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Open Access Research article

Use of a chemically induced-colon carcinogenesis-prone Apc-mutant rat in a chemotherapeutic bioassay

Kazuto Yoshimi1, Takao Hashimoto2, Yusuke Niwa2, Kazuya Hata2, Tadao Serikawa1, Takuji Tanaka3 and Takashi Kuramoto1*

Author affiliations

1 Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

2 Sunplanet Co., Ltd, 4388 Makita, Kamiishizu, Ogaki, 503-1602, Japan

3 Cancer Research and Prevention, The Tohkai Cytopathology Institute, 4-33 Minami-Uzura, Gifu, 500-8285, Japan

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Citation and License

BMC Cancer 2012, 12:448  doi:10.1186/1471-2407-12-448

Published: 3 October 2012

Abstract

Background

Chemotherapeutic bioassay for colorectal cancer (CRC) with a rat model bearing chemically-induced CRCs plays an important role in the development of new anti-tumor drugs and regimens. Although several protocols to induce CRCs have been developed, the incidence and number of CRCs are not much enough for the efficient bioassay. Recently, we established the very efficient system to induce CRCs with a chemically induced-colon carcinogenesis-prone Apc-mutant rat, Kyoto Apc Delta (KAD) rat. Here, we applied the KAD rat to the chemotherapeutic bioassay for CRC and showed the utility of the KAD rat.

Methods

The KAD rat has been developed by the ENU mutagenesis and carries a homozygous nonsense mutation in the Apc gene (S2523X). Male KAD rats were given a single subcutaneous injection of AOM (20 mg/kg body weight) at 5 weeks of age. Starting at 1 week after the AOM injection, they were given 2% DSS in drinking water for 7 days. Tumor-bearing KAD rats were divided into experimental and control groups on the basis of the number of tumors observed by endoscopy at week 8. The 5-fluorouracil (5-FU) was administrated intravenously a dose of 50 or 75 mg/kg weekly at week 9, 10, and 11. After one-week interval, the 5-FU was given again at week 13, 14, and 15. At week 16, animals were sacrificed and tumor number and volume were measured macroscopically and microscopically.

Results

In total 48 tumors were observed in 27 KAD rats with a 100% incidence at week 8. The maximum tolerated dose for the KAD rat was 50 mg/kg of 5-FU. Macroscopically, the number or volume of tumors in the 5-FU treated rats was not significantly different from the control. Microscopically, the number of adenocarcinoma in the 5-FU treated rats was not significantly different (p < 0.02) from that of the control. However, the volume of adenocarcinomas was significantly lower than in the control. Anticancer effect of the 5-FU could be obtained only after the 16 weeks of experimental period.

Conclusion

The use of the AOM/DSS-treated tumor-bearing KAD rats could shorten the experimental period and reduce the number of animals examined in the chemotherapeutic bioassay. The efficient bioassay with the AOM/DSS-treated tumor-bearing KAD rats would promote the development of new anti-tumor drugs and regimens.

Keywords:
Adenomatous polyposis coli; Colorectal cancer; Endoscopy; Rat; Chemotherapy; 5-fluorouracil