title: Dual targeting of endothelial cells and pericytes in antivascular therapy for ovarian carcinoma.
abstract: OBJECTIVE
  Pericytes are known to provide a survival advantage for endothelial cells. We hypothesize that strategies aimed at dual targeting of tumor-associated endothelial cells and pericytes will be highly efficacious.
  
  
  METHODS
  Paclitaxel-sensitive (HeyA8 and SKOV3ip1) or paclitaxel-resistant (HeyA8-MDR) orthotopic tumors in mice were examined for therapeutic efficacy by targeting the endothelial cells (using a vascular endothelial growth factor receptor inhibitor, AEE788) and pericytes (using STI571) alone or in combination. Additional therapy and survival studies in combination with paclitaxel were also done. Following therapy, tumors were examined for endothelial cell apoptosis, pericyte coverage, microvessel density, and proliferation.
  
  
  RESULTS
  AEE788 inhibited tumor growth by 45% and 59% in the HeyA8 and SKOV3ip1 models, respectively, whereas STI571 alone was not effective. AEE788 plus STI571 resulted in 69% to 84% inhibition of tumor growth in both models. Moreover, combination of these agents with paclitaxel was even more effective, resulting in up to 98% inhibition of tumor growth. The triple combination was even effective in the HeyA8-MDR model. Remarkably, this triple combination also resulted in improved survival compared with all other groups (P<0.001) and caused regression of formed tumors. Pericyte coverage was significantly decreased in the STI571 treatment groups, and microvessel density was significantly reduced in the AEE788 treatment groups. AEE788 induced endothelial cell apoptosis, which was further enhanced by the addition of STI571.
  
  
  CONCLUSIONS
  Strategies targeting both endothelial cells and pericytes are highly effective for in vivo treatment of ovarian carcinoma. This antiangiogenic effect may be partially due to decreased pericyte coverage, thus increasing the sensitivity of tumor vasculature to therapy. These encouraging data support the development of clinical trials based on this strategy.
authors.affiliation: Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Aparna A
authors.initials: AA
authors.lastname: Kamat
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
authors.forename: William M
authors.initials: WM
authors.lastname: Merritt
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Kim
authors.forename: Whitney
authors.initials: W
authors.lastname: Spannuth
authors.forename: Thiru
authors.initials: T
authors.lastname: Arumugam
authors.forename: Liz Y
authors.initials: LY
authors.lastname: Han
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.forename: Craig
authors.initials: C
authors.lastname: Logsdon
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jaffe
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D020286:Pericytes / Q000187:drug effects / Q000473:pathology*; D011687:Purines / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D011687:Purines; D066246:ErbB Receptors; C489254:AEE 788