRC protein expression levels reflected the SRC pathway genomic signature in the cell lines with the lowest (SKOV3) and highest (IGROV1) pathway expression, but not in those with intermediate expression (OVCAR3, A2780). Dasatinib treatment caused loss of pSRC in all cell lines, with 50% growth inhibition for IGROV1 at 70 nM, OVCAR3 at 34 nM, A2780 at 4.1 μM and SKOV3 at 530 nM. Dasatinib combined with cytotoxics yielded a synergistic effect (CI=0.46 to 0.79) in all cell lines except SKOV3.
  
  
  CONCLUSIONS
  Dasatinib in combination with standard chemotherapeutic agents appears to interact in a synergistic manner in some ovarian cancer cell lines. Further research is needed to evaluate tumor cell characteristics which predict response to dasatinib.
authors.affiliation: Division of Gynecologic Oncology, Duke Comprehensive Cancer Center, Durham, NC 27710, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Teoh
authors.forename: Tina A
authors.initials: TA
authors.lastname: Ayeni
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Rubatt
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Lisa
authors.initials: L
authors.lastname: Grace
authors.forename: Mark D
authors.initials: MD
authors.lastname: Starr
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.forename: Angeles Alvarez
authors.initials: AA
authors.lastname: Secord
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines; D013844:Thiazoles; D016190:Carboplatin; D016392:Proto-Oncogene Proteins pp60(c-src); D017239:Paclitaxel; D000069439:Dasatinib