Combination Of COX-2 Inhibitors Research Articles

Novel Combination of COX-2 Inhibitor and Antioxidant Therapy for Modulating Oxidative Stress Associated with Intestinal Ischemic Reperfusion Injury and Endotoxemia.

Background: Intestinal ischemic reperfusion (I/R) injury is associated with a high mortality rate; this condition is also related to significant endotoxemia and systemic inflammation. The preservation of tissue perfusion and a sufficient blood flow are required to deliver nutrients and oxygen, preserve metabolic pathways, and eliminate waste products. Oxidative stress plays a fundamental role in intestinal I/R injury and leads to disruption of the mucosal barrier and necrosis, allowing the migration of endotoxins and luminal bacteria into the systemic circulation. In this study, we evaluated the beneficial effects of a cyclooxygenase (COX)-2 inhibitor—firocoxib—plus the antioxidant vitamin C in a rat model of intestinal I/R injury. Methods: We used a rat model of I/R injury in which the superior mesenteric artery was clamped for 30 min by a vascular clamp, and the animals were then allowed 1 h of reperfusion. Results: Our results show the importance of combined anti-inflammatory and antioxidant treatment for the prevention of intestinal I/R injury that leads to reduced systemic endotoxemia. We observed a significantly synergistic effect of firocoxib and vitamin C in reducing intestinal wall damage and oxidative stress, leading to a significant reduction of inflammation and endotoxemia. Conclusions: Our results indicate that this approach could be a new pharmacological protocol for intestinal colic or ischemic injury-induced endotoxemia.

EP1.01-95 Up-Regulation of c-Met by Cox-2 Promotes Resistance of Gefitinib in NSCLC Patients

c-Met amplification is one of the reasons for Gefitinib resistance in NSCLC patients. 1.Explore the mechanism of the up-regulation of c-Met by Cox-2; 2.Combination of Cox-2 inhibitor and Gefitinib can overcome Gefitinib resistance in cells or animal study; 3.Test the expression pattern or activity of Cox-2 in NSCLC patients, and evaluate the possibility of Cox-2 serving as biomarker for Gefitinib resistance and prognosis for NSCLC patients. 1.Both c-met and Cox-2 are highly expressed in Gefitinib resistant lung cancer cell lines; 2.Cox-2 is highly expressed in malignant lung adenocarcinoma than in matched normal tissues; 3.Inhibition of Cox-2 can decrease c-Met expression， and promote apoptosis induced by Gefitinib in Gefitinib resistant cells. Up-regulation of c-Met by Cox-2 promotes resistance of Gefitinib in NSCLC patients

Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan.

BackgroundOsteoarthritis (OA) is the most common form of arthritis associated with an increased prevalence of type 2 diabetes mellitus (T2DM), however their impact on decreasing joint replacement surgery has yet to be elucidated. This study aimed to investigate if the combination of COX-2 inhibitor and metformin therapy in OA with T2DM were associated with lower the rate of joint replacement surgery than COX-2 inhibitor alone.MethodsIn total, 968 subjects with OA and T2DM under COX-2 inhibitor and metformin therapy (case group) between 1 January to 31 December 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 1936 patients were the 1:2 gender-, age-, and index year-controls matched without metformin therapy (control group) in this study. Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years of follow-up.ResultsAt the end of follow-up, 438 of all enrolled subjects (15.08%) had received the joint replacement surgery, including 124 in the case group (12.81%) and 314 in the control group (16.22%). The case group tended to be associated with lower rate of receiving the joint replacement surgery at the end of follow-up than the control group (p = 0.003). Cox proportional hazards regression (HR) analysis revealed that study subjects under combination therapy with metformin had lower rate of joint replacement surgery (adjusted HR 0.742 (95% CI = 0.601–0.915, p = 0.005)). In the subgroups, study subjects in the combination metformin therapy who were female, good adherence (>80%), lived in the highest urbanization levels of residence, treatment in the hospital center and lower monthly insurance premiums were associated with a lower risk of joint replacement surgery than those without.ConclusionsPatients who have OA and T2DM receiving combination COX-2 inhibitors and metformin therapy associated with lower joint replacement surgery rates than those without and this may be attributable to combination therapy much more decrease pro-inflammatory factors associated than those without metformin therapy.

