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Prevention of Colon Cancer by Low Doses of Celecoxib,a Cyclooxygenase Inhibitor, Administered in DietRich in W-3 Polyunsaturated Fatty Acids Bandaru S. Reddy,1 Jagan M. Patlolla,2 Barbara Simi,1S.H. Wang,1 and Chinthalapally V. Rao2 1Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Rutgers State University ofNew Jersey, Piscataway, New Jersey and 2University of Oklahoma Health Science Center, OU Cancer Center,Department of Medicine, Oklahoma City, Oklahoma etiology of colon cancer (3). A report by an expert panel assembledby the American Institute for Cancer Research and World Cancer Epidemiologic and animal studies suggest that a high-fat diet Research Fund came to the scientific consensus that evidence for an containing mixed lipids promotes colorectal cancer, whereas association between the intake of saturated fat and/or animal fat fish oil lacks promoting effect. Although cyclooxygenase-2 and colon cancer risk is very strong (3). Continuing population (COX-2) inhibitors are effective chemopreventive agents studies revealed that diets particularly high in animal fat are against colon carcinogenesis, administration of high doses of generally associated with increased risk of developing colon cancer, these agents over time may induce side effects. Here, we whereas diets high in fish oil or fish reduces this risk (4, 5). In a compared the efficacy of moderately high and low doses of phase II clinical trial of patients with colonic polyps, dietary fish oil celecoxib administered in diets high in mixed lipids (HFML) or supplements inhibited cell proliferation in the colonic mucosa (6).
fish oil (HFFO) against azoxymethane-induced colon carcino- In support of this, several animal studies using well-established genesis in male F344 rats. One day after the last azoxymethane colon cancer models provided ample and consistent experimental treatment (15 mg/kg body weight once weekly for 2 weeks), evidence that diets containing high levels of saturated fatty acids, groups of rats were fed the HFML and HFFO diets containing such as those in Western diets, promote colon carcinogenesis, 0, 250, 500, and 1,000 ppm celecoxib. Rats were killed 26 weeks whereas diets high in N-3 polyunsaturated fatty acids (PUFA) had no later and colon tumors were subjected to histopathologic such promoting effect (7–11). An assay in mice showed that a high- examination and analyzed for total COX and COX-2 synthetic fat diet simulating the mixed lipid composition of the average activities and COX-2 expression. Rats fed the HFFO diet American diet induced dysplastic lesions in the colon, indicative of showed significantly lower colon tumor incidence and tumorigenesis (12). Existing evidence suggests that the N-3 PUFA– multiplicity compared with rats fed the HFML diet. Celecoxib induced colon tumor inhibition is mediated in part through the at 250, 500, and 1,000 ppm in either diet significantly suppression of cyclooxygenase-2 (COX-2) activity and increases in suppressed colon carcinogenesis. Inhibition of colon adeno- apoptosis in colon tumors (7, 13–15). Also, dietary N-3 PUFAs may carcinomas were more pronounced in animals given 250 ppm protect against colon carcinogenesis by decreasing DNA adduct celecoxib in HFFO diet compared with 250 ppm celecoxib formation and/or enhancing DNA repair (14).
given in HFML diet, suggesting some synergism between W-3 Studies using either transgenic and knockout mice have provided polyunsaturated fatty acids (PUFA) and celecoxib. Inhibition convincing evidence for the association between COX-2 expression of colon tumors by celecoxib was associated with lower levels and colon tumorigenesis (16, 17). The discovery that COX-2 of COX-2 activity and expression in colon tumors. These inhibitors, such as celecoxib, inhibit development of colonic polyps studies support the use of low doses of celecoxib in W-3 PUFA– in patients with familial adenomatous polyposis is a seminal rich diet as a promising approach for clinical trials. (Cancer advance in the chemoprevention of colon cancer (16, 18). Studies Res 2005; 65(17): 8022-7) conducted by several investigators clearly show that celecoxib,rofecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID) are effective for the prevention and regression of adenomas in the Colon cancer, which is the fourth most common cancer in the mouse model of adenomatous polyposis (19–25). The results from world, is one of the leading causes of cancer death in both men and our studies have provided convincing evidence that celecoxib women in Western countries, including the United States where administered during the initiation, postinitiation, and progression f145,290 new cases of colorectal cancer are estimated for the year stages of colon carcinogenesis inhibits colon carcinogenesis in 2005 (1, 2). Therefore, it is a major public health problem worldwide.
chemically induced colon carcinogenesis (26–28).
