SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model

Rachel Ackerman, Joseph M. Backer, Marina Backer, Sini Skariah, Carl V. Hamby

Research output: Contribution to journalArticle

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 elanoma 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.

Original languageEnglish
Pages (from-to)2242-2257
Number of pages16
JournalToxins
Volume2
Issue number9
DOIs
Publication statusPublished - 1 Sep 2010
Externally publishedYes

Fingerprint

Shiga Toxins
Vascular Endothelial Growth Factor A
Tumors
Melanoma
Neoplasm Metastasis
Recurrence
Lung
Survival
Vascular Endothelial Growth Factor Receptor-2
Neoplasms
Endothelial cells
Endothelial Cells
Nude Mice
Growth
Intradermal Injections
Cytotoxins
Pancreatic Neoplasms
Prostatic Neoplasms
Therapeutics
Breast Neoplasms

Keywords

  • Angiogenesis
  • Biological therapeutics
  • Melanoma
  • Metastasis
  • Shiga-like toxin
  • SLT-VEGF
  • VEGF receptor targeting

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model. / Ackerman, Rachel; Backer, Joseph M.; Backer, Marina; Skariah, Sini; Hamby, Carl V.

In: Toxins, Vol. 2, No. 9, 01.09.2010, p. 2242-2257.

Research output: Contribution to journalArticle

Ackerman, Rachel ; Backer, Joseph M. ; Backer, Marina ; Skariah, Sini ; Hamby, Carl V. / SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model. In: Toxins. 2010 ; Vol. 2, No. 9. pp. 2242-2257.
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