Imaging COX‐2 expression in cancer using PET/SPECT radioligands: current status and future directions

The role of cyclooxygenase (COX)-2 as a driving force in early tumourigenesis and the current interest in the combination of COX-2 inhibitors with standard therapy in clinical trials creates an urgent need to establish clinically relevant diagnostic tests for COX-2 expression. Molecular imaging using small-molecule probes radiolabelled for both positron emission tomography (PET) and single photon emission computed tomography (SPECT) offers the potential to meet this need, providing a minimally invasive readout for the whole disease burden. This review summarises current approaches to the radiolabelling of small-molecule COX-2 inhibitors and their analogues for PET and SPECT imaging, and gives an overview of their biological evaluation and likely success of clinical application.

Up-regulation of p53 and mitochondrial signaling pathway in apoptosis by a combination of COX-2 inhibitor, Celecoxib and Dolastatin 15, a marine mollusk linear peptide in experimental colon carcinogenesis

Up-regulation of p53 and mitochondrial signaling pathway in apoptosis by a combination of COX-2 inhibitor, Celecoxib and Dolastatin 15, a marine mollusk linear peptide in experimental colon carcinogenesis

P5-07-02: Could the Combination of COX-2 Inhibitor and Calcitriol Be a New Chemopreventive Approach To Decrease the Incidence of Breast Cancer?

Abstract Background COX-2 is a potential molecular prognostic factor for breast cancer and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is described as a tumour suppressor in cancer. The antiproliferative effects of calcitriol (1,25(OH)2D3) mediated via the vitamin D receptor (VDR) render vitamin D a promising target in breast cancer therapy. Material and Methods: The expression of the prostaglandin (PG) metabolising enzymes (COX-2, 15-PGDH), the PG receptors, the vitamin D metabolising enzymes (1-alpha-hydroxylase, 24-hydroxylase) and the VDR were determined in benign and malignant breast cell lines as well as in normal and malignant breast tissue. Measurement of PGE2 and 25(OH)2D3 serum level in healthy women and breast cancer patients was performed in winter and summertime. Additionally, the influence of calcitriol on cell proliferation was determined. In addition we examined the effect of calcitriol on the enzyme expression. Results: We found an inverse correlation between the expression of the PG metabolising enzymes with the VDR as well as with the vitamin D metabolising enzymes by investigating the tissue samples. Moreover, we detected an inverse correlation between the PGE2 and 25(OH)2D3 serum level in breast cancer patients during wintertime. Furthermore the PG receptors were associated with an increased carcinogenesis. The breast cell experiments presented a dysregulated vitamin D metabolism, especially in the invasive breast cell line. Calcitriol showed an antiproliferative effect only in the benign but not in the malignant cell lines, and the expression of COX-2 and 15-hydroxyprostaglandindehydrogenase was influenced by calcitriol only in the benign breast cell line. Conclusions: These results suggest a link between vitamin D and PG metabolism and therefore a possible synergism between COX-2 inhibition and calcitriol in breast cancer cells. For the first time, we could show an inverse correlation between the two metabolisms in breast cancer on different levels. Thus, the chemopreventive combination of calcitriol and/or vitamin D analogue with a COX-2 inhibitor might decrease the incidence of breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-07-02.

Is the combination of COX-2 inhibitor and calcitriol a new chemopreventive approach to decrease the incidence of breast cancer?

e11103 Background: COX-2 is a potential molecular prognostic factor for breast cancer and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is described as a tumour suppressor in cancer. The antiproliferative effects of calcitriol (1,25(OH)2D3) mediated via the vitamin D receptor (VDR) render vitamin D a promising target in breast cancer therapy. Methods: The expression of the prostaglandin (PG) metabolising enzymes (COX-2, 15-PGDH), the PG receptors, the vitamin D metabolising enzymes (1-alpha-hydroxylase, 24-hydroxylase) and the VDR were determined in benign and malignant breast cell lines as well as in normal and malignant breast tissue. Measurement of PGE2 and 25(OH)2D3 serum level in healthy women and breast cancer patients was performed in winter and summertime. Additionally, the influence of calcitriol on cell proliferation was determined. In addition we examined the effect of calcitriol on the enzyme expression. Results: We found an inverse correlation between the expression of the PG metabolising enzymes with the VDR as well as with the vitamin D metabolising enzymes by investigating the tissue samples. Moreover, we detected an inverse correlation between the PGE2 and 25(OH)2D3 serum level in breast cancer patients during wintertime. Furthermore the PG receptors were associated with an increased carcinogenesis. The breast cell experiments presented a dysregulated vitamin D metabolism, especially in the invasive breast cell line. Calcitriol showed an antiproliferative effect only in the benign but not in the malignant cell lines, and the expression of COX-2 and 15-hydroxyprostaglandindehydrogenase was influenced by calcitriol only in the benign breast cell line. Conclusions: These results suggest a link between vitamin D and PG metabolism and therefore a possible synergism between COX-2 inhibition and calcitriol in breast cancer cells. For the first time, we could show an inverse correlation between the two metabolisms in breast cancer on different levels. Thus, the chemopreventive combination of calcitriol and/or vitamin D analogue with a COX-2 inhibitor might decrease the incidence of breast cancer.

