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ORIGINAL RESEARCH ARTICLE

-TEA Plus Cisplatin Reduces Human Cisplatin-Resistant Ovarian Cancer Cell Tumor Burden and Metastasis

Kristen Anderson^*, Karla A. Lawson^*, Marla Simmons-Menchaca^*, Luzhe Sun, Bob G. Sanders^* and Kimberly Kline^*,1

^* Division of Nutrition and School of Biological Sciences, University of Texas, Austin, Texas 78712; Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78220

To whom requests for reprints should be addressed at ¹ Division of Nutrition/A2703, University of Texas at Austin, Austin, TX 78712-1097. E-mail: k.kline{at}mail.utexas.edu

A novel nonhydrolyzable ether-linked acetic acid analog of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (-TEA) in combination with cisplatin, reduces tumor burden of A2780/cp70 (cp70) cisplatin-resistant human ovarian cancer cells xenografted into immune compromised nude mice. Two xenograft studies were conducted using cp70 cells stably expressing green fluorescent protein (cp70-GFP) subcutaneously transplanted into NU/NU mice. For studies 1 and 2, -TEA was formulated in liposomes and delivered by aerosol such that approximately 36 µg and 72 µg of -TEA were deposited in the respiratory tract of each mouse each day, respectively. Cisplatin at 5 mg/kg was administered by intraperitoneal injections once weekly for the first 3 weeks in Study 1 and on the third and 10th days following treatment initiation in Study 2. The combination -TEA + cisplatin treatment reduced tumor burden and metastasis of cp70-GFP cells in comparison to control mice or mice treated with -TEA or cisplatin singly. A significant reduction (P < 0.001) in growth of subcutaneous transplanted tumors was obtained with -TEA + cisplatin for both studies. Visible metastases were observed in the lungs of animals from control and cisplatin-treated groups but not in animals from the -TEA- or -TEA + cisplatin–treated groups. The -TEA + cisplatin significantly reduced the total number of lung and axillary lymph node micrometastasis (P < 0.03 and P < 0.0001, respectively). Analyses of tumor sections showed the -TEA + cisplatin treatment group, in comparison to control, to have a significantly lower level of cell proliferation (Ki-67 staining; P < 0.0001) and a significantly higher level of apoptosis (terminal deoxynucleotidyl transferase–mediated nick end labeling [TUNEL]; P < 0.0001). In summary, combinations of -TEA + cisplatin significantly reduced tumor burden and metastases in a xenograft model of cisplatin-resistant human ovarian cancer cells. These data show promise for combination -TEA + cisplatin chemotherapy for ovarian cancer.

Key Words: vitamin E analog (-TEA) • cisplatin • metastasis • antitumor agents • xenograft ovarian cancer model

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