Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model.
Ovarian cancer is characterized by i.p. carcinomatosis and massive ascites. Vascular endothelial growth factor (VEGF) plays a pivotal role in tumor angiogenesis and vascular leakage leading to ascites. We assessed the efficacy of a soluble decoy receptor (VEGF Trap) combined with paclitaxel, in a mouse model of human ovarian cancer. Tumor burden after VEGF Trap plus paclitaxel was reduced by approximately 98% versus controls. No measurable ascites developed in the treated group. Morphologic studies showed that most residual tumor had degenerative changes. Diaphragmatic and hepatic tumors were not found in the VEGF Trap plus paclitaxel group in contrast to controls, indicating lack of metastasis. In vivo FITC-lectin tumor vessel imaging showed sparse, short, straight vessels in treated mice as compared to controls, in which vessels were numerous, irregular, tortuous, and leaky. In a survival study, all controls underwent euthanasia between 29 and 58 days after tumor cell inoculation (cachexia, extensive ascites, and tumor masses). In the VEGF Trap plus paclitaxel group, mice were ambulating and eating normally with no signs of disease for at least 81 days after tumor cell inoculation, and survival occurred for 129.9 +/- 38.88 days with no further treatment. We conclude that combination therapy with VEGF Trap plus paclitaxel may provide a novel, long-lasting therapeutic strategy for treatment of patients with ovarian cancer associated with ascites.
Hu
Limin
L
Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143-0556, USA.
Hofmann
Judith
J
Holash
Jocelyn
J
Yancopoulos
George D
GD
Sood
Anil K
AK
Jaffe
Robert B
RB
D000704:Analysis of Variance; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001201:Ascites / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel