Experimental cancer therapy using restoration of NAD+ -linked 15-hydroxyprostaglandin dehydrogenase expression.

Academic Article

Abstract

  • Preclinical and clinical evidence shows that cyclooxygenase-2 (Cox-2)-mediated prostaglandin E(2) (PGE(2)) overexpression plays an important role in tumor growth, metastasis, and immunosuppression. It has been shown that expression of NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme responsible for PGE(2) inactivation, is suppressed in the majority of cancers, including breast and colon carcinoma. We have developed adenoviral vectors (Ad) encoding the 15-PGDH gene under control of the vascular endothelial growth factor receptor 1 (VEGFR1/flt-1; Adflt-PGDH) and the Cox-2 (Adcox-PGDH) promoters. The purpose of this study was to investigate cytotoxicity in vitro and therapeutic efficacy in vivo of 15-PGDH-mediated cancer therapy. The levels of PGE(2) and VEGF expression were correlated with PGE(2) receptor and Cox-2 and flt-1 expression in cancer cells. The in vitro study showed that Ad-mediated 15-PGDH expression significantly decreased proliferation and migration of cancer cells. Animal breast and colon tumor therapy studies showed that 15-PGDH gene therapy produced a significant delay in 2LMP and LS174T tumor growth. Combined therapy using 15-PGDH and anti-VEGF antibody (bevacizumab) significantly increased inhibition of growth of LS174T tumor xenografts in comparison with agents alone. These results suggest that 15-PGDH-mediated regulation of PGE(2) catabolism in the tumor microenvironment represents a novel approach for therapy of human breast and colon cancer.
  • Published In

    Keywords

  • Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Bevacizumab, Breast Neoplasms, Cell Growth Processes, Cell Line, Tumor, Cell Movement, Colonic Neoplasms, Combined Modality Therapy, Cyclooxygenase 2, Dinoprostone, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genetic Therapy, Humans, Hydroxyprostaglandin Dehydrogenases, Immunohistochemistry, Mice, Mice, Nude, Promoter Regions, Genetic, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, Xenograft Model Antitumor Assays
  • Digital Object Identifier (doi)

    Pubmed Id

  • 16302761
  • Author List

  • Kaliberova LN; Kusmartsev SA; Krendelchtchikova V; Stockard CR; Grizzle WE; Buchsbaum DJ; Kaliberov SA
  • Start Page

  • 3130
  • End Page

  • 3139
  • Volume

  • 8
  • Issue

  • 11