Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice.
A large number of epidemiological studies have shown that regular use of aspirinor other nonsteroidal anti-inflammatory drugs (NSAIDs) results in a 40-50% reduced risk of colorectal cancer (CRC). Furthermore, NSAIDs cause the regression of preexisting adenomas in patients with familial adenomatous polyposis and significantly inhibit tumor growth in animal models of CRC. To establish a CRC liver metastasis model, we implanted mouse colon tumor MC-26 cells into the splenic subcapsule of BALB/c mice, after which mice were given either standard chow or chow containing the cyclooxygenase (COX)-2-specific inhibitor rofecoxib, alone or in combination with the standard antineoplastic agents, 5-fluoruracil or irinotecan. After 14 days, mice that were given rofecoxib or irinotecan, but not 5-fluoruracil, had significantly smaller primary tumors and fewer metastases. Rofecoxib, at clinical anti-inflammatory plasma concentrations, enhanced the effects of both antineoplastic agents when used in combination. Biochemical analyses of the primary splenic tumor in rofecoxib-treated mice showed no alteration in COX-1 expression, but significant decreases in the expression of the tumor-promoting proteins COX-2, cyclin D1, cytosolic beta-catenin, matrix metalloproteinases-2 and -9, and vascular endothelial cell- derived growth factor. Rofecoxib also decreased growth-enhancing prostaglandin E(2) and tumor-suppressive interleukin-10, whereas antineoplastic interleukin-12 was increased. Two separate survival studies were performed. When mice were fed chow containing 0.01% rofecoxib beginning on day 0 after tumor cell implantation, which achieved clinical anti-inflammatory plasma concentrations, survival time was significantly longer compared with mice given control chow. After 30 days, mortality in the control group was 90%, whereas only one mouse (5%) treated with rofecoxib had died after 30 days. In the second survival study, all of the mice were initially fed with regular chow after tumor cell implantation. On day 7, mice were randomly divided into three dietary groups: control chow, low-dose (0.01%) rofecoxib chow, and high-dose (0.025%) rofecoxib chow. After 28 days, mortality was 100%, 20%, and 10% in control, low-, and high-dose rofecoxib fed groups, respectively. These studies demonstrate that rofecoxib decreases the growth and metastatic potential of CRC in mice through multiple mechanisms. These studies in mice also provide important information that supports the benefit of COX-2 inhibition, not only in the prevention of CRC, but also potentially in the treatment of this common malignancy. Clinical trials will be necessary to assess the utility of COX-2 inhibitors as adjuvant therapy for early-stage disease and as potential agents, either alone or in combination, with more established drugs, for the treatment of refractory CRC.
Yao
Min
M
Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118, USA.
Kargman
Stacia
S
Lam
Eugene C
EC
Kelly
Colleen R
CR
Zheng
Yaxin
Y
Luk
Pauline
P
Kwong
Elizabeth
E
Evans
Jilly F
JF
Wolfe
M Michael
MM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000096:biosynthesis; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005472:Fluorouracil / Q000008:administration & dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D000077146:Irinotecan; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007783:Lactones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D013450:Sulfones; D015534:Trans-Activators / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; C495267:CTNNB1 protein, mouse; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003598:Cytoskeletal Proteins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D007783:Lactones; D008222:Lymphokines; D008565:Membrane Proteins; D013450:Sulfones; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; C116926:rofecoxib; D016753:Interleukin-10; D019938:Cyclin D1; D018664:Interleukin-12; D000077146:Irinotecan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone; D005472:Fluorouracil; D002166:Camptothecin