الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Colorectal cancer is a major cause of death; its incidence is increasing worldwide. Investigations have been used in an attempt to clarify effects of food constituents on induced colon cancer. Increasing attention has been paid particularly to fat intake and colon preneoplastic interaction with the hope of identifying its correlation with preventive or carcinogenic effects.
In the current study, colorectal pathological changes were identified in male albino rats using 1, 2 dimethyl hydrazine as a chemical carcinogen.
DMH model represented invaluable research tool for studying CRC and for developing and evaluating of a variety of novel chemopreventive agents.
1, 2 DMH, is a potent colon carcinogen, induced colorectal tumors in experimental animals and is a well-established model, widely used in experimental colon carcinogenesis. It has many morphological similarities to human sporadic colorectal cancer (CC).
In the present study studies of 1, 2 DMH allowed monitoring the step-wise development of CRC under defined experimental conditions. Examination of the dissected colons of selected rats after 8 weeks of 1,2 DMH injection showed that induction of colon cancer was a multistep process involving a series of pathological alterations, such as formation of aberrant cryptic foci .
1, 2 Dimethylhydrazine undergoes metabolic activation in the liver to DNA-reactive metabolites by a series of reactions through intermediates and to the ultimate carcinogenic metabolite.
Nonsteroidal anti-inflammatory drugs (NSAIDs) use is important in the treatment and prevention of cancer. Epidemiologic studies in human suggested that the therapeutic effect of NSAIDs on colon cancer was mediated by inhibition of COX-2, which was up regulated in many premalignant and malignant neoplasms.
Meloxicam as a derivative of oxicam fell in the enolic acid group of non-steroidal anti-inflammatory drugs (NSAIDs). It was widely used to treat pain and/or inflammation in humans, and animals. It was chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2- benzothiazine-3-carboxamide-1,1-dioxide.
The present study evaluated the chemopreventive efficacy of meloxicam against 1,2 DMH induced colon tumor in albino rat and its relationship with the crypts mucosa (ACF) as precursors in colon cancer progression in albino rat model in terms of histopathological, histochemical changes and immunoassay estimation of CEA expression as a marker of inflammation and tumor promotion in rat colon .
Furthermore, meloxicam treatment prevented deteriorative effects induced by DMH through a protective mechanism. Food components as well were found to affect colon cancer development which was exhibited by colonic cell proliferation and ACF elevation with increasing dietary fat.
Sixty albino male rats of six weeks old at the beginning of the experiment, weighing from 100-120g were used .The experiment was performed in line with the ethical considerations recommended by Alexandria University, Egypt.
The animals were kept in the animal house, 4 per cage in a temperature and light controlled room. They were maintained on appropriate diet and allowed free access to water ad libitum throughout the experiment.
Colon carcinogenesis was established through weekly subcutaneous injections of 1,2 DMH (20 mg/kg body weight) and sacrificed after 8 weeks, of the injections.
The animals were divided into 5 groups, 12 animals in each group, labeled from A to E.
Group A: The animals were served as control; received S.C.injections of saline solution.
Group B: The animals received S.C.injections of 1,2 DMH dissolved in sterile physiological saline solution in the interscapular region using a tuberculin syringe with a 24-gauge needle once weekly for 8 weeks , fed standard diet and water ad libitum.
Group C: The rats received 1, 2 DMH as in group B with ad libitum access to water and high fat diet.
Group D: The rats fed high fat diet and water ad libitum.
Group E: The rats received S.C.injections of 1,2 DMH as in group B and oral 15mg/kg.b.w. daily meloxicam /0.1 ml saline via gastric tube 1 hour before DMH administration, fed high fat diet and water ad libitum.
Standard diet for groups A & B consisted of 5% fat, 53% carbohydrate, 23% protein, with total caloric value 25 kJ/kg.
High-fat diet for group C,D & E consisted of 30% fat, 48% carbohydrate, and 20% protein with total caloric value 44.3 kJ/kg were used.
The histopathological results suggested that the enhancement of 1,2 DMH induced colon cell proliferation and carcinogenesis was elevated by high fat diet and inhibited by meloxicam.
Histochemical investigation of mucin using Alcian blue pH 2.5 revealed that the numbers of mucus-secreting cells in the colonic mucosa were increased during progression of colon carcinogenesis. Intriguingly, meloxicam caused the numbers and integrity of the mucus-secreting cells to retain close to normal levels. The mechanism was likely to be through its inhibitory effects on early cellular proliferation and modulation of mucin secretion properties in the initiated colonic mucosa.
The study of Feulgen nuclear staining of DNA indicated that 1,2 DMH-induced DNA damage and oxidative stress in albino male rat colon carcinogenesis and reduced effectively using meloxicam which inhibited most of the DNA damage .
Methylene blue staining of whole mounts colon showed morphologically identifiable lesions for colonic carcinogenesis. Aberrant crypt foci (ACFs) were putative preneoplastic lesions in the colonic mucosa identified by examining stained whole mounts of colon. Examination of the mucosal surface of 1,2 DMH treated rats of group B, fed standard diet showed microscopic surface abnormalities that represented an early precursor lesion to colorectal cancer which became more evident in group C that treatd with 1,2 DMH and fed high fat diet .However , AC lesions were less pronounced in colons after meloxicam treatement of rats of group E.
Immunoassay (ECLIA) of serum CEA levels were determined in all studied groups using a ready- for- use electrochem-iluminescence immunoassay Kit (ECLIA-Roche) according to manufacturer’s protocol. The correlations between the changes in the serum CEA levels and the pathological outcomes were analysed. The statistical analysis of the data showed an elevated CEA level which indicated colon preneoplastic progression. The serum levels of CEA in group B and C were significantly greater than CEA level of group A. whereas the serum level of CEA in group E of meloxicam treated rats was similar to almost that of group A. In group C, the serum level of CEA was significantly greater than group B. The elevated level normalized after meloxicam treatment in group E.
More effort should be dedicated to a search for developing and evaluating of a variety of natural and chemopreventive agents, which could block or attenuate CRC process.
The results of the current study confirmed the efficacy of meloxicam a nonsteroidal anti-inflammatory Drug (NSAID), has been known for its anti-inflammatory action with analgesic and fever reducer effects, used in the treatment of rheumatic arthritis and in the protection against abnormal cellular transformation of colon mucosa as well. The growth of aberrant crypt foci in colon was delayed or incompleted after meloxicam use and this was shown to be a good evidence of its effectiveness in colon cancer protection.
We should also put in mind watching the food intake constituents in particular fat content which was proved to be a major factor in enhancing of transformation of normal coloncytes into aberrant foci. The increased quantity of fat in diet has a deteriorated action on the crypts fission and showed a significant increase in proliferation of cells. Hence, it is highly recommended that high fat diet should be avoided or limited and replaced by a healthy balanced food.