Specific COX-2 inhibitors rofecoxib and celecoxib may prevent colorectal adenomas occurrence and recurrence. A nested case-control study

Relative RJsk1(95%Ci)for Users of HMG-CoAReductlmeInhlbltorsVs. Non-U|ses Subjects

Antloxldset PPSZ(n=73a)

Any Adseoma

0.70 (0.28, 1.75)

Any Advanced

2.15(0.55,8.40)

Adjoin, hltiple/~lseo.

CalciumPPS2 Asplrin/FohitePPS2 PooledData (n=824) 1,=t076) (n=Z638) 1,07 (0,74, 1.55) 0.98 (0.38,

2,54) 125 (0.66, 2,37)

1.04 (0.86, 1.27)

1,03 (0.87, 1.23)

1.15 (0.63, 2.10)

1.13(0,70, 1,81)

1,25 (0.95, 0.64(0.10, 3.96) 1.31 (1.00, 1,90) ms 1.65) 1Adjustedfor age, sex, center, limeto followupexam, lifetimenumberof adenomas,treatment assignment,and BMI;zPPS=polypprevenlionstudy

S1659

Suppression Of Colon Tumorgenesis By PPARgamma Nobutaka Fu]isawa, Emi Osawa, Atsushi Nakajima Backgrounds: The biological roles of peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, has been highlighted recently. Although PPARgamma figand is suspected to play an important rote in carcinogenesis, contradictory results have been reported. Geoffrey D. Girnun et all. has recently reported the tumor suppressive role of PPARgammma by use of mice heterozygous for PPARgamma. Purpose: Our study was conducted to confirm the effects of PPARgamma ligands on the development of aberrant crypt foci(ACF) and induction of colon tumors induced by azoxymethane (AOM). And to investigate the tumor suppressive role of this receptor,especially early steps of tumorgenesis, we used mice heterozygous for PPARgamma with the same chemical models and ACF formation were investigated. Methods: In the first experiment, three PPARgamma ligands, piogfitazone (Pio) (200 ppm), msigfitazone (Rust) (200 ppm), and troghtazone (Tro) (1,000ppm) were orally adiministered to BALB/c mice, and then they were injected i.p. with 10mg/kg AOM Induction of aberrant crypt foci (ACF), colon tumor formation, and dosedependency of a PPAR~ ligand was examined. In the second experiment, we used mice heterozygons loss of PPARgamma. 14 PPAR§ and 14 PPAR+~- 8-week mice were injected i.p. with 10mg/kg AOM once a week for two weeks. Three weeks after the second injection, colons were removed and examined under a dissecting microscope Results: PPARgamma ligands reduced the ACF formation by AOM and induction of colon tumors were also markedly suppressed by a continuous feeding of Pio at 200 ppm. On the other hand, heterozygons loss of PPARgamma causes a greater ACF formation by AOM compared with wild-type mice. Conclusions:Our results suggest that PPARgamma is a suppressor of colon tumorgenesis and synthetic PPARgamma ligands can inhibit the ACF formation and colon tumorgenesis.

$1657 Speeifm COX-2 tnhibitors Rofecoxib and Celeeoxib May Prevent Coloreeta[ Adenomas Occurrence and Recurrence. A Nested Case-Control Study Elham Rahme, Alan N. Barkun, Youssef M. Toubouti, Marc Bardou Background: Colorectal cancers (CRC) develop mainly from adenomatous polyps. It has been suggested that COX-2 inhibitors (combs) may protective against colorectal adenomas (CRA) The aim of this study was to examine any association between rofecoxib, celecoxib, and CRA. Methods: We obtained medical, pharmaceutical and demographic data on patients 65 years and older who underwent a diagnostic procedure for CRA or CRC between April and September 2001 from the Govemment of Quebec Health Insurance agency (RAMQ) database. The date of the first diagnostic procedure was termed index date. Data were available on all patients for at least 8 months and 4 years prior to the index date for pharmaceutical and in/outpatient medical data, respectively. All patients were followed up for 90 days. Patients with a diagnosis or procedure for CRA or CRC, and those with more than one day of hospitalization (all causes) anytime within the past 240 days, were excluded. Logistic regression models were used to determine the association between a diagnosis of CRA and at least 90 days of exposure to rofecoxib, celecoxib, non selective NSA1Ds or aspirin, respectively - all compared to exposure to at least 90 days of acetaminopben. Results: A total of 2,947 patients were found to be free of either CRA or CRC in follow-up (controls), 884 patients were diagnosed with only CRA (cases), and the other 225 patients were diagnosed with CRC (CRC group). Factors independently associated with CRA were a prior diagnosis of CRA (3.4l, 95% C1 [2.79, 4.17]), or CRC (3.14, [2.18, 4.521). Exposures to rofecoxib, celecoxib and non-selective NSAIDs were each found to reduce CRA risk (0.53, [0.35, 0.82], 0.67, [0.46, 0 98], and 0.47, [0.24, 0.95], respectively. The effect of rofecoxib in reducing the occurrence of CRA was even higher in patients w~th a prior diagnosis of CRA or CRP (0.37, [0.16, 0.87]). No dose-dependent effect was noted. Conclusion: COX2 inhibitors may exert a protectwe effect against CRA, particularly in patients with a prior diagnosis of CRA or CRC

