TIME-DEPENDENT VASCULAR REGRESSION AND PERMEABILITY CHANGES IN ESTABLISHED HUMAN TUMOR XENOGRAFTS INDUCED BY AN ANTIVASCULAR ENDOTHELIAL GROWTH-FACTOR VASCULAR-PERMEABILITY FACTOR ANTIBODY

The hyperpermeability of tumor vessels to macromolecules, compared wit h normal vessels, is presumably due to vascular endothelial growth fac tor/vascular permeability factor (VEGF/VPF) released by neoplastic and /or host cells, In addition, VEGF/VPF is a potent angiogenic factor, R emoval of this growth factor may reduce the permeability and inhibit t umor angiogenesis. To test these hypotheses, we transplanted a human g lioblastoma (U87), a human colon adenocarcinoma (LS174T), and a human melanoma (P-MEL) into two locations in immunodeficient mice: the crani al window and the dorsal skinfold chamber, The mice bearing vasculariz ed tumors were treated with a bolus (0.2 ml) of either a neutralizing antibody (A4.6.1) (492 mu g/ml) against VEGF/VPF or PBS (control). We found that tumor vascular permeability to albumin in antibody-treated groups was lower than in the matched controls and that the effect of t he antibody was time-dependent and influenced by the mode of injection , Tumor vascular permeability did not respond to i.p. injection of the antibody until 4 days posttreatment, However, the permeability was re duced within 6 h after i.v. injection of the same amount of antibody, In addition to the reduction in vascular permeability, the tumor vesse ls became smaller in diameter and less tortuous after antibody injecti ons and eventually disappeared from the surface after four consecutive treatments in U87 tumors, These results demonstrate that tumor vascul ar permeability can be reduced by neutralization of endogenous VEGF/VP F and suggest that angiogenesis and the maintenance of integrity of tu mor vessels require the presence of VEGF/VPF in the tissue microenviro nment. The latter finding reveals a new mechanism of tumor vessel regr ession-i.e., blocking the interactions between VEGF/VPF and endothelia l cells or inhibiting VEGF/VPF synthesis in solid tumors causes dramat ic reduction in vessel diameter, which mag block the passage of blood elements and thus lead to vascular regression.