The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies

It is well admitted that the link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways, which act during the different steps of tumorigenesis. The cyclooxygenases (COXs) are a family of enzymes, which catalyze the rate-limiting step of prostaglandin biosynthesis. This family contains three members: ubiquitously expressed COX-1, which is involved in homeostasis; the inducible COX-2 isoform, which is upregulated during both inflammation and cancer; and COX-3, expressed in brain and spinal cord, whose functions remain to be elucidated. COX-2 was described to modulate cell proliferation and apoptosis mainly in solid tumors, that is, colorectal, breast, and prostate cancers, and, more recently, in hematological malignancies. These findings prompt us to analyze here the effects of a combination of COX-2 inhibitors together with different clinically used therapeutic strategies in order to further improve the efficiency of future anticancer treatments. COX-2 modulation is a promising field investigated by many research groups.

Treatment With Cyclooxygenase-2 Inhibitors Enables Repeated Administration of Vaccinia Virus for Control of Ovarian Cancer

Metastatic ovarian cancer is the leading cause of death among women with gynecologic malignancies in the United States. The lack of effective treatment for patients with advanced ovarian cancer warrants development of innovative therapies. Cancer therapy using oncolytic viruses represents a promising new approach for controlling tumors. Vaccinia virus has been shown to preferentially infect tumor cells but not normal tissue. However, oncolytic therapy using recombinant viruses faces the limitation of viral clearance due to generation of neutralizing antibodies. In the current study, we found that cyclooxygenase-2 (Cox-2) inhibitors circumvented this limitation, enabling repeated administration of vaccinia virus without losing infectivity. We quantified the antivaccinia antibody response using enzyme-linked immunosorbent assay (ELISA) and neutralization assays to show that treatment of Cox-2 inhibitors inhibited the generation of neutralizing antibodies. Furthermore, we showed that combination treatment of Cox-2 inhibitors with vaccinia virus was more effective that either treatment alone in treating MOSEC/luc tumor-bearing mice. Thus, the combination of Cox-2 inhibitors and vaccinia virus represents a potential innovative approach to controlling ovarian tumors.

The Relative Efficacies of Gastroprotective Strategies in Chronic Users of Nonsteroidal Anti-inflammatory Drugs

There are numerous gastroprotective strategies recommended for reducing the risk of upper gastrointestinal (GI) complications in long-term users of nonsteroidal anti-inflammatory drugs (NSAIDs). The relative efficacy of the different strategies alone or in combination is uncertain. We used the Manitoba Population Health Research Data Repository to perform a population-based matched case-control analysis. All NSAID users (nonselective and cyclooxygenase [COX]-2-specific) users admitted to the hospital with a primary diagnosis for an upper gastrointestinal complication were matched to NSAID-using controls in the community. We used conditional logistic regression analysis to determine the relative efficacy of different gastroprotective strategies (proton pump inhibitors [PPIs], COX-2 inhibitors, and low-dose/high-dose misoprostol) either alone or in combination and to adjust for multiple pertinent covariates. A total of 1382 NSAID/COX-2 users with upper GI complications were matched to 33,957 age- and sex-matched controls. Cotherapy with PPIs or misoprostol or use of a COX-2 inhibitor all significantly reduced the risk of upper GI complications. COX-2 inhibitors were not statistically more likely to prevent upper GI complications than PPIs, although they were superior to low-dose misoprostol. The combination of COX-2 inhibitors with a PPI was associated with the greatest degree of upper GI complication risk reduction. All of the commonly accepted gastroprotective strategies reduce the risk of upper GI complications in NSAID users, although the combination of COX-2 inhibitors with PPIs promotes the greatest risk reduction for NSAID-related upper GI complications. Celecoxib use specifically may be superior to the combination of nonselective NSAIDs with a PPI.