Epidemiologic studies suggest that dietary factors, particularly Preclinical studies conducted in our laboratory have affirmed caloric intake and saturated fat, may be of importance in the that colon tumor inhibition by celecoxib at 40% maximum tolerateddose is much more effective than by traditional NSAIDs, includingaspirin, ibuprofen, piroxicam, and sulindac, administered at 80%maximum tolerated doses (29). Patients with familial adenomatous Requests for reprints: Bandaru S. Reddy, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, 164 Frelinghuysen polyp after 6 months of twice daily treatment with 400 mg celecoxib Road, Piscataway, NJ 08854. Phone: 732-445-3400; Fax: 732-445-0687; E-mail: had 31% reduction in polyposis number; whereas 200 mg celecoxib twice daily reduced polyp number to 12% (18). Regression of rectal 2005 American Association for Cancer Research.
polyps was reported in placebo-controlled studies by Giardiello Cancer Res 2005; 65: (17). September 1, 2005 Colon Cancer Prevention by Celecoxib in w-3 PUFA Diet et al. (30) and Nugent et al. (31) using sulindac. However, rapid Table 1. Percentage composition of experimental diets recurrence of adenomas was observed in 3 to 4 months afterdiscontinuation of sulindac therapy. Long-term studies, as well as direct comparisons of these two classes of NSAIDs, could furtherdefine the clinical benefits of these two classes of agents. However, the cardiovascular and renal effects in humans of long-term administration of very high doses of COX-2 inhibitors raise several concerns for their large-scale clinical applications. Also, there is limited evidence in preclinical models to indicate the efficacy of doses lower than 500 ppm celecoxib. Therefore, it is important to design strategies with low doses of celecoxib that will be clinically favorable without any side effects for longer periods. Additionally, there is increasing interest in the use of combinations of low doses Choline bitartrate of chemopreventive agents that differ in modes of action ratherthan administering a single agent at a higher dose as a means ofobtaining increased efficacy and minimized toxicity. Studies NOTE: All diets were formulated on the basis of the AIN standard conducted in our laboratory have provided convincing evidence reference diet with the modification of varying sources of carbohy- that the combination approach indeed provides greater efficacy drate (10, 15).
than the chemopreventive agents administered alone (27, 32).
*Mixed lipid diet containing American blend fat developed by the Although both epidemiologic and animal studies have provided Institute of Shortening and Edible Oils was formulated to simulate the evidence for the beneficial effects of diets rich in N-3 PUFAs, it should lipid content of the average American diet. The composition of mixed be recognized that intervention with nutritional supplements and/ lipids is described in detail in Materials and Methods.
or diet modification alone may not be sufficient for secondaryprevention of colorectal cancer in high-risk patients, such as thosewith hereditary polyposis and sporadic colon polyps. There is a need continued on the standard low-fat (5% corn oil), semipurified AIN-76A diet.
to combine the lifestyle factors with chemopreventive agents and to Then, beginning at 7 weeks of age, all rats in each dietary group (n = 24), use this regimen as a cancer preventative strategy. This study was except the vehicle-treated control groups, received s.c. azoxymethane designed to examine the efficacy of different levels of celecoxib (15 mg/kg body weight) once weekly for 2 weeks (Fig. 1). Rats in the vehicle- when administered in diets high in mixed lipids (saturated and treated groups (n = 12) received an equal volume of normal saline. One day unsaturated fats) that are consumed in Western countries, including after the last second azoxymethane or saline injection (postinitiation stage), the United States, or N-3 PUFAs against azoxymethane-induced groups of animals were transferred to their respective HFML and HFFO colon carcinogenesis in F344 rats. In addition, we determined the diets with 0, 250, 500, and 1,000 ppm celecoxib and maintained on their effects of these diets on the total COX activity and COX-2 activity and dietary regimen until termination of the study at 26 weeks after the second expression in colon tumors (i.e., to provide an understanding of the azoxymethane or normal saline treatment. The rats in each group wereweighed once weekly until they were 16 weeks of age and then measured effects of these types of dietary fats and celecoxib on the modulation once every 4 weeks.
of molecular events relevant to colon carcinogenesis).
