However, research efforts have yielded some promising leads, one of which is the apparent association between NSAID use and decreased cancer risk. Two surgeons, Waddell and Loughry, observed that in patients with Familial Adenomatous Polyposis FAP , a familial form of colorectal cancer, sulindac decreased intestinal polyp burden.
The relative risk of colon cancer for individuals reporting use of 16 or more aspirin tablets a month was 0. There was no protective effect found with acetaminophen, an analgesic which does not affect cyclooxygenase activity. Follow-up studies indicated that aspirin use also reduced deaths from esophageal, gastric and rectal cancer Thun et al. In , Labayle et al. Treatment of these patients with sulindac led to significant repression of polyps.
In , in a carefully designed, randomized, double-blind, placebo-controlled study of 40 patients with FAP, Giardiello et al. That same year, Nugent et al. These studies added to the mounting evidence that NSAIDs had antineoplastic effects, and could affect the development of colorectal cancer, even at the earliest stages. If NSAIDs do reduce the risk of developing colon cancer, by what mechanism do they achieve this effect?
If cyclooxygenase contributed to tumor growth, then one might expect that levels of downstream metabolites i. The increase in prostaglandins may be explained by increased cyclooxygenase expression or increased cyclooxygenase catalytic activity. Other laboratories have since confirmed this observation Kargman et al.
Further evidence implicating COX-2 in colorectal carcinogenesis can be found in studies of animal models of colorectal cancer. One animal model for colorectal cancer is the genetically predisposed Multiple Intestinal Neoplasia Min mouse. The polyps arise almost exclusively in the small intestine, and rarely, if ever, progress to carcinoma, probably because the animals die due to intestinal obstruction or anemia within the first year of life. Another commonly used animal model of colorectal cancer is the azoxymethane AOM treated rat.
The lesions arising in the AOM rat seem to progress from aberrrant crypt foci ACF , to polyp, and finally to carcinoma. Sulindac sulfide effectively prevents polyp formation and causes rapid regression of existing polyps in the Min mouse Boolbol et al. These animal studies, paralleling epidemiological and clinical data in humans, further support the role of cyclooxygenase in colorectal carcinogenesis. To directly test the role COX-2 plays in tumorigenesis, researchers turned to a genetic model.
Mice heterozygous for an adenomatous polyposis coli APC mutant allele develop hundreds of intestinal polyps. This experiment provided direct genetic evidence that COX-2 is important for polyp promotion.
Interestingly, residual tumors were still present in the cox-2 null background. A possible explanation for continued tumorigenesis is that compensation by COX-1 may have been occurring. This study underscores the crucial role COX-2 plays in tumor formation and growth in this animal model.
There are conflicting data regarding whether COX-2 is increased in the epithelial or the stromal component of tumors.
COX-2 has been found to be increased in the epithelium of adenomas in the multiple intestinal neoplasia mouse Min Williams et al. More recently, it has been found that COX-2 expression is increased in the stromal component of adenomas from the Min mouse Hull et al. It is possible that some of these differences in localization may be due to non-specific binding of the antibodies which were used for immunostaining or in tissue procurement or preparation.
Oshima et al. They observed LacZ expression in areas surrounding the adenoma, but no significant expression in the epithelial cells of the adenomas. Therefore, stromally derived COX-2 may promote tumor growth by producing bioactive prostaglandins which affect carcinoma cells in a paracrine fashion. This model supports the notion that COX-2 expression in the stromal component of the adenoma influences tumor growth.
Furthermore, colorectal cancer cell lines that do not express either cyclooxygenase isoform show similar sensitivity to high dose NSAID treatment. If cyclooxygenase were the only relevant target, then NSAIDs might be expected to have similar phenotypic effects. It is possible that in addition to these targets, NSAIDs may interact with other, as yet unidentified, cellular targets.
As illustrated above, most of the confusion regarding the molecular target for NSAIDs has been generated in cell culture assays. In vivo , there is much stronger evidence that COX-2 does play a role in tumor formation.
In vivo , the effective anti-neoplastic NSAID dose is comparable to the amount of drug required to inhibit prostaglandin production. Several investigators have shown that treatment of mice with low doses of selective and non-selective COX-2 inhibitors will attenuate growth of cancer cells grown as xenografts in mice Goldman et al.
Some of the same processes occur in both development and cancer. Indeed, the process of uterine decidualization sometimes is referred to as a pseudomalignant state. It is possible that understanding the role COX-2 plays in development will clarify its role in cancer and vice versa Figure 3. During blastocyst implantation and decidualization, a vascular network must be established to support the nutritional needs of the developing embryo.
In much the same way, the expansion of a tumor mass requires the genesis of a vascular network to support its metabolic demands. There is some evidence that COX-2 generated prostaglandins participate in angiogenesis, a process common to both development and cancer. Maximal tumor expansion occurs when the tumor is able to escape immunologic surveillance, thus avoiding the anti-tumoral onslaught of activated macrophages and cytotoxic T-cells.
