Resistance of clear cell carcinoma (CCC) of the ovary to platinum-based chemotherapy is associated with a poor prognosis. However, the mechanism underlying the resistance of CCC to platinum has not yet been understood. We conducted the present study to clarify the mechanism of cisplatin (CDDP) resistance in CCC cells. Eleven CCC and 5 serous adenocarcinoma (SAC) cell lines were used in this study. The IC50 to CDDP ranged from 1.3 to 18.0 µM for CCC cells and from 2.2 to 13.0 µM for SAC cells. There was no correlation between multidrug resistance-associated protein expression and the sensitivity to CDDP in CCC cells. In contrast, the doubling time for CCC cells was significantly longer than that for SAC cells (61.4 vs. 29.8 h). A significant reverse correlation between the S-phase fraction and the response to CDDP was observed (r = 0.647, p < 0.05). The present study suggests that the resistance of CCC to CDDP may be caused by low cell proliferation.

Keywords:
Ovarian cancer, Cisplatin, Resistance, Multidrug resistance-associated protein gene, Cell proliferation
1.
Serov SF, Scully RE, Robin IH: International Histologic Classification of Tumours: No. 9. Histological Typing of Ovarian Tumours. Geneva, World Health Organization, 1973, pp 37–42.
2.
Aure JC, Hoeg K, Kolstad P: Mesonephroid tumors of the ovary. Clinical and histopathologic studies. Obstet Gynecol 1971;37:860–867.
3.
Kennedy AW, Biscotti CV, Hart WR, Webster KD: Ovarian clear cell adenocarcinoma. Gynecol Oncol 1989;32:342–349.
4.
Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T, Suzuki M, Sato I, Taguchi K: Clinical characteristics of clear cell carcinoma of the ovary: A distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 2000;88:2584–2589.
5.
Goff BA, Sainz de la Cuesta R, Muntz HG, Fleischhacker D, Ek M, Rice LW, Nikrui N, Tamimi HK, Cain JM, Greer BE, Fuller AF Jr: Clear cell carcinoma of the ovary: A distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease. Gynecol Oncol 1996;60:412–417.
6.
Tammela J, Geisler JP, Eskew PN Jr, Geisler HE: Clear cell carcinoma of the ovary: Poor prognosis compared to serous carcinoma. Eur J Gynaecol Oncol 1998;19:438–440.
7.
Andrews PA, Velury S, Mann SC, Howell SB: cis-Diamminedichloroplatinum(II) accumulation in sensitive and resistant human ovarian carcinoma cells. Cancer Res 1988;48:68–73.
8.
Andrews PA, Howell SB: Cellular pharmacology of cisplatin: Perspectives on mechanisms of acquired resistance. Cancer Cells 1990;2:35–43.
9.
Godwin AK, Meister A, O’Dwyer PJ, Huang CS, Hamilton TC, Anderson ME: High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci USA 1992;89:3070–3074.
10.
Fujiwara Y, Sugimoto Y, Kasahara K, Bungo M, Yamakido M, Tew KD, Saijo N: Determinants of drug response in a cisplatin-resistant human lung cancer cell line. Jpn J Cancer Res 1990;81:527–535.
11.
Kasahara K, Fujiwara Y, Nishio K, Ohmori T, Sugimoto Y, Komiya K, Matsuda T, Saijo N: Metallothionein content correlates with the sensitivity of human small cell lung cancer lines to cisplatin. Cancer Res 1991;51:3237–5242.
12.
Lautier D, Canitrot Y, Deeley RG, Cole SP: Multidrug resistance mediated by the multidrug resistance protein (MRP) gene. Biochem Pharmacol 1996;52:967–977.
13.
Ishikawa T, Bao JJ, Yamane Y, Akimaru K, Frindrich K, Wright CD, Kuo MT: Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem 1996;271:14981–14988.
14.
Bonetti A, Zaninelli M, Rodella S, Molino A, Sperotto L, Piubello Q, Bonetti F, Nortilli R, Turazza M, Cetto GL: Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma. Breast Cancer Res Treat 1996;38:289–297.
