A monoclonal antibody that blocks VEGF binding to VEGFR2 (KDR/Flk-1) inhibits vascular expression of Flk-1 and tumor growth in an orthotopic human breast cancer model.
Vascular endothelial growth factor (VEGF) is a primary stimulant of tumor angiogenesis. We previously raised a neutralizing anti-VEGF monoclonal antibody 2C3 that blocks the interaction of VEGF with VEGFR2 (KDR/Flk-1) but not with VEGFRI (FLT-1/flt-1). Here, we describe the therapeutic effects of 2C3 on tumor growth in an orthotopic model of MDA-MB-231 human breast carcinoma implanted in the mammary fat pads (MFP) of nude mice. Administration of 2C3 to mice with 100-150 mm3 tumors inhibited tumor growth by 75%, as compared to recipients of the isotype-matched irrelevant control IgG, C44. Treatment with 2C3 also inhibited the establishment of tumor colonies and reduced tumor burden in the lungs of mice injected intravenously with MDA-MB-231 cells. No toxicity was observed in these studies. The mean microvascular density (MVD) of tumors in 2C3-treated mice was 55 +/- 5 per mm2, as compared to 188 +/- 5 per mm2 in the C44-treated control group. The decrease in MVD closely correlated with the degree of inhibition of tumor growth. Treated tumors mostly contained mid-size and large vessels. Microvessels were mainly confined to the peripheral layer of tumor that bordered on the normal MFP epithelium. Tumor vessels had decreased expression of VEGFR2, indicating that neutralization of tumor-derived VEGF by 2C3 down-regulates the expression of VEGFR2 on tumor vasculature. This, in turn, may limit reinitiation of angiogenesis by either tumor-derived or stromal VEGF. These findings suggest that 2C3 is a candidate for treating primary cancer and for preventing the outgrowth of tumor metastases in cancer patients.
Zhang
Wei
W
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8594, USA.
Ran
Sophia
S
Sambade
M
M
Huang
Xianming
X
Thorpe
Philip E
PE
D020533:Angiogenesis Inhibitors / Q000276:immunology / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology*; D016228:Endothelial Growth Factors / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008222:Lymphokines / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2