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.
Highlights
Preclinical and clinical evidence shows that prostaglandins (PG) play an important role in the growth of tumors
prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) Secretion Are Associated with Expression of Prostaglandin Receptors, Cox-2, and VEGFR1 in Cancer Cells
2LMP breast cancer cells and MCF 10A normal mammary gland epithelial cells were tested for PGE2 EP1-4 receptor, Cox-2, and VEGFR1 mRNA expression, as well as VEGF and PGE2 protein secretion
Summary
Preclinical and clinical evidence shows that prostaglandins (PG) play an important role in the growth of tumors. Cox-2 is overexpressed in the majority of epithelial tumors, including breast and colon cancers. Aberrant upregulation of Cox-2 expression is correlated with prognostic markers that reflect a poor chance for survival, which includes tumor size, axillary node metastases, tumor grade, ductal histology, receptor negative disease, and overexpression of HER-2 [3, 4]. Elevated Cox-2 expression was significantly associated with reduced survival and recognized as an independent prognostic factor in colorectal cancer patients [5]. Cox-2 is involved in activation of tumor-associated angiogenesis and in the inhibition of cancer cell apoptosis [6, 7]. Elevated Cox-2 expression has recently been shown to correlate with distant breast cancer metastases [8]. It was shown that activation of the Cox-2 signaling pathway leads to intestinal epithelial and colon tumor cell proliferation [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