COXgenerated prostaglandins have been demonstrated to be immunosuppressive. In tumor models, macrophage-secreted PGE 2 suppresses both macrophage mediated and natural killer cell-mediated cytotoxicity. It has also been demonstrated that PGI 2 is essential for embryo implantation. It is possible that during implantation, PGI 2 is immunosuppressive, and helps to establish an immune-privileged environment in the decidualization zone.
Eicosanoids contribute to normal physiologic processes such as inflammation, development and immune function. Phenotypic analyses of Cox1 and cox-2 null mice have made it clear that the role of these genes in a developing organism is much more complicated than was once thought. For example, the fact that Cox1 null mice do not spontaneously develop ulcers raises the possibility that NSAID-induced gastric ulceration could occur through mechanisms other than, or in addition to, COX-1 inhibition.
Unexpected characteristics are not limited to COX Recently, COX-2 has been demonstrated to play a role in the resolution of inflammation and in ulcer healing. Thus, an expanded role for COX-generated eicosanoids must be considered in the maintenance of mucosal integrity. There is ample genetic and pharmacologic evidence to implicate COX-2 in neoplasia. The precise contribution of COX-2 to neoplastic growth has not been elucidated. However, there is some evidence which suggests that COX-2 may blunt the apoptotic response in tumor cells.
In this way, COX-2 may play a direct role in tumor cell growth. Additionally, there is evidence that COX-2 may indirectly modulate tumor expansion.
It has been demonstrated that COX-2 induces angiogenesis in vitro , and can downregulate natural killer T-cell function; thus, COX-2 in the stromal compartment may influence tumor growth.
Hopefully, future experiments will elucidate the specific roles of the cyclooxygenases in neoplasia and inflammation, and will thereby contribute to the development of safe, effective therapeutic interventions.
USA 91 : — Google Scholar. Cancer 79 : — Kinzler KW and Vogelstein B. USA 93 : — Miller TA. Pollard M and Luckert PH. Pugh S and Thomas GA. In contrast, COX-2 is referred to as an 'inducible isoform', which is believed to be undetectable in most normal tissues, but can be up-regulated during various conditions, many of them pathological.
Even though the role of COX in homeostasis and disease in now well appreciated, controversial information is available concerning the distribution of COX isoforms in normal human tissues.
There is mounting evidence that it is much more complex than generally believed. Our aim was therefore to analyse the expression and distribution of COX isoforms in normal human tissues, using immunohistochemistry, Western blotting and real-time RT-PCR.
NSAIDs such as ketoprofen that are cleared by alternate pathways can be safely used in cats. Glucuronidation also results in significant enterohepatic recirculation. This tends to be greater in dogs than in other species, such as humans. GI prostaglandins are natural inhibitors of gastric acid secretion and support mucosal blood flow. NSAID inhibition of prostaglandin biosynthesis results in increased acidity and decreases mucosal blood flow and mucous production, leading to ulcer formation.
NSAIDs should not be used in conjunction with glucocorticoids as they potentiate gastrointestinal toxicity. Misoprostol, an orally administered synthetic prostaglandin E, may be beneficial in patients at risk for ulceration. Hematological Toxicity: NSAIDs especially aspirin, ketoprofen, and tolfenamic acid should not be used in animals with concurrent hematological disorders or potential bleeding disorders, including thrombocytopenias and von Willebrand's disease.
Their use should be avoided during or near surgeries where hemorrhage may be a problem. NSAIDs typically have little effect on renal function in normal animals. However, they decrease renal blood flow and glomerular filtration rate in patients with congestive heart failure, hypotension, or hypovolemia especially during anesthesia and surgery , or chronic renal disease. Under these circumstances, acute renal failure may be precipitated as NSAIDs block the ability of renal prostaglandins to mitigate the vasoconstrictive effects of norepinephrine and angiotensin II on the glomerular afferent arterioles.
Currently, it is thought that COX-1 is responsible for renal prostaglandin production, so COX-2 selective drugs may avoid this problem. Although attributed to impaired renal blood flow, other mechanisms such as direct nephrotoxicity of the drug or its metabolites may also be involved. Recent reports of carprofen-induced hepatotoxicity in dogs may reflect an idiosyncratic reaction with this drug.
In dogs and cats overdosed with acetaminophen, hepatic necrosis may occur if they survive the primary hematological toxicity. All NSAIDs have the potential to be hepatotoxic however and should be used with caution in animals with underlying liver disease. The time period between switching drugs to allow for safe administration of the 2nd product. An interaction has been demonstrated between prednisolone and ketoprofen or meloxicam Narita et al , and there are case reports of GI perforations when dericoxib is used concurrently with steroids or other NSAIDs.
Although various washout schedules have been published, the exact time required when switching NSAIDs is not definitively known. One rule of thumb is to observe 10 half-lives of the first drug so that Remember that aspirin has an irreversible effect on platelet function which persists long after the drug is eliminated from the body. J Vet Intern Med. J Vet Pharmcol Therap.
Aragon CL et al, Systematic review of clinical trials of treatments for osteoarthritis in dogs. JAVMA ; 4 Steagall PVM et al, Evaluation of the adverse effects of oral firocoxib in healthy dogs.
J Vet Pharmacol Therap. J Vet Med Sci.
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