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Suppression by peroxisome proliferator activated receptora ligand of intestinal polyp development in APCMin mice
April 2000
AGAA657
3604 EXISULIND PREVENTS ADENOMA FORMATION IN FAMILIAL ADENOMATOUS POLYPOSIS(FAP). Carol Burke, Ros~ind van Stolk, Nadir Arber, Rolf Hultcrantz, Jan Bjork, Sapna Syngal, Miguel Rodriquez, Martin Luchtefeld, V. Alin Botomon, Lawrence Wruble, Scott Kuwada, Robin Ks Phillips, Cleveland Clin Fdn, Cleveland, OH; Tel-Aviv Sourasky Med Ctr, Tel-Aviv, Israel; Karolinska Inst, Stockholm, Sweden; Dana-Farber Cancer Institute, Boston, MA; Roswell Park Cancer Institute, Buffalo, NY; Ferguson-Blodgett Research Fdn, Grand Rapids, MI; Cleveland Clin Fdn, Ft. Lauderdale, FL; MidSouth Clin Research Institute. Memphis, TN; Univ of Utah, Salt Lake City, UT; St Mark's Hosp, Middlesex, United Kingdom. Exisulind, an inhibitor of a novel cGMP-phosphodiesterase, has broad pro-apoptotic antineoplastic activity in cancer cell lines, murine cancer prevention models and human cancer xenograft models. Exisulind is the sulfone met~bo~it~. of sulindac, but induces apoptosis independently of COX I or r.r inhibition, p53: bcl2 o.r cell cycle arrest, and lacks the gastric and renal side effects associated With NSAIDs. This study assessed exisu!ind's efficacy in p~eventing adenoma formation in FAP patients with ileorectal anastamosis/Ik.A). METHODS: 73 patients with IRA were randomized (1:1) to exisulind 150 mg qid or placebo for 12 months in this double-blind. multi-center study. All rectal polyps were counted and ablated at baseline, 6 and 12 months. Since polyp formation rates are variable, !he study was designed to detect a difference in patients forming approximately 10 to 40 new polyps per year (Target Group). Endoscopic records from exams closest to one year before randomization were used to calculate historical polyp formation rates. RESULTS:65 patients completed the s~udy. (All Patients); 34 were in the Target Group. Demography and histoncal ~olyP formation ra~es w.ere similar in the treatment and placebo groups. Exisulind-treated patients 10 the Target Group had a 53% reduction in mean and median number of polyps formed vs placebo (p=0.020). Exisul!nd-treated patients historically forming 10 or more polyps showed reductions of 34% vs placebo(p=.026). Those treated in the All Patients group showed a 25% reduction vs placebo(p=ns). Exisulind was well tolerated, with 90% of patients completing one year. CONCLUSIONS: Exisulind induces a clinically significant reduction in adenoma formation in FAP. patients during the .first year. of therapy. Exisulind is clinically ~eneficlal ~ a c.he~opreventl~e agent 10 the management of colonic polyps 10 FAP. Exisulind s efficacy 10 the long term prevention of colonic adenomas continues to be studied. Median Cumulative Number of Polyps Formed During 12Months - Historical Polyp Fonnation Rate (polyps/yr)
Exisulind (n)
Placebo (n)
Difference (%Reduction)
p value (Wilcoxon Test)
10·40 ~ 10 All Patients
18(15) 23(19) 24(30)
38(19) 35(23) 32 (35)
20 (53) 12(34) 8 (25)
0.020 0.026 ns
3605 EXISULIND CONTINUES TO PREVENT COLONIC ADENOMA FORMATION IN FAMILIAL ADENOMATOUS POLYPOSIS (FAP) PATIENTS TREATED FOR 18 MONTHS. Carol Burke, Nad!r Arber, R:obin Ks Ph!llips, Rolf Hultcrantz, Jan Bjork, Sapna Syngal, Miguel Rodnquez, Martin Luchtefeld, V. Alin Botomon, Lawre~ce Wruble, Scott Kuwada, Cleveland Clin Fdn, Cleveland, OH; Tel.-Avlv .SouraskyMed Ctr, Tel-Aviv, Israel; St Mark's Hosp, Middlesex, Umted Kingdom; Karolinska Inst, Stockholm, Sweden; Dana-Farber Cancer Institute, Boston, MA; Roswell Park Cancer Institute, Buffalo, NY; Ferguson-Blodgett Research Fdn, Grand Rapids, MI; Cleveland Clin Fdn, Ft. .Lauderdale, FL; Mid-South Clin Research Institute, Memphis, TN; Univ of Utah, Salt Lake City, UT. Exisulind, a selective apoptotic antineoplastic drug (SAAND), decreased colorectal ade~oma formation in patients with FAP by 53% during a one year double-blind, placebo controlled multi-center study (DBPC Trial). It has also demonstrated broad in vitro and in vivo activity via inhibition of a novel cGMP-phosphodiesterase. Exisulind induces apoptosis independently of COX I or II inhibition, p53, bcl2 or cell cycle arrest, and lacks the gastnc and renal side effects associated with NSAIDs. This study assesses the durability of exisulind's chemopreventive activity on adenoma forma-
