Dual targeting of endothelial cells and pericytes in antivascular therapy for ovarian carcinoma.
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.
Lu
Chunhua
C
Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kamat
Aparna A
AA
Lin
Yvonne G
YG
Merritt
William M
WM
Landen
Charles N
CN
Kim
Tae Jin
TJ
Spannuth
Whitney
W
Arumugam
Thiru
T
Han
Liz Y
LY
Jennings
Nicholas B
NB
Logsdon
Craig
C
Jaffe
Robert B
RB
Coleman
Robert L
RL
Sood
Anil K
AK
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
D011687:Purines; D066246:ErbB Receptors; C489254:AEE 788