SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model 英文参考文献.docVIP

Toxins 2010, 2, 2242-2257; doi:10.3390/toxins2092242 OPEN ACCESS toxins ISSN 2072-6651 /journal/toxins Article SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model Rachel Ackerman 1, Joseph M. Backer 2, Marina Backer 2, Sini Skariah 1 and Carl V. Hamby 1,* 1 Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; E-Mails: rb.ackerman@ (R.A.); sini_skariah@ (S.S.) 2 SibTech, Inc., Brookfield, CT 06804, USA; E-Mails: jbacker@ (J.M.B); mbacker@ (M.B.) * Author to whom correspondence should be addressed; E-Mail: hamby@; Tel.: +1-914-594-4195; Fax: +1-914-594-4176. 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 impr