tion in FAP patients with ileorectal anastamosis(IRA). METHODS: A one year open label extension study was offered to all patients completing the DBPC Trial. Investigators and patients remain blinded to the original treatment assignment. All patients are receiving exisulind 150 mg qid. All rectal polyps are counted and ablated at 6 month intervals. The number of pol~ps form~d by each patient during the extension are compared to their semi-annualized polyp formation rate obtained during DBPC Trial. RESULTS: 48 of 55 patients have continued beyond six months of the extension. The DBPC Trial placebo patients crossing-over to exisulind (X-over) and the D~PC Tt;i~ exisulind-treated patients (Continuing) ~roups are.demographlcally Similar.Both groups showed a 50% reduction 10 the median number of polyps formed after six months on the extension. !he additional 50% reduction in the Continuing patients historically form109 -10 to 40 polyps/year led to an overall reduction in polyp formation of 75% after 18 months of therapy. Exisulind was well tolerated. CONCLUSIONS:. Exisulind induces a clinically significant reduction in adenoma formation among FAP patients with as little as six months of therapy. The response to exisulind continues to improve with therapy beyond one year. Median Cumulative Number of Polyps Formed - 6 Month Interim Analysis Patient Groups
Continuing (n=23) (n=25) X-over
DepC Trial Semi· Annual Polyp Fonnation Rate
6Months on Open·label Extension
12 18
Difference p value (%Reduction) (Wilcoxon Test)
6(50) 9(50)
0.005 0.006
3606 SUPPRESSION BY PEROXISOME PROLIFERATOR ACTI· VATED RECEPTORA LIGAND OF INTESTINAL POLYP DEVEL· OPMENT IN APC MIN MICE. Lucina M. Jackson, Andrew J. Bennett, Susan Watson Teresa Morrison Philip Clarke, David Bell, Chris J. Hawkey, Univ Hosp Nottingham' Nottingham, United Kingdom. ' Introduction:Colon cancer is associated with high fat intake and with upregulation of cyclooxygenase (COX)-2 expression. The nuclear factor peroxis?me proliferator activated receptor (PPAR)a stimulates fatty acid catabolism, has a response element in the COX-2 promoter region and mod~lates COX2 expression. We have previously shown that PPAR a protem levels are reduced in human colonic tumours compared to normal colonic mucosa. In this study we investigated whether a PPARa agonist could inhibit tumour formation in vivo in the APCM in / + (Min) mouse model of familial adenomatous polyposis. Methods:Once weaned, male and female C57BLl6J APCM w /+ (Min) mice were commenced on methylclofenapate 25mg/kg/daily (made up in safflower oil) (n= 13) or safflower ?il alone (~= I~) which was administered by oral gavage. At time of sacnfice, the mtestme was flushed, opened lengthways and fixed in fo~ol calcium. The tissue was immersed in thiazine dye (Baxter) for 5 rmns and then returned to 70% CzHsOH for 24 hrs before drying. Tissue was scanned and number, size and location of tumors analyzed using Qwinstandard (Leica) quantitation. Results:The methylclofenapate was well tolerated and food intake was similar in both groups. Treated group lived a mean of 14.8 weeks vs. 13.8 weeks (control group). There was a significant .redu~tion in the number of small (p= 0.004) and large (p=0.OO9) intestinal polyps 10 the treated group compared to control with an overall reduction in tumour bulk and rate of development. Conclusions: We have demonstrated a significant reduction in tumour number in Min mice receiving a specific PPARa ligand. The effects of PPARa ligands may warrant investigation in humans large Intestine
No. polyps Polypslweek Polarea (mm2) Polarea/week Mean polarea
Control 6.6±0.78 0.46±0.005 9.82±1.93 0.66±0.113 1.47+0.23
'p<0.05, "p<0.001, '''p<0.005
Treated 3. 54±0.73" 0.27±0.006' 3.85±0.82' 0.28±0.006" 1.2±0.19
Small Intestine Control 23.07±2.14 1.63±0.163 19.5±2.57 1.36±0.17 0.83±0.006
