Induction of apoptosis by sulindac in azoxymethane-induced possible colonic premalignant lesions in rats.
We have reported that beta-catenin-accumulated crypts (BCAC), which do not have the appearance of aberrant crypt foci (ACF) are possible colonic premalignant lesions in rats. Suppression of the occurrence and advancement of such lesions should have critical relevance to cancer prevention. This study examined whether sulindac, a chemopreventive nonsteroidal anti-inflammatory drug is able to induce apoptosis in such premalignant lesions. At 6 weeks of age, rats groups 1 - 3 were given azoxymethane (AOM) (15 mg/kg-body weight) once weekly for 3 weeks. Two groups were given sulindac in the diet (200 and 400 ppm), starting at 9 weeks of age. The rats were sacrificed at the termination, and the colons were carefully examined. The incidence and crypt multiplicity of BCAC and ACF were significantly less than those of the control group. The effect of sulindac on the expression of BCAC was greater than that on ACF. Exposure to sulindac significantly increased the apoptotic index (terminal deoxynucleotide transferase dUTP nick-end labeling (TUNEL)-positive cells) in BCAC. However, no significant increase of the index was found in the case of ACF. These results suggest that the chemopreventive effect of sulindac in rats is related to the induction of apoptosis in premalignant lesions. Our results also provide additional evidence that BCAC are premalignant lesions in colon carcinogenesis in rodents.
Kuno
Toshiya
T
First Department of Pathology, Gifu University School of Medicine, Gifu 500-8705, Japan.
Yamada
Yasuhiro
Y
Hirose
Yoshinobu
Y
Katayama
Masaki
M
Sakata
Keiko
K
Hara
Akira
A
Saji
Shigetoyo
S
Mori
Hideki
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003598:Cytoskeletal Proteins; D004032:Diet; D020287:In Situ Nick-End Labeling; D015994:Incidence; D008297:Male; D009697:Nucleolus Organizer Region / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D012834:Silver / Q000737:chemistry; D013467:Sulindac / Q000494:pharmacology*; D015534:Trans-Activators; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002273:Carcinogens; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D013467:Sulindac; D012834:Silver; D001397:Azoxymethane