The combination of COX-2 absence (or inhibition) and the topical effect of NSAIDs lead to changes characteristic of NSAID enteropathy without concomitant COX-1 inhibition and/or associated decreases in mucosal prostaglandins. COX-2 appears to be more important for maintaining small bowel integrity than COX-1.
The side effects of NSAIDs are equally evident in the stomach and the small bowel. The latter is increasingly seen as being clinically significant, contributing substantially to the iron-deficiency anaemia that is so common in patients with rheumatoid arthritis. Furthermore, NSAID-enteropathy may be associated with life-threatening events. The pathogenesis of NSAID-enteropathy is uncertain but inhibition of COX-1 is believed to be of pivotal importance. However there is increasing evidence that COX-2 inhibition and the topical effect may have a synergistic detrimental action. We examined the role of COX-1, COX-2 and the so called topical effect of acidic NSAIDs. We found that COX-1 or COX-2 inhibition and the topical effect alone do not damage the GI tract. Dual inhibition of COX-1 and COX-2 results in intestinal inflammation similar to that caused by Indomethacin. The topical effect may act synergistically in this damage. The conventional view that the mechanism of gastrointestinal damage is principally caused by COX-1 inhibition needs to be revised in view of recent studies using selective inhibitors of the COX enzymes and COX knockout animals.
The pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced gastroenteropathy may involve a number of key events leading to increased intestinal permeability and inflammation (topical effect) and the development of ulcers (micro-vascular effects of COX-1 inhibition and prostaglandin deficiency). Many strategies have been employed in an attempt to reduce the toxic effects of NSAIDs and these have been targeted at the different pathogenic stages of lesion development. One of the latest in this long chain of damage limitation has been the development of nitric oxide (NO) sequestering NSAIDs (NO-NSAIDs). It is suggested that the NO, which is released as the compounds are broken down, may counteract the consequences of the NSAID-induced decrease in mucosal prostaglandins. Here we examine the proposed mechanisms for NSAID-induced gastrointestinal damage together with some of the methods employed to address these mechanisms. We also consider the physiologic roles of NO in the gut together with how it may be potentially employed as an agent for limiting the side effects of NSAIDs in the gastrointestinal tract.
Naproxen and AZD3582 are equally associated with increased small intestinal permeability and inflammation, which is the consequence of their topical effect. The reduced small bowel ulcer counts with AZD3582 accords with the suggestion that vascular factors are the main driving force for NSAID-induced ulcer formation.
Introduction: Immunotherapies such as immune checkpoint inhibitors have had limited success in treating breast cancers. We observed that women with HIV infection and even AIDS have an unusually low incidence of breast cancer. The Tat protein of HIV-1 modulates innate immunity through activation of antigen presenting cells (APCs), and thus could be the reason for this finding. A Tat protein derivative designed to eliminate elements contributing to HIV-1 mediated immunosuppression was expressed as a recombinant protein in E. coli and found to stimulate monocytes to differentiate into antigen presenting cells. This protein, designated PIN-2, was tested in the syngeneic 4T1 murine breast cancer model, a poorly immunogenic and invasive triple negative breast cancer (TNBC) cell line. Methods: In vitro activity of PIN-2 was confirmed using a human monocyte activation assay that determined cell surface expression of CD80 and CD86 by flow cytometry after 72h of incubation with PIN-2, compared with controls. BALB/c mice were implanted orthotopically in the mammary fat pad with 10000 4T1 cells (ATCC No. CRL-2593). Treatment was initiated 7 days after implantation. Mice were administered 100ng PIN-2 intravenously 3x/week for 3 weeks. Tumors were measured 2x/week starting 12 days after implantation using a standard caliper method. Mice were sacrificed 29 days after implantation and examined macroscopically for spontaneous pulmonary metastases. Results: PIN-2 significantly increased human monocyte cell surface expression of costimulatory molecules CD80 and CD86 in vitro at concentrations as low as 30ng/mL culture compared to the negative control (P<0.01). The activation was dose dependent. In vivo, PIN-2 treatment reduced tumor volume to less than 60% of the tumor volume of untreated mice 29 days after tumor implantation (686 mm3 tumor size in placebo vs. 407mm3 in treated mice, p<0.01). Moreover, PIN-2 significantly inhibited the development of spontaneous 4T1 lung metastases (p< 0.05 when compared to placebo). Preliminary examination indicates that 90% of the mice in the control group had visible nodules on the surface of the lungs. Macroscopically visible metastases were reduced to only 50% of the PIN-2 treated mice. There was no evidence of weight loss or apparent toxicity by PIN-2. Conclusion: PIN-2 stimulates cell surface expression of costimulatory molecules that serve as markers for activated antigen presenting cells and are essential for cytotoxic T-cell activation. It reduces primary and metastatic tumor burden in an orthotopic murine model of TNBC. These data suggest that PIN-2 functions as an innate immune agonist to facilitate adaptive anti-tumor immune responses in a poorly immunogenic model of breast cancer. Moreover, PIN-2 appears to be well tolerated, supporting further evaluation of PINS in human breast cancer clinical trials. Citation Format: Christoph M. Hotz-Behofsits, Sophie J. Hanscom, Joshua B. Goldberg, Colin B. Bier. A new class of immunomodulators derivatized from the Tat protein of HIV-1 in a murine breast cancer model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4279. doi:10.1158/1538-7445.AM2015-4279
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