There is a growing interest in the role of the nonsteroidal anti-inflammatory drugs (NSAIDs), in particular the cyclooxygenase (COX)-2 inhibitors, in the prevention and treatment of cancer. The benefit of these drugs in reducing the risk of breast cancer has been suggested by recent case control, prospective, and animal studies. The NSAIDs inhibit COX, the enzyme that converts arachidonic acid into prostaglandins (PG). The COX-1 form is constitutive while COX 2 is inducible and overexpressed in human breast tumors, breast cancer cell lines, and rodent mammary tumors. The newly developed COX-2 inhibitors have been shown to reduce the incidence of colon and mammary tumors in rodents and inhibit the growth of established mammary tumors. Although the mechanism of action is not clear, these drugs have been shown to inhibit the COX enzyme, reduce PG production, suppress angiogenic factors, and inhibit angiogenesis. Blocking COX reduced angiogenesis in mice with spontaneous mammary tumors. The ability of the specific COX-2 inhibitors to control the growth of mammary tumors by regulating angiogenesis has not been evaluated. The purpose of this study is to test the hypothesis that inhibition of COX-2 reduces the growth of mammary tumors in a mouse model with overexpression of HER-2/neu by regulating angiogenesis through modulation of the angiogenic factors: vascular endothelial growth factor, basic fibroblast growth factor, and platelet- derived growth factor. We have selected the HER-2/neu mouse model because HER-2 is expressed in 30% of all breast cancers and increased HER-2 expression has been shown to upregulate COX-2. In view of this evidence the specific aims are to: 1. evaluate the effect of COX-1 and COX-2 inhibition on the growth of established mammary tumors; 2. examine the effect of COX-1 and COX-2 suppression on the expression of angiogenic factors; 3. investigate the effect of COX-1 and COX-2 inhibition on angiogenesis; 4. evaluate the effect of COX-1 and COX-2 inhibition on immune function in the mammary gland by determining the presence of immune cells (macrophages and lymphocytes) in the mammary gland and the production of Th-1 and Th-2 cytokines and prostaglandins by normal mouse epithelial cells and mouse tumor cells. The results of this study will define the role of COX inhibitors as an important therapeutic strategy in controlling the progression of breast cancer.
| Lanza-Jacoby, Susan; Dicker, Adam P; Miller, Sheldon et al. (2004) Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice. Mol Cancer Ther 3:417-24 |
