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

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.

• Authors: Kazuto Yoshimi, Takao Hashimoto, Yusuke Niwa, Kazuya Hata, Tadao Serikawa, Takuji Tanaka, Takashi Kuramoto
• Journal: BMC cancer (BMC Cancer) Vol. 12 Pg. 448 (Oct 03 2012) ISSN: 1471-2407 [Electronic] England
• PMID: 23031214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenomatous Polyposis Coli Protein
• Antimetabolites, Antineoplastic
• Dextran Sulfate
• Azoxymethane
• Fluorouracil

Topics

• Adenocarcinoma (chemically induced, drug therapy, genetics)
• Adenomatous Polyposis Coli Protein (genetics)
• Animals
• Antimetabolites, Antineoplastic (administration & dosage, pharmacology)
• Azoxymethane
• Colon (drug effects, pathology)
• Colonic Neoplasms (chemically induced, drug therapy, genetics)
• Dextran Sulfate
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Screening Assays, Antitumor (methods)
• Fluorouracil (administration & dosage, pharmacology)
• Injections, Intravenous
• Male
• Mutation
• Rats
• Reproducibility of Results