15.
O’Reilly SM, Camplejohn RS, Rubens RD, Richards MA: DNA flow cytometry and response to preoperative chemotherapy for primary breast cancer. Eur J Cancer 1992;28:681–683.
16.
Chevillard S, Pouillart P, Beldjord C, Asselain B, Beuzeboc P, Magdelenat H, Vielh P: Sequential assessment of multidrug resistance phenotype and measurement of S-phase fraction as predictive markers of breast cancer response to neoadjuvant chemotherapy. Cancer 1996;77:292–300.
17.
Mosmann T: Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55–63.
18.
Park JG, Kramer BS, Steinberg SM, Carmichael J, Collins JM, Minna JD, Gazdar AF: Chemosensitivity testing of human colorectal carcinoma cell lines using a tetrazolium-based colorimetric assay. Cancer Res 1987;47:5875–5879.
19.
Young LC, Campling BG, Voskoglou-Nomikos T, Cole SP, Deeley RG, Gerlach JH: Expression of multidrug resistance protein-related genes in lung cancer: Correlation with drug response. Clin Cancer Res 1999;5:673–680.
20.
Gorai I, Nakazawa T, Miyagi E, Hirahara F, Nagashima Y, Minaguchi H: Establishment and characterization of two human ovarian clear cell adenocarcinoma lines from metastatic lesions with different properties. Gynecol Oncol 1995;57:33–46.
21.
Nooter K, Stoter G: Molecular mechanisms of multidrug resistance in cancer chemotherapy. Pathol Res Pract 1996;192:768–780.
22.
Kigawa J, Minagawa Y, Cheng X, Terakawa N: γ-Glutamyl cysteine synthetase up-regulates glutathione and multidrug resistance-associated protein in patients with chemoresistant epithelial ovarian cancer. Clin Cancer Res 1998;4:1737–1741.
23.
Kamazawa S, Kigawa J, Minagawa Y, Itamochi H, Shimada M, Takahashi M, Sato S, Akeshima R, Terakawa N: Cellular efflux pump and interaction between cisplatin and paclitaxel in ovarian cancer cells. Oncology 2000;59:329–335.
24.
Nooter K, Brutel de la Riviere G, Looke MP, van Wingerden KE, Henzen-Logmans SC, Scheper RJ, Flens MJ, Klijn JG, Stoter G, Foekens JA: The prognostic significance of expression of the multidrug resistance-associated protein (MRP) in primary breast cancer. Br J Cancer 1997;76:486–493.
25.
Kool M, de Haas M, Scheffer GL, Van Eijk MJ, Juijn JA, Baas F, Borst P: Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res 1997;57:3537–3547.
26.
Dimanche-Boitrel MT, Pelletier H, Genne P, Petit JM, Le Grimellec C, Canal P, Ardiet C, Bastian G, Chauffert B: Confluence-dependent resistance in human colon cancer cells: Role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells. Int J Cancer 1992;50:677–682.
27.
Barcellos-Hoff MH, Marton LJ, Deen DF: Differential drug sensitivity conferred by growth status detected in a mixed population of cycling and noncycling cells. Cancer Res 1990;50:3551–3555.
28.
Schmidt RA, Conrad EU 3rd, Collins C, Rabinovitch P, Finney A: Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer 1993;72:2593–2601.
29.
Kolfschoten GM, Hulscher TM, Pinedo HM, Boven E: Drug resistance features and S-phase fraction as possible determinants for drug response in a panel of human ovarian cancer xenografts. Br J Cancer 2000;83:921–927.
30.
Kel AE, Kel-Margoulis OV, Farnham PJ, Bartley SM, Wingender E, Zhang MQ: Computer-assisted identification of cell cycle-related genes: New targets for E2F transcription factors. J Mol Biol 2001;25:99–120.
31.
Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, Harris CC, Deng CX: Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 2001;28:266–271.
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2002
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