The vascular-ablative agent VEGF(121)/rGel inhibits pulmonary metastases of MDA-MB-231 breast tumors.
VEGF(121)/rGel, a fusion protein composed of the growth factor VEGF(121) and the recombinant toxin gelonin (rGel), targets the tumor neovasculature and exerts impressive cytotoxic effects by inhibiting protein synthesis. We evaluated the effect of VEGF(121)/rGel on the growth of metastatic MDA-MB-231 tumor cells in SCID mice. VEGF(121)/rGel treatment reduced surface lung tumor foci by 58% compared to controls (means were 22.4 and 53.3, respectively; P < .05) and the mean area of lung colonies by 50% (210 +/- 37 m(2) vs 415 +/- 10 m(2) for VEGF(121)/rGel and control, respectively; P < .01). In addition, the vascularity of metastatic foci was significantly reduced (198 +/- 37 vs 388 +/- 21 vessels/mm(2) for treated and control, respectively). Approximately 62% of metastatic colonies from the VEGF(121)/rGel-treated group had fewer than 10 vessels per colony compared to 23% in the control group. The VEGF receptor Flk-1 was intensely detected on the metastatic vessels in the control but not in the VEGF(121)/rGel-treated group. Metastatic foci present in lungs had a three-fold lower Ki-67 labeling index compared to control tumors. Thus, the antitumor vascular-ablative effect of VEGF(121)/rGel may be utilized not only for treating primary tumors but also for inhibiting metastatic spread and vascularization of metastases.
Ran
Sophia
S
Simmons Comprehensive Cancer Center and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mohamedali
Khalid A
KA
Luster
Troy A
TA
Thorpe
Philip E
PE
Rosenblum
Michael G
MG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020128:Inhibitory Concentration 50; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D012313:RNA / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; D040301:Vascular Endothelial Growth Factor Receptor-2