Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: A review and report of personal experience

Table 1 Selective COX-2 inhibitors (coxibs) and chemoprevention in gastrointestinal tract tumors

Generic name	Brand name	PhCob	Esophagus				Stomach			Colorectum
			Cancer cell line	CIAc	reflux-induced animal	Human (BEd)	Cancer cell line	CIAc	MIAe	Cancer cell line	CIAc	MIAe	Human (FAPf)
Tricyclic
Celecoxib	Celebrex	Pfizer			(23)			(46,47)	(75)	(76,77)	(81,82)	(54)	(56)
MF-tricyclic	ECa	Merck			(21)							(53,87)
Rofecoxib	Vioxx	Merck				(24)						(55)
Tilmacoxib	Japan Tobacco			(20)						(78)		(88,89)
Valdecoxib Bextra	Pfizer
EtoricoxibArcoxia	Merck
Methanesulphonamide
NS-398	ECa	Taisho	(18,19,70,71)				(44,45,72)		(49)	(72)	(83)
Nimesulide	Mesulid	Helsinn					(73)	(48)			(84)	(90)
Flosulide			Schering	(70)
Others
Nabumetone	Relafen	Glaxo Smith Kline									(85)	(91)
Meloxicam	Mobic	Boehringer Ingelheim								(79,80)	(86)
Etodolac	Lodine	Wyeth					(74)			(74)
Lumiracoxib	Prexige	Novartis

ECa, experimental compound; PhCob, Pharmaceutical company; CIAc, carcinogen-induced animal; BEd, Barrett's esophagus; MIAe, mutation-induced animal; FAPf, familial adenomatous polyposis; Numbers in parentheses show reference numbers

Table 2 Incidences of inflammatory changes, Barrett’s esophagus, and adenocarcinoma in a rodent duodenoesophageal reflux model

Wk	Group	n	RT#	BCH$	Incidence (%) of
					Barrett's esophagus	Adeno- carcinom
10	Control	10	100c	100c	10	0
	Celecoxib	5	40	40	0	0
20	Control	10	100c	100c	40	0
	Celecoxib	5	40	40	20	0
30	Control	10	100c	100c	50	10
	Celecoxib	5	40	40	40	0
40	Control	19	100c	100c	89a	47b
	Celecoxib	8	38	38	25	0

RT#, Regenerative thickening; BCH$, Basal cell hyperplasia;

^aP < 0.005 and

^cP < 0.05, respectively, control vs celecoxib group, Fisher's exact test.

Table 3 Chemopreventive effects of coxibs on intestinal tumors using animal models

Drug				Outcomes		Reference
Name	Concentration	Term	Animal model	Inhibition rate (%)	P value	Reporter (#)	Year
carcinogen-induced rat model
Celecoxib	1500 ppm	5-16 wk	F344 rat, AOMa	40 (ACF)	P < 0.001	Reddy et al (92)	1996
NS-398	1 mg/kg•bw	5-11 wk	F344 rat, AOMa	34 (ACF)	P < 0.05	Yoshimi et al (83)	1997
	10 mg/kg•bw			47 (ACF)	P < 0.01
Celecoxib	1500 ppm	5-50 wk	F344rat, AOMa	93(colontumor)	P<0.00001	Kawamori et al (81)	1998
Nimesulide	200 ppm	6-30 wk	ICRmouse,AOMa	36(adenocarcinoma)	NS	Fukutake et al (84)	1998
	400 ppm			50(adenocarcinoma)	P < 0.05
Celecoxib	500 ppm	5-58 wk	F344 rat, AOMa	55(adenocarcinoma)	P < 0.001	Reddyet al (82)	2000
	1000 ppm	5-58 wk		62(adenocarcinoma)	P < 0.001
	1500 ppm	5-58 wk		77(adenocarcinoma)	P < 0.0001
	1500 ppm	22-58 wk		47(adenocarcinoma)	P < 0.01
Nabumetone	750 ppm	for18 wk	F344 rat, AOMa	15 (ACF)	P < 0.05	Roy et al (85)	2001
	1500 ppm			37 (ACF)	P < 0.01
Apc gene mutant mouse model
MF-tricyclic	3,5 mg/kg•d	3-11 wk	ApcΔ716	52(intestinalpolyp)	P = 0.0037	Oshima et al (53)	1996
	14 mg/kg•d			62 (intestinal polyp)	P < 0.0001
Nimesulide	400 ppm	4-15 wk	ApcΔ850 (Min)	48 (intestinal polyp)		Nakatsugi et al (90)	1997
Celecoxib	150 ppm	30-80 d	ApcΔ850 (Min)	48 (intestinal polyp)	P < 0.05	Jacoby et al (54)	2000
	500 ppm			29(intestinalpolyp)
	1500 ppm			71(intestinalpolyp)
JTE-522	0.001 (%)	4-12 wk	ApcΔ474	9 (intestinal polyp)	NS	Sasai et al (88)	2000
	0.01 (%)			32 (intestinal polyp)	P < 0.05
Nabumetone	900 ppm	5-15 wk	ApcΔ850 (Min)	50(smallbowelpolyp)	P < 0.05	Roy et al (91)	2001
				65(largebowelpolyp)	P < 0.05
MF-tricyclic	13 mg/kg/d	3-7 wk	ApcΔ850 (Min) +	48 (intestinal polyp)	P < 0.001	Lal et al (87)	2001
			Msh2-/-
Rofecoxib	0.0025 (%)	3-11 wk	ApcΔ716	36 (intestinal polyp)		Oshima et al (55)	2001
	0.0075 (%)			55 (intestinal polyp)
JTE-522	0.01 (%)	4-12 wk	ApcΔ474	49 (large adenoma)	P < 0.01	Sunayama et al (89)	2001
				-28 (small adenoma)		NS

AOM^a, azoxymethane; Reporter (#), Name of reporter and (#) shows reference number