Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor

Hwai Loong Kong, Dalit Hecht, Wenru Song, Imre Kovesdi, Neil R. Hackett, Avner Yayon, Ronald Crystal

Research output: Contribution to journalArticle

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Abstract

Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, is overexpressed in most solid tumors. On the basis of the knowledge that solid tumor growth beyond a small volume is critically dependent on angiogenesis, and that adenovirus (Ad) vectors can mediate efficient in vivo gene transfer and expression, we hypothesized that Ad-mediated transfer of a secreted form of the extracellular domain of the flt-1 VEGF receptor (Adsflt) would suppress tumor growth on a regional basis. To evaluate this concept, three tumor models were examined using a murine colon carcinoma cell line and syngeneic BALB/c mice. First, mice with preestablished splenic CT26.CL25 tumors and liver metastases were given Adsflt on AdNull intravenously and, after 15 days, spleens and livers were harvested to quantify tumor burden. Adslft-treated animals had minimal residual splenic tumors and liver metastases; in contrast, control animals had bulky splenic tumors and extensive liver metastases (p < 0.003). Second, mice with preestablished lung metastases showed a significant reduction in pulmonary metastases with regionally administered Adslft (intratracheal, p < 0.02) but not when the vector was systemically administered (intravenous, p > 0.9). Finally, mice with primary subcutaneous tumors treated with intratumoral administration of Adslft showed significant tumor suppression (p < 0.05) not observed in AdNull-treated mice or mice given Adslft intravenously (p > 0.3). We conclude that Ad-mediated in vivo regional delivery of a secreted form of the extracellular domain of the flt-1 VEGF receptor can effectively inhibit regional tumor growth, a strategy that may provide a means to control tumor growth within the treated organ without the risk of systemic antiangiogenesis.

Original languageEnglish
Pages (from-to)823-833
Number of pages11
JournalHuman Gene Therapy
Volume9
Issue number6
Publication statusPublished - 10 Apr 1998
Externally publishedYes

Fingerprint

Vascular Endothelial Growth Factor Receptor-1
Complementary DNA
Growth
Neoplasms
Adenoviridae
Liver
Neoplasm Metastasis
Residual Neoplasm
Tumor Burden
Vascular Endothelial Growth Factor A
Colon
Spleen
Carcinoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor. / Kong, Hwai Loong; Hecht, Dalit; Song, Wenru; Kovesdi, Imre; Hackett, Neil R.; Yayon, Avner; Crystal, Ronald.

In: Human Gene Therapy, Vol. 9, No. 6, 10.04.1998, p. 823-833.

Research output: Contribution to journalArticle

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