Impact of celecoxib on inflammation during cancer surgery: a randomized clinical trial (original) (raw)
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Celecoxib Can Prevent Tumor Growth and Distant Metastasis in Postoperative Setting
Cancer Research, 2004
Much evidence suggests that an inflammatory condition provides a microenvironment favorable for tumor growth. One of the main components in the healing wound is the induction of cyclooxygenase-2 (COX-2) and prostaglandins, and many solid tumors have been known to overexpress COX-2. The present study investigated the relationship between surgical wounds and tumor growth and the roles of COX-2 and inflammatory reaction in this microenvironment. We created surgical wounds in syngeneic mice for the implantation of SCC VII murine cancer cell line. Accelerated tumor growth and increased angiogenesis by surgical wounds were clearly observed in C3H/HeJ mice with SCC VII tumor. The COX-2 expression of peritumoral tissues and leukocyte infiltration partly explained the accelerated tumor growth, especially in the early phase after surgical wounding. Celecoxib had a significantly suppressive effect on tumor growth, angiogenesis, and metastasis in tumor-implanted mice with surgical wounds. This ...
Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention
Cancer Detection and Prevention, 2004
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutic agents in the treatment of pain, inflammation and fever. They may also have a role in the management of cancer prevention, Alzheimer's disease and prophylaxis against cardiovascular disease. These drugs act primarily by inhibiting cyclooxygenase enzyme, which has two isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Selective COX-2 inhibitors provide potent anti-inflammatory and analgesic effects without the side effects of gastric and renal toxicity and inhibition of platelet function. Celecoxib is a potent COX-2 inhibitor being developed for the treatment of rheumatoid arthritis and osteoarthritis. Chemoprevention is the use of pharmacological or natural agents to prevent, suppress, interrupt or reverse the process of carcinogenesis. For this purpose, celecoxib is being used for different cancer types. The effects of NSAIDs on tumor growth remain unclear, but are most likely to be multifocal. In this article, we reviewed COX-2 selectivity, the pharmacological properties of celecoxib, the use of celecoxib for cancer prevention and the mechanisms of chemoprevention.
Chemotherapy Induces the Expression of Cyclooxygenase-2 in Non-Small Cell Lung Cancer
Clinical Cancer Research, 2005
Purpose: To determine the effect of taxane-based chemotherapy on intratumoral levels of cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ) in patients with non^small cell lung cancer (NSCLC). Experimental Design: Lung specimens obtained at the time of surgery were used to measure levels of COX-2 and PGE 2 in tumors and adjacent nontumorous tissues in three subsets of NSCLC patients who underwent: (A) surgical resection only (n = 16); (B) surgical resection after preoperative taxane-based chemotherapy (n = 13); or (C) surgical resection after preoperative chemotherapy coadministered with the selective COX-2 inhibitor, celecoxib 400 mg bid (n = 17). Results: Levels of intratumoral PGE 2 were nearly 3-fold higher among patients who received preoperative chemotherapy compared with those treated by surgery alone (P < 0.001). This difference was abrogated by the addition of celecoxib to preoperative chemotherapy (P < 0.001).
Cancer Research, 2004
Previous work has demonstrated that selective cyclooxygenase-2 (COX-2) inhibitors can act synergistically with radiotherapy to improve tumor debulking and control in preclinical models. The underlying mechanism of this remarkable activity has not yet been determined. Here, we report that radiation can elevate intratumoral levels of COX-2 protein and its products, particularly prostaglandin E(2) (PGE(2)). Furthermore, inhibition of COX-2 activity or neutralization of PGE(2) activity enhances radiotherapy even in tumors where COX-2 expression is restricted to the tumor neovasculature. Direct assessment of vascular function by direct contrast enhancement-magnetic resonance imaging showed that the combination of radiation and celecoxib lead to enhanced vascular permeability. These observations suggest that an important mechanism of celecoxib-induced radiosensitization involves inhibition of COX-2-derived PGE(2), thus removing a survival factor for the tumor and its vasculature.
