Antitumor and antivascular effects of AVE8062 in ovarian carcinoma.
The purpose of this study was to examine the therapeutic efficacy and underlying mechanisms of action of a vascular-disrupting agent, AVE8062, and to determine its effects on tumor metabolic activity. The in vitro and in vivo effects of AVE8062 alone and in combination with docetaxel were tested in chemotherapy-sensitive and chemotherapy-resistant ovarian cancer models. Tumors were analyzed for necrosis, microvessel density, endothelial cell apoptosis, and proliferation following treatment. The effect of AVE8062 on tumor regression and metabolic activity was examined by magnetic resonance (MR) or by [18F]fluorodeoxyglucose ([18F]FDG) uptake by positron emission tomography (PET) with MR imaging, respectively. AVE8062 monotherapy was effective in inhibiting tumor growth in all models (range 43-51% versus control; P < 0.05). Combination therapy was even more effective in inhibiting tumor growth (range 76-90% compared with controls, P < 0.01). AVE8062 in combination with chemotherapy significantly prolonged survival in HeyA8-injected mice (P < 0.001) compared with other groups. AVE8062-based therapy resulted in rapid development of central tumor necrosis, decreased microvessel density, decreased proliferation, and induction of apoptosis of tumor-associated endothelial cells. MR imaging showed regression of established HeyA8 ovarian tumors and [18F]FDG PET with MR showed rapid decrease in metabolic activity after AVE8062 therapy. Combination of AVE8062 plus docetaxel results in potent inhibition of ovarian cancer growth. These results suggest that AVE8062 may be useful as a clinical therapeutic approach for ovarian cancer patients and that functional [18F]FDG PET imaging may predict clinical response before an anatomic reduction in tumor size.
Kim
Tae Jin
TJ
Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Ravoori
Murali
M
Landen
Charles N
CN
Kamat
Aparna A
AA
Han
Liz Y
LY
Lu
Chunhua
C
Lin
Yvonne G
YG
Merritt
William M
WM
Jennings
Nicholas
N
Spannuth
Whitney A
WA
Langley
Robert
R
Gershenson
David M
DM
Coleman
Robert L
RL
Kundra
Vikas
V
Sood
Anil K
AK
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005260:Female; D019788:Fluorodeoxyglucose F18; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012694:Serine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D019275:Radiopharmaceuticals; D043823:Taxoids; D019788:Fluorodeoxyglucose F18; D000077143:Docetaxel; D012694:Serine; C400245:AC 7700