Experimental Study Of Cyclooxygenase-2 Inhibitors In Combination With Radiotherapy

Background: Recently, it was established that there exist two isoforms of enzymes that synthesize PGs :Cox-l and Cox-2. Cox-1 is a ubiquitous constitutive enzyme that has a housekeeping physiological function, whereas Cox-2 is an inducible from that is induced by diverse inflammatory stimuli, oncoproteins, and growth factors. Increasing evidence shows that Cox-2 promotes carcinogenesis as well as the growth of established tumors. Cox-2 is up-regulated in a high percentage of common cancers in humans and is associated with invasive and metastatic tumor behavior. Thus, the specific expression of Cox-2 in tumors but not in normal tissue may serve as a potential target for anticancer therapy Newly developed selective inhibitors of Cox-2 have been shown to prevent carcinogenesis and to slow the growth of tumors in experimental animals. There is evidence that the mechanism involves PGs, which can modulate cellular injury induced by a wide array of agents, including ionizing radiation. A number of natural PGs and their synthetic analogues have shown the ability to protect cells and tissue from radiation injury. With respect to canner, prodution of PG by tumors was found to be associatedwith tumor radioresi stance. Tumors were made more responsive to radation when their production of PGs was suppressed by NSAIDs(non-steroidal anti-inflammatory drugs). In addition, NSAIDs increased radiosensitivity of cancer cells in vitro. Because commonly used NSAIDs inhibit both Cox-1 and Cox-2, treatment with these agents may be limited by normal tissue toxicity, particular that of the gastrointestinal tract. Because selective Cox-2 inhibitors exert potent anti-inflammatory activity but cause fewer unwanted side effectsPurpose: To investigate whether Rofecoxib, a selective inhibitor of Cox-2, potentiates anti-tumor efficacy of radiation. Methods: C57BL/6 mice bearing the Lewis tumors(LLC) were treated with IR alone (6MV-X, 5Gy/day d^u^is), Cox-2 inhibitor alone (Rofecxib, 0.4mg/kg/day, intragastric administration, di2-i6), Normal saline(200ul per mice, intragastric administration, d12-i6) and IR plus Rofecoxib (6MV-X, 5Gy/day di2,i4,i6,i8 ; Rofecxib, 0.4mg/kg/day, intragastric administration, d.12-16) when tumors reached 5-7mm in diameter, Tumor size was recorded , Every 3 days during the treatment and mouse models were killed for measuring the tumor volum after completion oftreatment. After the completion of therapy. Tumor metastases to lung were examinated. Microvessel density(MVD), Cox-2, P53 and Bcl-2 were evaluated by immunohistochemical means,Tumor apoptosis was evaluated by Tunel assay.Results: As compared with three other groups, the combined treatment group with IR and Cox-2 inhibitor (Rofecoxib) therapy significantly reduced tumor volume and prolonged the life span of tumor burden mice as well. In addition, the average lung weight and the number of metastases per lung were lower in IR plus Cox-2 inhibitor group than that of any other group. Immunohistochemical analysis and Tunel assay demonstrated a decreased MVD and a higher apoptosis cell rate in IR plus Cox-2 inhibitor group.Conclusion: The antitumor effect of IR can be potentiated by Cox-2 inhibitor therapy. These findings suggest a promising way to overcome tumor radiotherapy resistance by Cox-2 inhibitor therapy. .