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Indoleamine 2,3-Dioxygenase Serves as a Marker of Poor Prognosis in Gene Expression Profiles of Serous Ovarian Cancer Cells

Authors' Affiliations: Departments of ¹ Obstetrics and Gynecology, ² Gene Therapy, Institute of DNA Medicine, ³ Pathology, ⁴ Clinical Oncology, and ⁵ Pediatrics and ⁶ Division of Clinical Research and Development, Jikei University School of Medicine; ⁷ Pharmaceutical Research Department 2, Research Division, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan; and ⁸ Department of Cellular Pharmacology, Graduate School of Medicine Hokkaido University, Sapporo, Japan

Requests for reprints: Mitsuyoshi Urashima, Division of Clinical Research and Development, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan. Phone: 81-3-3433-1111, ext. 2405; Fax: 81-3-5400-1250; E-mail: urashima{at}jikei.ac.jp.

Purpose: We aimed to find key molecules associated with chemoresistance in ovarian cancer using gene expression profiling as a screening tool.

Experimental Design: Using two newly established paclitaxel-resistant ovarian cancer cell lines from an original paclitaxel-sensitive cell line and four supersensitive and four refractory surgical ovarian cancer specimens from paclitaxel-based chemotherapy, molecules associated with chemoresistance were screened with gene expression profiling arrays containing 39,000 genes. We further analyzed 44 genes that showed significantly different expressions between paclitaxel-sensitive samples and paclitaxel-resistant samples with permutation tests, which were common in cell lines and patients' tumors.

Results: Eight of these genes showed reproducible results with real-time reverse transcription-PCR, of which indoleamine 2,3-dioxygenase gene expression was the most prominent and consistent. Moreover, by immunohistochemical analysis using a total of 24 serous-type ovarian cancer surgical specimens (stage III, n = 21; stage IV, n = 7), excluding samples used for GeneChip analysis, the Kaplan-Meier survival curve showed a clear relationship between indoleamine 2,3-dioxygenase staining patterns and overall survival (log-rank test, P = 0.0001). All patients classified as negative survived without relapse. The 50% survival of patients classified as sporadic, focal, and diffuse was 41, 17, and 11 months, respectively.

Conclusion: The indoleamine 2,3-dioxygenase screened with the GeneChip was positively associated with paclitaxel resistance and with impaired survival in patients with serous-type ovarian cancer.

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