As scheduled, all rats were killed by CO2 asphyxiation. After laparotomy, the entire stomach, small intestine, and large intestine were resected. Theywere opened longitudinally and the contents were flushed with normal saline.
Materials and Methods They were examined for intestinal tumors, and the location and number of Materials. Azoxymethane was purchased from the Midwestern Research tumors were assessed with a dissection microscope and recorded. Colons Institute (Kansas City, MO). 14C-Arachidonic acid was purchased from were laid flat on a glass plate, and the tumor-free colonic mucosa was scraped Amersham (Detroit, MI). Precoated silica G plastic thin layer chromatog- off with a glass slide. Colon tumors with a diameter of >0.5 cm were cut into raphy plates were bought from Fisher Scientific Co. (Springfield, NJ) and halves; one portion of the tumor was assayed for COX enzyme activity and Amberlite XAD-2 (50-70 mesh) was purchased from V.W.R. Scientific Co.
expression levels, and other halves of the tumors and neoplasms <0.5 cm were (Piscataway, NJ). Celecoxib was donated by Pfizer, Inc. (Chesterfield, MO).
used for histopathologic examination. The mucosal scrapings and portions of Animals and diets. A total of 230 male F344 rats received at weaning colon tumors were quickly frozen in liquid nitrogen and stored at 80jC until from the Charles River Breeding Laboratory (Kingston, NY) were analysis. The rationale for determining COX-2 activity and expression in quarantined for 7 days and had access to modified American Institute of colon tumors has been based on the observation that COX-2 gene Nutrition (AIN)-76A control diet. All ingredients of experimental diets were expression and protein expression are markedly elevated in human colon obtained from Dyets, Inc. (Bethlehem, PA) and were stored at 4jC before tumors and also in chemically induced colon tumors in rats compared with the preparation of the diets. The composition of the experimental diets that accompanying colon mucosa (28, 33–35). Therefore, we investigated whether was based on AIN-76A diet was adjusted so that all diets would provide the the modulation of colon tumorigenesis by celecoxib administered in high-fat same amount of calories, protein, vitamins, minerals, and fiber (Table 1).
diets containing mixed lipids and N-3 PUFAs is mediated through COX-2 Fish oil was donated by the Menhaden Oil Refinery of Zapata Protein, Inc.
activity in colon tumors. The mucosal scrapings were not used to determine (Reedville, VA) In the high-fat mixed lipid (HFML) diet, 20% fat content was the COX activity because our previous studies have shown that the total COX formulated using a slight modification of the American blend fat developed activity and COX-2 activity were very low in colonic mucosa and were not by the Institute of Shortening and Edible Oils (15). The mixed lipids contain influenced by chemopreventive agents (15, 28). Therefore, activities of these beef tallow (16%), lard (10%), butter fat (12%), hydrogenated soybean oil enzymes were determined in colon tumors. However, we did investigate (30%), peanut oil (5%), and corn oil (27%). The high-fat fish oil (HFFO) diet whether low dose of celecoxib in HFFO and HFML diets modulates the contained 10% mixed lipids and 10% fish oil (Table 1).
COX-2 expression levels in colon mucosa and tumors.