Treated 12.8±2.51'" 0.96±0.187' 9.74±1.88" 0.73±0.14' 0.79±0.008
AGAA657
3604 EXISULIND PREVENTS ADENOMA FORMATION IN FAMILIAL ADENOMATOUS POLYPOSIS(FAP). Carol Burke, Ros~ind van Stolk, Nadir Arber, Rolf Hultcrantz, Jan Bjork, Sapna Syngal, Miguel Rodriquez, Martin Luchtefeld, V. Alin Botomon, Lawrence Wruble, Scott Kuwada, Robin Ks Phillips, Cleveland Clin Fdn, Cleveland, OH; Tel-Aviv Sourasky Med Ctr, Tel-Aviv, Israel; Karolinska Inst, Stockholm, Sweden; Dana-Farber Cancer Institute, Boston, MA; Roswell Park Cancer Institute, Buffalo, NY; Ferguson-Blodgett Research Fdn, Grand Rapids, MI; Cleveland Clin Fdn, Ft. Lauderdale, FL; MidSouth Clin Research Institute. Memphis, TN; Univ of Utah, Salt Lake City, UT; St Mark's Hosp, Middlesex, United Kingdom. Exisulind, an inhibitor of a novel cGMP-phosphodiesterase, has broad pro-apoptotic antineoplastic activity in cancer cell lines, murine cancer prevention models and human cancer xenograft models. Exisulind is the sulfone met~bo~it~. of sulindac, but induces apoptosis independently of COX I or r.r inhibition, p53: bcl2 o.r cell cycle arrest, and lacks the gastric and renal side effects associated With NSAIDs. This study assessed exisu!ind's efficacy in p~eventing adenoma formation in FAP patients with ileorectal anastamosis/Ik.A). METHODS: 73 patients with IRA were randomized (1:1) to exisulind 150 mg qid or placebo for 12 months in this double-blind. multi-center study. All rectal polyps were counted and ablated at baseline, 6 and 12 months. Since polyp formation rates are variable, !he study was designed to detect a difference in patients forming approximately 10 to 40 new polyps per year (Target Group). Endoscopic records from exams closest to one year before randomization were used to calculate historical polyp formation rates. RESULTS:65 patients completed the s~udy. (All Patients); 34 were in the Target Group. Demography and histoncal ~olyP formation ra~es w.ere similar in the treatment and placebo groups. Exisulind-treated patients 10 the Target Group had a 53% reduction in mean and median number of polyps formed vs placebo (p=0.020). Exisul!nd-treated patients historically forming 10 or more polyps showed reductions of 34% vs placebo(p=.026). Those treated in the All Patients group showed a 25% reduction vs placebo(p=ns). Exisulind was well tolerated, with 90% of patients completing one year. CONCLUSIONS: Exisulind induces a clinically significant reduction in adenoma formation in FAP. patients during the .first year. of therapy. Exisulind is clinically ~eneficlal ~ a c.he~opreventl~e agent 10 the management of colonic polyps 10 FAP. Exisulind s efficacy 10 the long term prevention of colonic adenomas continues to be studied. Median Cumulative Number of Polyps Formed During 12Months - Historical Polyp Fonnation Rate (polyps/yr)
Exisulind (n)
Placebo (n)
Difference (%Reduction)
p value (Wilcoxon Test)
10·40 ~ 10 All Patients
18(15) 23(19) 24(30)
38(19) 35(23) 32 (35)
20 (53) 12(34) 8 (25)
0.020 0.026 ns
3605 EXISULIND CONTINUES TO PREVENT COLONIC ADENOMA FORMATION IN FAMILIAL ADENOMATOUS POLYPOSIS (FAP) PATIENTS TREATED FOR 18 MONTHS. Carol Burke, Nad!r Arber, R:obin Ks Ph!llips, Rolf Hultcrantz, Jan Bjork, Sapna Syngal, Miguel Rodnquez, Martin Luchtefeld, V. Alin Botomon, Lawre~ce Wruble, Scott Kuwada, Cleveland Clin Fdn, Cleveland, OH; Tel.-Avlv .SouraskyMed Ctr, Tel-Aviv, Israel; St Mark's Hosp, Middlesex, Umted Kingdom; Karolinska Inst, Stockholm, Sweden; Dana-Farber Cancer Institute, Boston, MA; Roswell Park Cancer Institute, Buffalo, NY; Ferguson-Blodgett Research Fdn, Grand Rapids, MI; Cleveland Clin Fdn, Ft. .Lauderdale, FL; Mid-South Clin Research Institute, Memphis, TN; Univ of Utah, Salt Lake City, UT. Exisulind, a selective apoptotic antineoplastic drug (SAAND), decreased colorectal ade~oma formation in patients with FAP by 53% during a one year double-blind, placebo controlled multi-center study (DBPC Trial). It has also demonstrated broad in vitro and in vivo activity via inhibition of a novel cGMP-phosphodiesterase. Exisulind induces apoptosis independently of COX I or II inhibition, p53, bcl2 or cell cycle arrest, and lacks the gastnc and renal side effects associated with NSAIDs. This study assesses the durability of exisulind's chemopreventive activity on adenoma forma-
