title: SLT-VEGF reduces lung metastases, decreases tumor recurrence, and improves survival in an orthotopic melanoma model.
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 × 10(6) 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.
authors: Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA. rb.ackerman@gmail.com
authors: Rachel
authors: R
authors: Ackerman
authors: Joseph M
authors: JM
authors: Backer
authors: Marina
authors: M
authors: Backer
authors: Sini
authors: S
authors: Skariah
authors: Carl V
authors: CV
authors: Hamby
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D008136:Longevity / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D022621:Shiga Toxin / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: D011993:Recombinant Fusion Proteins; D022621:Shiga Toxin; D040262:Receptors, Vascular Endothelial Growth Factor