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¹ Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center; ² Program in Gene Therapy and Virology, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas; and ³ Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China

Requests for reprints: Bingliang Fang, Department of Thoracic and Cardiovascular Surgery, Unit 445, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-4039; Fax: 713-794-4669. E-mail: Bfang{at}mdanderson.org

5-Fluorouracil (5-FU) is commonly used to treat human colon cancers but resistance to this compound is frequently observed in clinics. To characterize mechanisms of resistance to 5-FU and to develop new strategies for overcoming it, we established two cell lines that were resistant to 5-FU but not other chemotherapeutic agents from parental 5-FU-sensitive cell lines. Western blot analysis revealed that these resistant cells overexpressed the proteins Bcl-XL, Bcl-Xs, and Bik, and further data showed that the cells were resistant to 5-FU-induced DNA damage and cell cycle disorder. However, in parental cells, enforced expression of Bcl-XL protein provided only limited protection from 5-FU-induced apoptosis and overexpression of Bcl-XL protein did not affect 5-FU-induced DNA damage or cell cycle changes; these findings suggested that overexpression of Bcl-XL protein was not the major contributor to 5-FU resistance in any of our cells lines. Even so, knockdown of Bcl-XL protein expression by Bcl-XL-specific small interfering RNA could inhibit proliferation more effectively in 5-FU-resistant cells than in 5-FU-sensitive cells, and the combination of Bcl-XL-specific small interfering RNA and 5-FU had additive effect on the inhibition of 5-FU-resistant cells. These results suggest that down-regulation of Bcl-XL protein expression might provide a new treatment strategy for human 5-FU-resistant colon cancer therapy.

Key Words: 5-Fluorouracil • Resistance • Colon cancer • Bcl-XL • Small interfering RNA

Grant support: National Cancer Institute grants RO1 CAO92487O1A1 (B. Fang), RO1 CAO9858201A1 (B. Fang), and CA-16672.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/ 1/04; revised 12/ 8/04; accepted 12/30/04.