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 E2 (PGE2) 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 PGE2 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 PGE2 and VEGF expression were correlated with PGE2 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 PGE2 catabolism in the tumor microenvironment represents a novel approach for therapy of human breast and colon cancer. Copyright © 2009 American Association for Cancer Research.
  • Published In

    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