The Chemosensitizing and Radiosensitizing Eeffect of COX Inhibitors on Gliomas

Many of cyclooxygenase (COX) inhibitors, the non-steroidal anti-inflammatory drugs (NSAIDs) are known to be used for the treatment and prevention of various human cancers. The chemosensitizing and radiosensitizing effect of COX inhibitors on the treatment of gliomas are investigated in this study. Using the colorimetric MTT [3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide] assay, the combination effect of COX inhibitors with other anti-cancer agents on the survival of gliomas was evaluated. The combined use of COX inhibitors (celecoxib, mefenamic acid, nimesulide) with ceramides (phytosphingosine, N-acetyl phytosphingosine N,N-dimethyl phytosphingosine) increased the cytotoxicity of human U87MG, U251MG and U373MG glioma cells, resulted in synergistic growth inhibition of these cell lines. Also, using colony forming assay, the radiosensitizing effect of COX inhibitors on glioma cell lines was tested. The treatment of COX inhibitors prior to ionizing radiation increased the cytotoxic effect of radiation on the glioma cell lines tested. The combination of COX-2 inhibitors with radiation or anti-cancer drugs may increase the therapeutic effects in the cancer treatment, and may reduce the side effects induced by radiation or anti-cancer agents.

Increased risk of gastrointestinal adverse effects under SSRI/NSAID combination may be due to pharmacokinetic interactions

We read with great interest the article by de Jong et al.[1] on the combined use of SSRIs and NSAIDs. The report describes that the combination of NSAIDs with SSRI increased the use of peptic ulcer drugs, which were used as proxy for gastrointestinal adverse effects. Tricyclic antidepressants augmented the risk of peptic ulcer drug use less than SSRIs. Furthermore, the authors emphasize that there are until now no reports about adverse effects caused by the combination of Cox-2 inhibitors and SSRIs. As no separate analyses were presented for the different SSRIs and the different NSAIDs, the report suggests a class effect for SSRIs explaining the observations. The results are discussed by the authors as indicating a pharmacodynamic interaction of the two substance classes, since both classes are independently associated with these types of side-effects. They finally identify the impairment of the haemostatic function due to inhibition of serotonin reuptake as a plausible basis of the observed interaction. These conclusions call for some comments. Firstly, a risk of bleeding disturbances has also been shown for this type of substance, and has been related to alterations of thrombocyte aggregation [2], which weakens the hypothesis of a pharmacodynamic interaction. More importantly, some NSAIDs are substrates of the cytochrome P450 2C9 (e.g. diclofenac, ibuprofen), whereas others in this drug category (e.g. ketoprofen) are not metabolized by this enzyme [3]. Besides, the cox-2-inhibitors celecoxib and rofecoxib are both not significantly metabolized by CYP2C9 [4]. On the other hand, SSRIs differ with regard to their antagonistic properties on this enzyme [5, 6]. Fluvoxamine is, for example, a strong CYP2C9 blocker, which increases its risk for pharmacokinetic interactions with CYP2C9 substrates, whereas the affinity of other SSRIs (e.g. sertraline) for this enzyme is rather weak. The relative risk of interactions may therefore be expected to vary among the class of SSRIs. Furthermore, frequently used tricyclic drugs like amitriptyline or clomipramine are not significant inhibitors of CYP2C9. In conclusion, it cannot be ruled out, that the observations reported by de Jong et al. might be due to pharmacokinetic interactions. The increased risk of gastrointestinal side-effects with NSAID/SSRI combination could be mostly due to increased plasma concentrations of NSAIDs when combined with some particular SSRIs, especially with fluvoxamine. Without analyzing separately the inhibiting and noninhibiting SSRIs on the one hand, and the CYP2C9 substrates on the other, the conclusion that SSRIs as a group may be associated in combination with NSAIDs with such an overproportional risk of gastrointestinal bleeding seems premature.