Experimental procedure. The experimental protocol is summarized in Intestinal tumors. For histopathologic evaluation, intestinal tumors Fig. 1. Following quarantine, all animals were distributed by weight into were fixed in 10% buffered formalin, embedded in paraffin blocks, and various experimental groups (treatment and appropriate controls) and processed by routine histologic procedures with H&E staining. The stained Cancer Res 2005; 65: (17). September 1, 2005 Figure 1. Experimental design andprotocols. Groups of male F344 rats weregiven azoxymethane (AOM ) at a dose levelof 15 mg/kg body weight, once weekly, s.c.,beginning at 7 and 8 weeks of age. Oneday after the second azoxymethanetreatment, rats were transferred to theirrespective experimental diets. All animalswere killed by CO2 asphyxiation at26 weeks after second azoxymethanetreatment and colon tumors were subjectedto histopathology (detailed information hasbeen discussed in Materials and Methods).
sections were examined for tumor types by a pathologist according to the classification of Pozharisski (36), which is followed routinely in our General observations. The body weights of rats treated with laboratory (15, 28). Most of the colon tumors were invasive or noninvasiveadenocarcinomas (15, 28).
azoxymethane and fed the HFML diet or the HFFO diet with or Total cyclooxygenase and cyclooxygenase-2 specific activity and without different levels of celecoxib were comparable throughout Western blot analysis of cyclooxygenase-2. Because COX enzyme is firmly the study (data not shown). In saline-treated rats, feeding of HFML bound to the luminal surface of the endoplasmic reticulum and nuclear and HFFO diets containing various levels of celecoxib did not envelope, the microsomal fractions of the colonic tumor samples from the produce any gross changes in several organs that would indicate animals fed the 250 ppm celecoxib in HFML and HFFO diets were prepared toxicity or adverse side effects.
as previously described (15). COX activities in colonic tumor samples were Efficacy of different levels of celecoxib administered in high- assayed by using previously published methods (15). Western blot analysis of fat mixed lipid and high-fat fish oil diets. There is no evidence of COX-2 in colonic mucosa and tumors was done as previously described (15).
colon tumors in saline-treated animals fed the control or Statistical analysis. Differences in colon tumor multiplicity and COX experimental diets. Azoxymethane-treated animals fed the control activities were compared between the animals fed HFFO and HFMLcontaining the same level of celecoxib diets. All results were expressed as HFFO diet had a significantly lower colon tumor incidence the mean F SE and analyzed by Student's t test. Tumor incidence was (percentage animals with tumors; P < 0.001; Fig. 2) and multiplicity analyzed by Fisher's exact probability test. Differences were considered (number of tumors/animal; P < 0.001; Fig. 3) when compared with significant at P < 0.05.
those fed the control HFML diet. Importantly, administration of Figure 2. Effects of different levels of celecoxibadministered in HFML and HFFO diets onazoxymethane-induced colon tumor incidence(percentage of animals with tumors) in male F344rats. Tumor incidences were compared by Fisher'sexact probability test. Columns, mean (n = 22-24rats). *, significantly different from their respectivecontrol diets by Fisher's exact probability test(P < 0.00001). H, significantly different from controlHFML diet at P < 0.001. I, significantly differentfrom control HFFO diet at P < 0.02. V, significantlydifferent from 250 ppm celecoxib in HFML diet atP < 0.05.
Cancer Res 2005; 65: (17). September 1, 2005 Colon Cancer Prevention by Celecoxib in w-3 PUFA Diet Figure 3. Effects of different levels of celecoxibadministered in HFML and HFFO diets onazoxymethane-induced colon tumor multiplicity(tumors per rat) in male F344 rats. Tumor multiplicitieswere compared by Student's t test. Columns, mean FSE (n = 22-24 rats). *, significantly different from theirrespective control diets at P < 0.00001. H, significantlydifferent from control HFML diet at P < 0.001.
