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Uniform TitleHypoxia inducible factor: targeted anticancer prodrug
NameWang, Yang (author), Minko, Tamara (chair), Michniak, Bozena (internal member), You, Guofeng (internal member), Gordon, Marion (outside member), Rutgers University, Graduate School - New Brunswick,
Degree Date2007-05
Date Created2007
SubjectPharmaceutical Science,
Cancer--Treatment,
Prodrugs,
Drug delivery systems
DescriptionIn vitro and in vivo antitumor effect of the combination of an inducer of cell death (anticancer drug) and a suppressor of cellular resistance (antisense oligonucleotides targeted to hypoxia-inducible factor 1 alpha, HIF1A, mRNA) was evaluated.
The proposed novel HIF targeted anticancer prodrug includes three main components: (1) drug carrier, (2) an apoptosis inducing agent (anticancer drug) and (3) a suppressor of HIF1A protein. Doxorubicin (DOX) and camptothecin (CPT) were used as anticancer drugs. ASO targeted to HIF1A mRNA was used as a suppressor of HIF1A protein. Two types of carriers have been used in vitro: liposomes and polyethylene glycol (PEG) polymer. Polymeric liposome is used as an in vivo carrier. Anticancer efficacy of proposed prodrugs has been evaluated in vitro using human ovarian and breast carcinoma cells and in vivo on nude mice bearing xenografts of multidrug resistant human ovarian tumor.
Both in vitro and in vivo experiments showed that ASO targeted to HIF1A mRNA decreased the overexpression of the HIF1A protein induced by hypoxia and anticancer drugs. The designed drug delivery system provided for intracellular delivery of active components and suppressed cellular antiapoptotic defense leading to the more pronounced induction of P53 and caspase-dependent signaling pathway of apoptosis when compared with an anticancer drug alone.
Data obtained in both in vitro and in vivo experiments showed that the proposed novel prodrug approach will form a foundation for a novel type of cancer therapy based on the combined use of a suppressor of HIF1A protein and an anticancer drug. Such combination therapy shows a high potential in preventing the development of resistance in tumor cells and thus will increase the efficacy of cancer therapy to an extent that cannot be achieved by individual components applied separately.
The proposed novel HIF targeted anticancer prodrug includes three main components: (1) drug carrier, (2) an apoptosis inducing agent (anticancer drug) and (3) a suppressor of HIF1A protein. Doxorubicin (DOX) and camptothecin (CPT) were used as anticancer drugs. ASO targeted to HIF1A mRNA was used as a suppressor of HIF1A protein. Two types of carriers have been used in vitro: liposomes and polyethylene glycol (PEG) polymer. Polymeric liposome is used as an in vivo carrier. Anticancer efficacy of proposed prodrugs has been evaluated in vitro using human ovarian and breast carcinoma cells and in vivo on nude mice bearing xenografts of multidrug resistant human ovarian tumor.
Both in vitro and in vivo experiments showed that ASO targeted to HIF1A mRNA decreased the overexpression of the HIF1A protein induced by hypoxia and anticancer drugs. The designed drug delivery system provided for intracellular delivery of active components and suppressed cellular antiapoptotic defense leading to the more pronounced induction of P53 and caspase-dependent signaling pathway of apoptosis when compared with an anticancer drug alone.
Data obtained in both in vitro and in vivo experiments showed that the proposed novel prodrug approach will form a foundation for a novel type of cancer therapy based on the combined use of a suppressor of HIF1A protein and an anticancer drug. Such combination therapy shows a high potential in preventing the development of resistance in tumor cells and thus will increase the efficacy of cancer therapy to an extent that cannot be achieved by individual components applied separately.
NotePh.D.
NoteIncludes bibliographical references.
Genretheses
Persistent URLhttp://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17105
LanguageEnglish
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.