Cancer, 2020
Despite dramatic improvements in survival for most cancers over the past decade, outcomes for cancer patients with metastatic disease continue to be dismal; for instance, 5-year survival for patients with stage IV colorectal cancer (CRC) is only 14%. 1 Considerable research and development efforts have expanded the number of available therapeutic options, but these efforts have resulted in marginal improvements in survival and are associated with exorbitant costs to the health care system. In addition, although inexpensive, US Food and Drug Administration (FDA)-approved medications for noncancer indications that may augment current cancer therapies are readily available, they have lain fallow, largely because of a lack of economic incentive. Momentum is building nationally-with both philanthropic and federal support-to introduce some of these drugs (which we have referred to as "financial orphans" 2) into human clinical trials when sufficient preclinical data exist. Ben-Eliyahu and colleagues have made significant contributions to drug repurposing 3 ; in this issue of Cancer, they follow their preclinical observations with a randomized trial of the perioperative combination of COX2 and β-adrenergic blockade in patients with resectable CRC. 4 The concept of perioperative interventions to alter the deleterious effects of surgery is not a new one, and the evidence to support the use of medications in the perioperative setting is abundant. 3,5-7 Cancer surgery and events surrounding the surgery result in a cascade of events that may enhance the metastatic potential of the tumors being resected. These events include removal of the tumor, which may also remove anti-angiogenic factors made by the tumor; creation of the wound required to remove the tumor, which leads to a fairly stereotyped wound-healing/injury response; anesthetic techniques and agents utilized; blood transfusions required during or after the operation; and variations in temperature throughout the perioperative period. In particular, the injury response events-characterized by hemostasis, tissue repair through inflammatory and immune mechanisms, and tissue remodeling through angiogenesis and epithelial/stromal cell proliferation-is an inevitable consequence of surgery and may exert detrimental effects on micrometastatic deposits existing at the time of surgery or on potentiating spread during surgery. Specifically, the influx of neutrophils, macrophages, mast cells, and platelets leads to local and systemic increase in cytokines skewing the immune response toward a repair-oriented/immunosuppressive environment through expansion of regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages. The resultant promotion of stem cell proliferation and epithelial-to-mesenchymal transition (EMT) may awake dormant micrometastases and/or increase the likelihood of residual disease to become aggressive recurrences. In summary, the injury response leads to the development of a tumor microenvironment conducive to proliferation and spread. It follows that medications that inhibit or at least minimize the injury response may prevent tumor progression locoregionally and/or distantly. The goal of these perioperative interventions is to reduce chemokines and growth factors, mitigate immune suppression, inhibit EMT, and reduce stem cell populations. Beta-blockers and COX2 inhibitors are 2 classes of drugs known to suppress these pathways; in preclinical models, blockade with propranolol and etodolac reduced postoperative metastases and/or mortality rates in animal models, including CRC. However, retrospective data have produced conflicting results. 8,9 Thus, there is a need to conduct prospective studies. In the accompanying study, Haldar et al 4 performed a double-blind randomized placebo-controlled trial of propranolol and etodolac in patients undergoing resection for CRC to test the hypothesis that this drug combination would alter the transcription profile away from prometastatic factors. Patients were given drug or placebo for a total of 20 days: 5 days before surgery, and 15 days after surgery. Compliance was measured but was dependent on patient reporting. The primary endpoint was the change in progression-related transcriptome profiles in the tumors measured using genome-wide transcriptional profiling and based on a priori hypotheses about CRC-related pathways thought to be affected by β-adrenergic or COX2 inhibition. Secondary endpoints included compliance, disease-free survival, and safety.
International Journal of Radiation Oncology*Biology*Physics, 2007
Purpose: To evaluate the toxicity and effectiveness of celecoxib in combination with definitive chemoradiotherapy (CRT) in women with locally advanced cervical cancer. Methods and Materials: Thirty-one patients were accrued to a phase I-II trial of celecoxib 400 mg by mouth twice per day for 2 weeks before and during CRT. Tumor oxygenation (HP 5 ) and interstitial fluid pressure (IFP) were measured before and 2 weeks after celecoxib administration alone. The median follow-up time was 2.7 years (range, 1.1-4.4 years). Results: The most common acute G3/4 toxicities were hematologic (4/31, 12.9%) and gastrointestinal (5/31, 16.1%) largely attributed to chemotherapy. Late G3/4 toxicity was seen in 4 of 31 patients (13.7% actuarial risk at 2 yr), including fistulas in 3 patients (9.7%). Within the first year of follow-up, 25 of 31 patients (81%) achieved complete response (CR), of whom 20 remained in CR at last follow-up. After 2 weeks of celecoxib administration before CRT, the median IFP decreased slightly (median absolute, -4.6 mm Hg; p ؍ 0.09; relative, -21%; p ؍ 0.07), whereas HP 5 did not change significantly (absolute increase, 3.6%; p ؍ 0.51; median relative increase, 11%; p ؍ 0.27). No significant associations were seen between changes in HP 5 or IFP and response to treatment ( p ؍ 0.2, relative HP 5 change and p ؍ 0.14, relative IFP change). Conclusions: Celecoxib in combination with definitive CRT is associated with acceptable acute toxicity, but higher than expected late complications. Celecoxib is associated with a modest reduction in the angiogenic biomarker IFP, but this does not correspond with tumor response.