I, significantly different from control HFFO diet atP < 0.05. V, significantly different from 250 ppmcelecoxib in HFML diet, P < 0.05.
celecoxib to rats at 1,000, 500, and 250 ppm levels in the HFML diet our previous studies, we have formulated the HFML diet so as to dramatically suppressed the incidence of adenocarcinomas by simulate the types of fat that are often consumed in the United 100%, 90%, and 84%, respectively, compared with those fed the States and other Western countries (15). The current study also control HFML diet without celecoxib (Fig. 2). Furthermore, investigated a HFFO diet that contained 10% mixed lipids and 10% celecoxib at 1,000, 500, and 250 ppm levels in HFFO diet also fish oil. Our aim for the present study was also to determine greatly inhibited the incidence of adenocarcinomas compared with whether celecoxib is effective in inhibiting colon carcinogenesis in those fed the control HFFO diet without celecoxib. It is noteworthy animals fed the high-fat diets. The results of this investigation that administration of 250 ppm celecoxib in HFFO diet significantly clearly show that consuming a diet rich in N-3 PUFAs (HFFO) had a (P < 0.05) inhibited colon tumor multiplicity compared with those higher potential to inhibit colon tumorigenesis compared with a fed the HFML diet containing 250 ppm celecoxib (P < 0.05; Fig. 3), Western-style diet high in mixed lipids, including saturated fats of suggesting that very low dose of celecoxib administered in N-3 animal origin as well as N-6 PUFAs (HFML).
PUFA diet inhibits colon carcinogenesis better than when it is In our previous study, the incidence of adenocarcinomas was administered in mixed lipid diet.
inhibited by 31% in the rats fed the HFFO diet (15) and in the Cyclooxygenase activity and expression. We investigated whether the inhibition of colon tumorigenesis by very low dose ofcelecoxib (250 ppm) administered in HFML and HFFO diets is Table 2. Effects of celecoxib administered in HFML and associated with the modulation of arachidonic acid metabolism by HFFO diets on total COX activity and COX-2 activity in COX activity and COX-2 expression in colonic tumors. Rats fed the HFFO diet had significant inhibition of total COX activity and COX-2activity in the colon tumors as indicated by the arachidonic Experimental group Total COX activity metabolites (eicosanoids) formed from arachidonic acid comparedwith rats fed the HFML diet (Table 2). Colonic tumors from rats fed HFML diet + 250 ppm the HFFO diet and very low dose (250 ppm) of celecoxib had lower COX activity (29% inhibition) and COX-2 activity (36% inhibition) compared with those fed the HFML diet and 250 ppm celecoxib. The HFFO diet + 250 ppm effects of very low dose of celecoxib administered in HFML and HFFO diets on COX-2 expression were determined in colonictumors. Figure 4 shows a representative Western blot analysis ofCOX-2 expression in colonic tumors and mucosa. COX-2 expression NOTE: As detailed in Materials and Methods, microsomal fractions of was not detected in colonic mucosa irrespective of dietary colonic tumors from animals fed the HFML and HFFO diets treatment. This supports our previous observations that COX-2 containing celecoxib at 0.250 ppm were assayed for COX-2 and COX expression was either minimally or not detected in the colon mucosa activities. The data represents mean F SE (n = 3-6 tumors). Total COX of rats treated with colon carcinogen (15, 34). It is noteworthy that activity is expressed as nanomoles of [14C]arachidonic acid metabo- the expression of COX-2 in colon tumors of rats received azoxy- lized per milligram of protein per 15 minutes. COX-2 activity isexpressed as nanomoles of [14C]15-R -hydroxyeicosatetraenoic acid methane treatment and fed 250 ppm celecoxib in HFFO diet is lower formed per milligram of protein per 15 minutes.
compared with those fed 250 ppm of celecoxib in HFML diet.
*Significantly decreased from their respective controls at P < 0.01 toP < 0.001 by Student's t test.
cSignificantly different from their respective controls at P < 0.003 to P <0.001 by Student's t test.
