Suppressive effect of CPT-11 on rat esophageal tumorigenesis induced by N-nitrosomethylbenzylamine.
Irinotecan hydrochloride (CPT-11) is a potent anti-cancer drug with suppressive effects against gastric and colorectal cancers. However, no evaluation of CPT-11 for esophageal squamous cell carcinoma has been performed in vivo. In this study, we examined the tumor suppressive effects of CPT-11 on N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. One hundred and fourteen rats were divided into six groups. Rats in groups 1-5 were treated with subcutaneous injection of NMBA at a dose of 0.5 mg/kg 3 times per week for 5 weeks. Rats in group 6 served as a control. Rats in groups 2 and 3 were treated with intragastric (i.g.) administration of CPT-11 at doses of 20 and 40 mg/kg, respectively, once a week simultaneously with NMBA-initiation up to the end of the experiment. Rats in groups 4 and 5 were treated with i.g. administration of CPT-11 at doses of 20 and 40 mg/kg, respectively, once a week after the NMBA-initiation period up to the end of the experiment. The incidence of papilloma and hyperplasia in the esophagus showed no difference between NMBA-treated groups. However, the multiplicity of hyperplasia was significantly reduced in all CPT-11 administration groups. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) was decreased on carcinogen-exposed squamous epithelium and preneoplastic lesions, although no significant differences were detected in the expression of single-strand DNA (ssDNA) and p53. These data suggest that CPT-11 has suppressive effects for esophageal tumors in the early step of the multistep process of carcinogenesis through antiproliferative mechanism.
Fujiwara
Yushi
Y
Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan. fujiwaray@msic.med.osaka-cu.ac.jp
Osugi
Harushi
H
Morimura
Keiichirou
K
Takemura
Masashi
M
Lee
Shigeru
S
Hirohashi
Kazuhiro
K
Fukushima
Shoji
S
Suehiro
Shigefumi
S
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004277:DNA, Single-Stranded / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000633:toxicity; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D000077146:Irinotecan; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D004277:DNA, Single-Stranded; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; C014707:nitrosobenzylmethylamine; D004128:Dimethylnitrosamine; D002166:Camptothecin