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Tumor neovascularization plays a key role in tumor development and metastatic spread. The cytokine vascular endothelial growth factor (VEGF) and its associated receptor fetal liver kinase-1 (Flk-1/KDR/VEGFR2), appear to play a central role in tumor neovascularization. In solid tumor biopsy specimens, Flk-1 is found frequently to be expressed in tumor vasculature at levels significantly higher than those found in the vasculature of adjacent normal tissue. Previous studies have defined a novel fusion construct of VEGF121 and the highly cytotoxic recombinant plant toxin gelonin (rGel). The VEGF121/rGel fusion toxin was highly toxic to endothelial cells overexpressing Flk-1/KDR, but not toxic to cells expressing the related Flt-1/FLT-1 receptor. Furthermore, VEGF121/rGel was able to inhibit the growth of human melanoma and prostate tumor xenografts in mice. In this study, we demonstrated that VEGF121/rGel, injected i.v. into SCID mice bearing orthotopic human MDA-MB-231 breast tumors, localizes specifically to the tumor vasculature. In addition, we evaluated the effect of VEGF121/rGel on the growth of human breast tumor cells in the lungs of SCID mice. Mice were injected i.v. with human MDA-MB-231 breast tumor cells and, following an eight day establishment period, treated six times with VEGF121/rGel (100 μg/dose) or free gelonin. Three weeks after completion of treatment, mice were sacrificed and lungs were harvested for examination. VEGF121/rGel treatment reduced surface lung foci by 58% compared to gelonin controls (means were 22.4 and 53.3, respectively; p<0.05). The mean area of lung colonies from VEGF121/rGel-treated mice was 50% less than in control mice (210 + 37 μm2 versus 415 + 10 μm2 for VEGF121/rGel and control, respectively; p< 0.01). In addition, pulmonary tumor foci vascularity in VEGF121/rGel-treated mice was reduced by 50% relative to control mice (198 + 37 versus 388 + 21 vessels per mm2 for VEGF/rGel-treated and control, respectively; p<0.02). Lung tumor foci also had a 3-fold lower proliferation (Ki-67 labeling) index than did control tumors. These data suggest strongly that the vascular targeting action of VEGF121/rGel might be utilized, not only for treating primary tumors, but also for inhibiting the development and vascularization of metastases. This research was conducted, in part, by the Clayton Foundation for Research, the Longenbaugh Foundation, and supported by DAMD 17-02-1-0457.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]