The present study is a part of an ongoing preclinical inves- bSignificantly decreased from HFML diet at P < 0.01 by Student's t test.
tigation of the effects on types of dietary fat and combinations of Significantly decreased from HFML diet at P < 0.05 by Student's t test.
chemopreventive agents against colon carcinogenesis. Here and in Cancer Res 2005; 65: (17). September 1, 2005


current study the inhibition reached f70% compared with those strategy for prevention of colon cancer. This approach is extremely fed the HFML diet. The major differences in these two studies were important to enhance the efficacy of a promising chemopreventive the composition of HFFO diet and duration of study period. In the agent, such as celecoxib, and to eliminate untoward side effects, if current study, HFFO diet contained 10% mixed lipids and 10% fish any, of very high dose of this agent. The results of the low dose of oil, and the animals were on the experimental diets for f24 weeks; celecoxib administered in HFML and HFFO diets are further whereas, in our previous study, the HFFO diet was formulated to evidence for the potential of this compound as a chemopreventive contain 17% fish oil and 3% corn oil, and all animals received this agent against colon carcinogenesis. Another important observation diet for 38 weeks (15). Earlier studies have shown that 1,500 ppm of the present study is that the colon tumor multiplicity is celecoxib administered in a low-fat AIN-76A diet 1 week before, significantly lower in animals given 250 ppm celecoxib in HFFO during, and after azoxymethane treatment (initiation and post- diet compared with those administered 250 ppm celecoxib in initiation stage) and 500 and 1,500 ppm celecoxib in a low-fat diet HFML diet. To our knowledge, this is the first demonstration of a during the promotion and progression stage significantly sup- moderate but significant chemopreventive effect of low dose of pressed colon carcinogenesis in rats (26, 28). Differences among celecoxib administered in N-3 PUFA–rich diet (healthy lifestyle) these studies compared with present study on the degree of compared with that of mixed-lipid diet.
inhibition of colon adenocarcinomas by different levels of celecoxib The present study shows that feeding of HFFO diet decreased the might be explained on the basis of when this agent was expression and formation of eicosanoids from the arachidonic acid administered (i.e., during the initiation, postinitiation, and/or (COX activity) in colon tumors. Arachidonic acid is metabolized to promotion and progression stage of colon carcinogenesis), what eisosanoids via COX enzyme. The results of the present study type of basal diet was used, and how many weeks the animals were support the findings of our earlier study that colon tumor inhibition on the experimental diets. These aspects might explain the by N-3 PUFA–rich diet is mediated through the suppression of COX difference in tumor inhibition between the two studies.
activity and COX-2 expression (15). As discussed above, several To our knowledge, this is the first study to show that reports indicate that eicosanoids have a role in the pathogenesis of administration of celecoxib at 250 ppm representing very low dose colon cancer (16, 33). Also, some studies indicate that dietary N-3 in HFML and HFFO diets significantly suppresses colon carcino- PUFAs may protect against carcinogenesis by either decreasing genesis. Furthermore, low and moderately high doses (250, 500, and DNA adduct formation and/or enhancing DNA repair as well as 1,000 ppm) of celecoxib suppressed the colon tumor incidence and increasing apoptosis (13–15). It has been shown that the inhibition multiplicity by f80% to 100% even in rats fed the HFML diet. This of colon carcinogenesis by N-3 PUFAs is mediated, in part, through finding is of clinical significance. It should be recognized, however, the activation of retinoid X receptors (RXR), an obligatory that administration of daily dose of 400 or 800 mg of COX-2 component of a large number of nuclear receptors (37–39), inhibitors have been shown to induce cardiovascular side effects in suggesting that N-3 PUFAs mediate growth inhibitory effects in humans as recently reported. Extrapolation of the results of the the colon RXR subunit of nuclear receptor heterodimers. Members present study in rats consuming 88 kcal/d to humans consuming on of the nuclear receptor superfamily are transcription factors that the average 2,000 kcal/d indicates that celecoxib at 250, 500, and selectively regulate cell proliferation (40). With regard to the mode 1,000 ppm dose levels used in our study translates to approximately of action of celecoxib against colon cancer, administration of daily doses of 100, 200, and 400 mg, respectively, in humans.
celecoxib suppresses both activity and expression of COX-2.
