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Breast cancer-specific activation of...

Day, Chi-Ping.

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Breast cancer-specific activation of topoisomerase IIalpha and its application in the tumor-targeting gene therapy.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Breast cancer-specific activation of topoisomerase IIalpha and its application in the tumor-targeting gene therapy./
Author:	Day, Chi-Ping.
Description:	132 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3072.
Contained By:	Dissertation Abstracts International66-06B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3180668
ISBN:	9780542209406

Breast cancer-specific activation of topoisomerase IIalpha and its application in the tumor-targeting gene therapy.
Day, Chi-Ping.

Breast cancer-specific activation of topoisomerase IIalpha and its application in the tumor-targeting gene therapy. - 132 p.

Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3072.

Thesis (Ph.D.)--The University of Texas Graduate School of Biomedical Sciences at Houston, 2005.

To ensure the success of systemic gene therapy, it is critical to enhance the tumor specificity and activity of the promoter. In the current study, we identified the breast cancer-specific activity of the topoisomerase IIalpha promoter. We further showed that cdk2 and cyclin A activate topoisomerase IIalpha promoter in a breast cancer-specific manner. An element containing an inverted CCAAT box (ICB) was shown to respond this signaling. When the ICB-harboring topoisomerase IIalpha minimal promoter was linked with an enhancer sequence from the cytomegalovirus immediate early gene promoter (CMV promoter), this composite promoter, CT90, exhibited activity comparable to or higher than the CMV promoter in breast cancer cells in vitro and in vivo, yet expresses much lower activity in normal cell lines and normal organs than the CMV promoter. A CT90-driven construct expressing BikDD, a potent pro-apoptotic gene, was shown to selectively kill breast cancer cells in vitro and to suppress mammary tumor development in an animal model of intravenously administrated, liposome-delivered gene therapy. Expression of BikDD was readily detectable in the tumors but not in the normal organs of CT90-BikDD-treated animals. Finally, we demonstrated that CT90-BikDD treatment potentially enhanced the sensitivity of breast cancer cells to chemotherapeutic agents, especially doxorubicin and taxol. The results indicate that liposomal CT90-BikDD is a novel and effective systemic breast cancer-targeting gene therapy, and its combination with chemotherapy may further improve the current adjuvant therapy for breast cancer.

ISBN: 9780542209406Subjects--Topical Terms:

1017730
Biology, Genetics.

Breast cancer-specific activation of topoisomerase IIalpha and its application in the tumor-targeting gene therapy.
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502 $a Thesis (Ph.D.)--The University of Texas Graduate School of Biomedical Sciences at Houston, 2005.
520 $a To ensure the success of systemic gene therapy, it is critical to enhance the tumor specificity and activity of the promoter. In the current study, we identified the breast cancer-specific activity of the topoisomerase IIalpha promoter. We further showed that cdk2 and cyclin A activate topoisomerase IIalpha promoter in a breast cancer-specific manner. An element containing an inverted CCAAT box (ICB) was shown to respond this signaling. When the ICB-harboring topoisomerase IIalpha minimal promoter was linked with an enhancer sequence from the cytomegalovirus immediate early gene promoter (CMV promoter), this composite promoter, CT90, exhibited activity comparable to or higher than the CMV promoter in breast cancer cells in vitro and in vivo, yet expresses much lower activity in normal cell lines and normal organs than the CMV promoter. A CT90-driven construct expressing BikDD, a potent pro-apoptotic gene, was shown to selectively kill breast cancer cells in vitro and to suppress mammary tumor development in an animal model of intravenously administrated, liposome-delivered gene therapy. Expression of BikDD was readily detectable in the tumors but not in the normal organs of CT90-BikDD-treated animals. Finally, we demonstrated that CT90-BikDD treatment potentially enhanced the sensitivity of breast cancer cells to chemotherapeutic agents, especially doxorubicin and taxol. The results indicate that liposomal CT90-BikDD is a novel and effective systemic breast cancer-targeting gene therapy, and its combination with chemotherapy may further improve the current adjuvant therapy for breast cancer.
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