Alpha-TEA plus cisplatin reduces human cisplatin-resistant ovarian cancer cell tumor burden and metastasis.

Abstract

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 (alpha-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, alpha-TEA was formulated in liposomes and delivered by aerosol such that approximately 36 microg and 72 microg of alpha-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 alpha-TEA + cisplatin treatment reduced tumor burden and metastasis of cp70-GFP cells in comparison to control mice or mice treated with alpha-TEA or cisplatin singly. A significant reduction (P < 0.001) in growth of subcutaneous transplanted tumors was obtained with alpha-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 alpha-TEA- or alpha-TEA + cisplatin-treated groups. The alpha-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 alpha-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 alpha-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 alpha-TEA + cisplatin chemotherapy for ovarian cancer.

• Authors: Kristen Anderson, Karla A Lawson, Marla Simmons-Menchaca, Luzhe Sun, Bob G Sanders, Kimberly Kline
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 229 Issue 11 Pg. 1169-76 (Dec 2004) ISSN: 1535-3702 [Print] England
• PMID: 15564444 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Liposomes
• Vitamin E
• 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid
• Cisplatin
• Tocopherols

Topics

• Administration, Inhalation
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• Cisplatin (administration & dosage)
• Disease Models, Animal
• Drug Resistance (physiology)
• Female
• Humans
• In Situ Nick-End Labeling
• Liposomes
• Mice
• Mice, Nude
• Neoplasm Metastasis (drug therapy)
• Neoplasm Transplantation
• Ovarian Neoplasms (drug therapy, pathology)
• Tocopherols
• Tumor Burden (drug effects)
• Vitamin E (administration & dosage, analogs & derivatives)