Cyclooxygenase-2 (Cox-2) Expression in Lymphomas

Lymphoma is a malign disease of the lymphoid system. A variety of risk factors have been described in pathogenesis of disease. We investigated the role of Cyclooxygenase-2 (Cox-2) in malign lymphomas. A total of 52 patients who were admitted to the Oncology Unit of Mersin University with histologically diagnosed lymphoma were enrolled to this study. Ten of the patients had Hodgkin's disease (HD), and 42 had non-Hodgkin's lymphoma (NHL). An immunuhistochemical method was used for Cox-2 expression. Cox-2 expression was detected in 24 of the 42 patients (57%) with NHL, and it was found in seven of the 10 patients (70%) with HD. The mean patient age expressing Cox-2 was 50.2+/-16.6 years and 48.0+/-15.5 years for patients without Cox-2 expression. This difference was not statistically significant (P = 0.660). The overall survival of Cox-2-positive patients was less than for those without Cox-2 expression but the difference was not significant statistically (16.4+/-11.4 vs. 14.7+/-8.2 months, respectively, P = 0.552) in NHL. There was a correlation between Cox-2 and stage of disease. As the stage increased the Cox-2 expression increased (P = 0.037) in NHL. The complete response rate to therapy was significantly higher in Cox-2-negative patients than the Cox-2-positive group (70.6% vs. 20.8%, respectively, P = 0.001) in NHL. There was no correlation between Cox-2 expression and IPI score, extranodal involvement, tumor grade, and B symptoms. Our findings demonstrate that there is a clinical correlation between the Cox-2 expression and prognostic factors in lymphoma patients. The combination of Cox-2 inhibitors with standard chemotherapeutics may enhance the potential of treatment options for malign lymphomas.

Cyclooxygenase-2: A Potential Target in Human Cancer

Cyclooxygenase-2: A Potential Target in Human Cancer

Potential for combined modality therapy of cyclooxygenase inhibitors and radiation.

In conclusion, COX-2 inhibitors have potent anti-tumorigenic activity. Results from animal studies strongly indicate that the likely mechanism for enhanced TGD and TCD50 in tumors treated with radiation and COX-2 inhibitors was the inhibition of angiogenesis. In our recent findings we observed that the antagonists of angiogenesis also inhibited the endogenous as well as phorbol-ester-mediated induction of COX-2 expression in human lung cancer cell lines and that in the xenograft model a combination of angiogenic antagonists and radiation significantly delayed tumor growth [ASCO 2002, Vol. 21 (Part 1); p445a, #1779]. In human tumor models, apoptosis was another mechanism of cell death. Furthermore, it was demonstrated that COX-2 inhibitors could change the intrinsic radiosensitivity of human cancer cells [41]. Therefore, inhibition of angiogenesis by COX-2 inhibitors may be the major mechanism for increased radiation effects in tumors. However, other mechanisms such as changes in tumor perfusion, apoptosis, and an increase in intrinsic radiation sensitivity must also be considered. Inhibitors of COX-2 in combination with radiation therapy may be an alternative strategy that can be tested in clinical trials. The combination of COX-2 inhibitors and radiation suggest a complementary strategy to target angiogenesis while potentially minimizing the impact on quality of life. Currently, the Radiation Therapy Oncology Group [www.rtog.org] is just one of the National Cancer Institute sponsored cooperative groups conducting clinical trials in cervix cancer, lung cancer and brain tumors, using inhibitors of COX-2 in combination with chemotherapy and radiation therapy. These clinical trials will help elucidate the role of this interesting class of agents in combination with cytotoxic therapy for the treatment of cancer.

COX-2 inhibitors in cancer treatment and prevention, a recent development.

Epidemiological and experimental studies have demonstrated the effect of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of human cancers. NSAIDs block endogenous prostaglandin synthesis through inhibition of cyclooxygenase (COX) enzymatic activity. COX-2, a key isoenzyme in conversion of arachidonic acid to prostaglandins, is inducible by various agents such as growth factors and tumor promoters, and is frequently overexpressed in various tumors. The contribution of COX-2 to carcinogenesis and the malignant phenotype of tumor cells has been thought to be related to its abilities to (i) increase production of prostaglandins, (ii) convert procarcinogens to carcinogens, (iii) inhibit apoptosis, (iv) promote angiogenesis, (v) modulate inflammation and immune function, and (vi) increase tumor cell invasiveness, although some studies indicated that NSAIDs have COX-2-independent effects. A number of clinical trials using COX-2 inhibitors are in progress, and the results from these studies will increase our understanding of COX-2 inhibition in both cancer treatment and prevention. The combination of COX-2 inhibitors with radiation or other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Recent progress in the treatment and prevention of cancers of the colon, esophagus, lung, bladder, breast and prostate with NSAIDs, especially COX-2 inhibitors, is also discussed.