Antivascular therapy for orthotopic human ovarian carcinoma through blockade of the vascular endothelial growth factor and epidermal growth factor receptors.
OBJECTIVE
We determined whether the administration of the tyrosine kinase inhibitor, AEE788, which targets the epidermal growth factor receptor and the vascular endothelial growth factor receptor, alone or in combination with paclitaxel, can inhibit progressive growth of human ovarian carcinoma in the peritoneal cavity of female nude mice.


METHODS
Western blot analysis and immunohistochemical analysis identified the optimal dose and schedule of AEE788 therapy. In several different experiments, paclitaxel-sensitive and paclitaxel-resistant human ovarian carcinoma cells were injected into the peritoneal cavity of nude mice. Seven days later, treatment with saline (control), AEE788 alone, paclitaxel alone, or a combination of AEE788 and paclitaxel began and continued for 45 days when the mice were necropsied. In independent survival experiments, the mice were necropsied when they became moribund.


RESULTS
Oral administration of AEE788 inhibited phosphorylation of the epidermal growth factor receptor and vascular endothelial growth factor receptor for up to 48 hours. Treatment with AEE788 plus paclitaxel significantly reduced tumor weight and increased survival of mice implanted with paclitaxel-sensitive cell lines compared with control mice or mice treated with AEE788 alone or paclitaxel alone. In mice implanted with paclitaxel-resistant cells, the combination therapy also significantly reduced tumor weight but did not prolong survival. The combination therapy induced apoptosis of both tumor cells and tumor-associated endothelial cells.


CONCLUSIONS
The administration of AEE788 and paclitaxel inhibits the progression of human ovarian carcinoma in the peritoneal cavity of female nude mice, in part, by inducing apoptosis of tumor-associated endothelial cells.
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1439, USA.
Premal H
PH
Thaker
Sertac
S
Yazici
Monique B
MB
Nilsson
Kenji
K
Yokoi
Rachel Z
RZ
Tsan
Junqin
J
He
Sun-Jin
SJ
Kim
Isaiah J
IJ
Fidler
Anil K
AK
Sood
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016019:Survival Analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D011687:Purines; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; C489254:AEE 788; D017239:Paclitaxel