Effects of long-term administration of sulindac on APC mRNA and apoptosis in colons of rats treated with azoxymethane.
OBJECTIVE
Non-steroidal anti-inflammatory drugs, including sulindac, have been shown to exhibit anti-colon cancer activity; however, the detailed mechanisms concerning continuous long-term administration are still unclear. Therefore, we examined the anti-colon carcinogenesis effects of sulindac after prolonged administration.


METHODS
Administration of AOM, a colon-specific carcinogen, induced colonic preneoplastic lesions, which can progress to carcinomas about 40-50 weeks after AOM administration. We studied the effects of sulindac on the incidence of preneoplastic lesions, proliferative activity of colonic cells (AgNORs), tumor suppressor adenomatous polyposis coli (APC) gene expression, and apoptosis using AOM-treated rat colon mucosa at 4 weeks and 40 weeks (early and late stage of colon carcinogenesis, respectively).


RESULTS
Sulindac suppressed the development of preneoplastic lesions induced by AOM at 4 weeks and 40 weeks by about 50% ( P<0.01); the proliferative activity of colonic cells increased by AOM was suppressed almost completely. Furthermore, APC expression was significantly increased by sulindac at both the early and late stages ( P<0.01). However, apoptosis was clearly increased at the early stage ( P<0.01), but not at the late stage.


CONCLUSIONS
APC overexpression induced by sulindac can suppress colon carcinogenesis at both the early and late stages, but apoptosis might work as one of anti-cancer mechanisms at the early stage of colon carcinogenesis.
Kishimoto
Y
Y
Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, Faculty of Medicine, Tottori University, 86 Nishicho, Yonago 683-8503, Japan. ykishimo@grape.med.tottori-u.ac.jp
Yashima
K
K
Morisawa
T
T
Ohishi
T
T
Marumoto
A
A
Sano
A
A
Idobe-Fujii
Y
Y
Miura
N
N
Shiota
G
G
Murawaki
Y
Y
Hasegawa
J
J
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane / Q000633:toxicity; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009697:Nucleolus Organizer Region / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013467:Sulindac / Q000008:administration & dosage*
D025601:Adenomatous Polyposis Coli Protein; D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D013467:Sulindac; D001397:Azoxymethane