Chemopreventive effect of 4-[3,5-Bis(trimethylsilyl) benzamido] benzoic acid (TAC-101) on MNU-induced colon carcinogenesis in a rat model.
OBJECTIVE
4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative. The chemopreventive effect and the mechanism of action of TAC-101 were investigated using a rat chemical colon carcinogenesis model.


METHODS
Colon tumors were induced using intra-rectal instillation of N-methyl-N-nitrosourea (MNU) in F344 rats. These rats were divided into five groups, control, high dose (TAC-101 8 mg/kg)-long period (four weeks), high dose-short period (one week), low dose (TAC-101 0.8 mg/kg)-long period and low dose-short period. After the large bowels were resected at 20 weeks, the number of aberrant crypt foci (ACF) and tumors in the colon were counted. Proliferating cell nuclear antigen (PCNA) positive index, apoptotic index (AI) and Fas expression were also evaluated using immunohistochemistry.


RESULTS
The tumor incidence and the tumor number in the high dose-long period group were decreased in comparison to those in the other groups, but not significantly. However, the number of ACF or PCNA positive indices in the high dose-long period group was significantly decreased in comparison to that in the other groups. On the other hand, the AI and the Fas expression pattern in the tumor and the normal appearing mucosa were not changed in any of the groups.


CONCLUSIONS
TAC-101 might inhibit MNU induced colon carcinogenesis via a decrease of ACF. The mechanism of this chemoprevention may be related to a reduction in cell proliferation, but is not directly associated with apoptosis.
Nakayama
Yoshifumi
Y
Department of Surgery 1, School of Medicine, University of Occupational Environmental Health, Yahata-nishi-ku, Kita-kyushu 807, Japan. nakayama@med.uoeh-u.ac.jp
Inoue
Yuzuru
Y
Minagawa
Noritaka
N
Onitsuka
Koji
K
Nagata
Jun
J
Shibao
Kazunori
K
Hirata
Keiji
K
Sako
Tatsuhiko
T
Nagata
Naoki
N
Yamaguchi
Koji
K
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014297:Trimethylsilyl Compounds / Q000627:therapeutic use*; D019014:fas Receptor / Q000378:metabolism
D000477:Alkylating Agents; D001565:Benzoates; C491898:Fas protein, rat; D018809:Proliferating Cell Nuclear Antigen; C112689:TAC 101; D014297:Trimethylsilyl Compounds; D019014:fas Receptor; D008770:Methylnitrosourea