tion in FAP patients with ileorectal anastamosis(IRA). METHODS: A one year open label extension study was offered to all patients completing the DBPC Trial. Investigators and patients remain blinded to the original treatment assignment. All patients are receiving exisulind 150 mg qid. All rectal polyps are counted and ablated at 6 month intervals. The number of pol~ps form~d by each patient during the extension are compared to their semi-annualized polyp formation rate obtained during DBPC Trial. RESULTS: 48 of 55 patients have continued beyond six months of the extension. The DBPC Trial placebo patients crossing-over to exisulind (X-over) and the D~PC Tt;i~ exisulind-treated patients (Continuing) ~roups are.demographlcally Similar.Both groups showed a 50% reduction 10 the median number of polyps formed after six months on the extension. !he additional 50% reduction in the Continuing patients historically form109 -10 to 40 polyps/year led to an overall reduction in polyp formation of 75% after 18 months of therapy. Exisulind was well tolerated. CONCLUSIONS:. Exisulind induces a clinically significant reduction in adenoma formation among FAP patients with as little as six months of therapy. The response to exisulind continues to improve with therapy beyond one year. Median Cumulative Number of Polyps Formed - 6 Month Interim Analysis Patient Groups
Continuing (n=23) (n=25) X-over
DepC Trial Semi· Annual Polyp Fonnation Rate
6Months on Open·label Extension
12 18
Difference p value (%Reduction) (Wilcoxon Test)
6(50) 9(50)
0.005 0.006
3606 SUPPRESSION BY PEROXISOME PROLIFERATOR ACTI· VATED RECEPTORA LIGAND OF INTESTINAL POLYP DEVEL· OPMENT IN APC MIN MICE. Lucina M. Jackson, Andrew J. Bennett, Susan Watson Teresa Morrison Philip Clarke, David Bell, Chris J. Hawkey, Univ Hosp Nottingham' Nottingham, United Kingdom. ' Introduction:Colon cancer is associated with high fat intake and with upregulation of cyclooxygenase (COX)-2 expression. The nuclear factor peroxis?me proliferator activated receptor (PPAR)a stimulates fatty acid catabolism, has a response element in the COX-2 promoter region and mod~lates COX2 expression. We have previously shown that PPAR a protem levels are reduced in human colonic tumours compared to normal colonic mucosa. In this study we investigated whether a PPARa agonist could inhibit tumour formation in vivo in the APCM in / + (Min) mouse model of familial adenomatous polyposis. Methods:Once weaned, male and female C57BLl6J APCM w /+ (Min) mice were commenced on methylclofenapate 25mg/kg/daily (made up in safflower oil) (n= 13) or safflower ?il alone (~= I~) which was administered by oral gavage. At time of sacnfice, the mtestme was flushed, opened lengthways and fixed in fo~ol calcium. The tissue was immersed in thiazine dye (Baxter) for 5 rmns and then returned to 70% CzHsOH for 24 hrs before drying. Tissue was scanned and number, size and location of tumors analyzed using Qwinstandard (Leica) quantitation. Results:The methylclofenapate was well tolerated and food intake was similar in both groups. Treated group lived a mean of 14.8 weeks vs. 13.8 weeks (control group). There was a significant .redu~tion in the number of small (p= 0.004) and large (p=0.OO9) intestinal polyps 10 the treated group compared to control with an overall reduction in tumour bulk and rate of development. Conclusions: We have demonstrated a significant reduction in tumour number in Min mice receiving a specific PPARa ligand. The effects of PPARa ligands may warrant investigation in humans large Intestine
No. polyps Polypslweek Polarea (mm2) Polarea/week Mean polarea
Control 6.6±0.78 0.46±0.005 9.82±1.93 0.66±0.113 1.47+0.23
'p<0.05, "p<0.001, '''p<0.005
Treated 3. 54±0.73" 0.27±0.006' 3.85±0.82' 0.28±0.006" 1.2±0.19
Small Intestine Control 23.07±2.14 1.63±0.163 19.5±2.57 1.36±0.17 0.83±0.006
Treated 12.8±2.51'" 0.96±0.187' 9.74±1.88" 0.73±0.14' 0.79±0.008