$1660 The New Coxib Drug R-109339 is a Very Effective Chemopreventive Agent for Decreasing Adenoma Multiplicity Russell F. Jacoby, Carolyn E. Cole, Ronald A. Lubet Coxib and other drugs are now under investigation for adenoma prevention in the general population at risk for recurrent colon adenomas. Celecoxib is the only chemopreventive agent now approved in the United States for treatment of adenomas in patients with familial adenomatous polyposis (FAP). However, the limited efficacy of this drug requires its use only as an adjunct to polypectomy and colectomy. Agents with a greater magnitude effect on adenoma reduction are needed to have true clinical benefit. We tested an investigational new coxib, R 109339 in the Min mouse model of adenomatous po|yposis. The comb R109339 caused a dose-dependent decrease in intestinal tumor multiplicity in the Min mouse that was highly significant at all doses (p < 0.0001). Adenomas were decreased by a factor of 25-fold by treatment with R-109339, much greater efficacy than we have observed with any other coxib, NSA1D, or any other agents previously tested in this model. There were no ulcerations observed in the gastrointestinal tracts of animals treated at these therapeutic doses These experiments suggest that cyclooxygenase inhibition with this new agent is a very promising approach for colon cancer prevention.

$1658 HMG-CoA Reductase Inhibitor Use and Recurrence of Colorectal Adenomas Jeffrey T. Wei, Leila A. Mott, John A. Baron, Robert S. Sandler BACKGROUND: In two large randomized controlled trials, colon cancer risk was reduced in patients receiving pravastatin and simvastatin HMG-CoA reductase inhibitors have reduced proliferation and induced apoptosis of colon cancer cells in vitro. The putative mechanism is by interrupting isoprenylation of crucial intracellular proteins. The objective of this study was to evaluate the effect of these agents on recurrence of colorectal adenomas. METHODS: Data from three large chemoprevention trials for colorectal adenomas was used for this analysis Eligible subjects had at least one histologically confirmed large-bowel adenoma removed within three months before recruitment. Medication use was reported at baseline and every 4 months. HMGrCoA reductase inhibitor use was defined as reported use on one or more questionnaires. The primary outcome measure was proportion of subjects in whom at least one adenoma was detected at follow-up endoscopy between 1 year after randomization and 3 or 4 years after randomization. Secondary outcome measures were detection of multiple adenomas or detection of an advanced adenoma, defined as a neoplastic polyp ->1 cm, at least 25% villous elements, or evidence of high-grade dysplasia. Relative risks were obtained from tog-linear models controlling for possible confounders. Analysis was performed on data from each individual study as well as on pooled data from all three studies. RESULTS: 2638 subjects underwent follow-up endoscopy and were eligible for analysis. 8.1% of patients reported use of HMG-CoA reductase inhibitors at any time. Compared to non-users, the pooled relatwe risk of users for any adenoma was 1.03 (95% CI 0.87-1.23), for any advanced adenoma 1.13 (95% C[ 0.70-1.81), and for multiple adenomas 1.25 (95% C[ 0.95-1.65) CONCLUSIONS: Contrary to prior expectation, HMG-CoA reductase inhibitor use did not reduce the risk for recurrence of colorectal adenomas, advanced adenomas, or muluple adenomfls

Tumor Prevention by Coxlb R.109339 in the MIn Mouse Model of Adseomato.z Polypozis Drug Dose (ppm In d~) 0 45 t50 250

# Mice n= 12 12 12 11 9

Tumors/mouse (mean) 20.6 5.2 4.7 2.4 0.9

(+1.Std. error) 2.3 0.9 0.8 0.7 0.4

(% control) 100 25 23 12 4

p-value < 0.0001 < 0.0001 < 0.0001 < 0.0001

s1661 FOLIC ACID REDUCES CELL PROLIFERATION AND NUCLEAR EXPRESSION OF [3-CATENIN 1N RECTAL MUCOSAL CRYPTS OF PATIENTS WITH COLORECTAL ADENOMAS Richard Jaszewski, Brett Miller, James Hatfield, Kiran K. Nagothu, Raphaela Finkenauer, Volkan Adsay, Amn K. Rishi, Adhip P. N Malumdar Accumulating evidence suggests that folic acid may have a chemopreventive role in colon carcinogenesis. However, the mechanism(s) involved is poorly understood. We demonstrated that folic acid inhibits cell proliferation and EGF-receptor (EGFR) activation in colon cancer cells (AlP 46: Cl142, 1999) suggesting a role for EGFR in regulating these processes. To elucidate the EGFR signaling events, we examined the effect of folic acid on cell proliferation and the distribution of [3-catenin (whose function is regulated by EGFR) in the rectal mucosa of patiems with colorectal adenomas. APC, axin and glycogen synthase kinase 3O(GSK3/]) form a complex with [3-cateinn and regulate its levels by targeting it for ubiqnitin-mediated

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AGA

Abstracts