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¹ Department of Molecular Genetics, Institute of DNA Medicine, and ² Department of General Medicine, Jikei University School of Medicine, Tokyo, Japan

Requests for reprints: Yasuhiro Arakawa, Department of Molecular Genetics, Institute of DNA Medicine, Jikei University School of Medicine, Nishi-Shimbashi 3-25-8 Minato-ku, Tokyo 105-8461, Japan. Phone: 81-3-3433-1111. E-mail: yarakawa{at}jikei.ac.jp

Irinotecan hydrochloride, a camptothecin derivative, is one of the most effective drugs for colorectal cancer, and SN-38 is its main active metabolite. Development of resistance is a major obstacle to the clinical application of this drug. We established an SN-38-resistant subline from DLD-1 human colon cancer cells by continuous exposure to SN-38 and studied the mechanisms of resistance. The resistant subline (designated as DLDSNR6) had 10- to 100-fold higher resistance to camptothecin derivatives but showed no cross-resistance to doxorubicin, mitomycin C, and etoposide. DLDSNR6 cells carried a missense mutation in one allele of the DNA topoisomerase I gene that substituted glycine for serine at amino acid residue 365 accompanied by loss of the latter part of the remaining wild-type allele. Topoisomerase I expression was equal in DLDSNR6 and DLD-1 cells, but the nuclear extract of DLDSNR6 cells showed lower topoisomerase I catalytic activity. Moreover, exposure to camptothecin caused less accumulation of topoisomerase I-DNA complexes in DLDSNR6 cells than in DLD-1 cells. These findings suggest that the mutation interfered with both the catalytic activity of topoisomerase I and the stability of the ternary complex between topoisomerase I, DNA, and SN-38. This SN-38-resistant DLDSNR6 cell line may be useful for understanding the mechanisms of topoisomerase I function and drug-enzyme interactions. [Mol Cancer Ther 2006;5(3):502–8]

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³ http://rsb.info.nih.gov/ij/

⁴ http://www.ncbi.nih.gov/SNP/

Received 7/14/05; revised 12/14/05; accepted 1/10/06.