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Induction of Pancreatic Islet Cell Tumors in Rats by Repeated Intravenous Administration of 4-hydroxyaminoquinoline 1-oxide

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan, imazawa{at}nihs.go.jp

Akiyoshi Nishikawa

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Makoto Shibutani

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Hiroyuki Ogasawara

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Fumio Furukawa

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Takako Ikeda

Showa Women's University, 1-7 Taishido, Setagaya-ku, Tokyo 158-8533, Japan

Koichi Suda

Department of Pathology, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

Masao Hirose

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

The inducibility of pancreatic islet cell tumors by administration of 4-hydroxyaminoquinolin e 1-oxide (4HAQO) was investigated in male 6-week-old Sprague—Dawley rats. Rats were given 4HAQO intravenously at a weekly dose of 5 mg/kg 4 times (group 1) or a single dose of 10 mg/kg (group 2). Control rats received the vehicle alone (group 3). Fifty-six weeks after the first 4HAQO administration, all surviving animals were killed and the pancreas was examined histopathologically, immunohistochemically and ultrastructurally. The incidences and multiplicities of islet cell tumors in groups 1, 2, and 3 were 52.3% (p < 0.05 vs group 2, p < 0.01 vs group 3), 19.2% and 0%, and 0.70/animal (p < 0.05 vs group 2, p < 0.01 vs group 3), 0.23 and 0, respectively. Islet cell carcinomas were induced only in group 1, accounting for 6/44 (26%) tumors. Islet cell hyperplasias were found in 61.4% (p < 0.05 vs group 3), 42.3% and 10.0% of groups 1, 2, and 3, with multiplicities of 0.95 ( p < 0.05 vs groups 2 and 3), 0.54 and 0.20, respectively. As compared with normal islets from control subjects, islet cell tumors showed an increase in the number of insulin positive cells associated with cytological features indicative of enhanced insulin synthesis and secretion, and a decrease in the number of glucagon positive cells without ultrastructural signs of modified secretory activity. Thus our results indicate that repeated intravenous administration of 4HAQO to rats is useful for the induction of islet cell tumors at high incidence.

Key Words: Immunohistochemistry • islet cell tumors • rat • 4HAQO

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