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SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model
Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA
SibTech, Inc., Brookfield, CT 06804, USA
* Author to whom correspondence should be addressed.
Received: 23 July 2010; in revised form: 20 August 2010 / Accepted: 26 August 2010 / Published: 27 August 2010
Abstract: SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 106 cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007), reduced the incidence of lung metastasis (p = 0.038), and improved survival (p = 0.002). These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions.
Keywords: biological therapeutics; shiga-like toxin; SLT-VEGF; melanoma; angiogenesis; metastasis; VEGF receptor targeting
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Ackerman, R.; Backer, J.M.; Backer, M.; Skariah, S.; Hamby, C.V. SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model. Toxins 2010, 2, 2242-2257.
Ackerman R, Backer JM, Backer M, Skariah S, Hamby CV. SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model. Toxins. 2010; 2(9):2242-2257.
Ackerman, Rachel; Backer, Joseph M.; Backer, Marina; Skariah, Sini; Hamby, Carl V. 2010. "SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model." Toxins 2, no. 9: 2242-2257.