title: Carboplatin selectively induces the VEGF stress response in endothelial cells: Potentiation of antitumor activity by combination treatment with antibody to VEGF.
abstract: Vascular Endothelial Growth Factor (VEGF) functions as a key regulator in tumor angiogenesis. In addition, VEGF is an important survival factor for endothelial cells under chemical or physical stress. In our report, we show that treatment of endothelial cells with the chemotherapeutic agent carboplatin significantly increased the expression of VEGF. Furthermore, neutralization of secreted VEGF with specific polyclonal anti-VEGF antibodies or monoclonal antibody sensitized endothelial cells to carboplatin treatment and increased apoptosis several-fold. Interestingly, carboplatin treatment did not alter VEGF expression in tumor cells. Similarly, antibody to VEGF did not change the chemosensitivity of tumor cells to this drug. Most importantly, tumor-bearing animals treated with carboplatin showed an increase in VEGF immunoreactivity in the tumor vasculature, confirming the in vitro studies. Based on these observations, we determined whether neutralization of VEGF could enhance the anti-tumor activity of carboplatin in an in vivo ovarian cancer model system. A combination therapy consisting of a suboptimal dose of carboplatin (32.5 mg/kg/inj., q3d x 5; i.p.) and polyclonal anti-VEGF antibody (2 mg/inj., q3d x 10; i.p.) significantly enhanced solid tumor growth inhibition over individual monotherapies and included multiple complete responses. These findings suggest that VEGF is a critical endothelial cell specific survival factor that is induced by carboplatin and contributes to the protection of tumor vasculature during chemotherapy treatment. In addition, these results provide evidence for a potential mechanism that underlies enhanced anti-tumor activity achieved with chemotherapy and anti-VEGF antibody combination treatment regimens as recently reported in a number of clinical trials. We conclude that a similar type of combination therapy may be applicable to many types of malignancies since VEGF expression was differentially induced in the tumor host environment (i.e., tumor vasculature) and not in the tumor cells themselves; hence, this phenomenon may be independent of the type and origin of the primary cancer.
authors.affiliation: Department of Pharmacology, Comprehensive Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.forename: Indira
authors.initials: I
authors.lastname: Subramanian
authors.forename: S
authors.initials: S
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016190:Carboplatin / Q000494:pharmacology*; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D016190:Carboplatin