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

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.