Although it is presently unknown that these moderately low doses Whereas it is well established that celecoxib predominately (100 and 200 mg) of celecoxib inhibit colorectal cancer in humans, it modulates colon tumor growth by acting on COX-2, there are is likely that in humans these dose levels will have a favorable safety studies to indicate that higher doses of COX-2 inhibitor modulates profile compared with a daily dose of 800 mg that have been used several COX-2–independent pathways, including cell cycle arrest recently in ongoing studies.
and enhanced apoptosis, strengthening the concept of several Our present study provided evidence that administration of a investigators that more than one molecular mechanism is involved very low dose of celecoxib in N-3 PUFA–rich diet would be an ideal in tumor inhibition by these chemopreventive agents (38–42).
Figure 4. Effects of 250 ppm of celecoxib administered inHFML and HFFO diets on Western analysis of COX-2expression in colon mucosa (M ) and tumors (T ) of rats.
1 to 4, colon tumors of rats fed 20% HFML (Western style)diet, 20% HFML diet + 250 ppm celecoxib, 10% fish oil +10% HFML (HFFO) diet, and HFFO diet + 250 ppmcelecoxib, respectively. Note that COX-2 expression wasnot detected in colonic mucosa. Colon tumors of rats fedHFFO diet + 250 ppm celecoxib diet (4T) showeddecreased COX-2 expression compared with tumors ofrats fed HFML diet + 250 ppm celecoxib (2T).
Cancer Res 2005; 65: (17). September 1, 2005 Colon Cancer Prevention by Celecoxib in w-3 PUFA Diet In summary, the present study shows that a high-fat diet human clinical trials. The use of low dose of celecoxib in containing fish oil and mixed lipids (saturated and unsaturated combination with healthy lifestyles seems to be a promising fats) induced fewer colon adenocarcinomas than did a high-fat approach that may evolve into a better chemopreventive strategy diet containing mixed lipids. We also show for the first time that for future human clinical trials.
varying doses of celecoxib administered in Western-style HFMLand HFFO diets suppressed colon carcinogenesis. Interestingly, low-dose level of celecoxib administered in HFFO diet caused asignificant inhibition of COX-2 activity and expression and tumor Received 1/21/2005; revised 5/25/2005; accepted 6/17/2005.
Grant support: USPHS grant CA-37663, CA-94962, and CA-17613 from the incidence compared with low dose of celecoxib in HFML diet.
National Cancer Institute.
Any human clinical trials using COX-2 inhibitors to prevent The costs of publication of this article were defrayed in part by the payment of page colorectal cancer in high-risk individuals should consider all charges. This article must therefore be hereby marked advertisement in accordancewith 18 U.S.C. Section 1734 solely to indicate this fact.
relevant data that reflect on the efficacy and safety of these We thank Sandi Selby for preparation of the manuscript, Dr. J. Landau for editorial agents at very high dose levels. The ability of celecoxib at assistance, staff of the Research Animal Facility at the American Health Foundationand the Histopathology Facility at the Cancer Institute of New Jersey for expert moderately high, low, and very low dose levels tested in the technical assistance, Zapata Protein for donating fish oil, and Pfizer, Inc., for providing present study may have important preventive implications in 16. Dannenberg AJ, Lippman SM, Mann JR, Subbaramaiah 30. Giardiello FM, Hamilton SR, Krush AJ, et al.
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With the evolving economic landscape companies have developed new strategies to effectively compete in the global marketplace. Recent trends show that successful companies are strengthening their marketing skills and instilling a customer-focused mindset in a critical mass of their managers with the goal of improved performances. Companies who are successful with this approach are those CEOs and top executives who make marketing a priority. In turn, changing the marketing mindset of a stagnant or post-recession company has meant making tough people decisions.

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La Voz deL Personaje Femenino en La ConstruCCión de una PosiCión reaLista CrítiCa desde La marquesa de YoLombó de tomás CarrasquiLLa amaLia FranCo Castaño la Voz dEl PErsonajE FEmEnino En la ConstruCCión dE una PosiCión rEalista CrítiCa dEsdE La Marquesa de YoLoMbó dE tomás Carrasquilla*1 Fecha de recepción: 22 de agosto de 2013 Fecha de aprobación: 25 de noviembre de 2013