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Molecular mechanism of interactions between estrogen receptor and estrogen receptor selective genotoxins

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dc.contributor.advisor John M. Essigmann. en_US
dc.contributor.author Lee, Annie S. (Annie Sang), 1975- en_US
dc.contributor.other Massachusetts Institute of Technology. Division of Bioengineering and Environmental Health. en_US
dc.date.accessioned 2012-09-27T15:23:55Z
dc.date.available 2012-09-27T15:23:55Z
dc.date.copyright 2000 en_US
dc.date.issued 2000 en_US
dc.identifier.uri http://hdl.handle.net/1721.1/73348
dc.description Thesis (S.M.)--Massachusetts Institute of Technology, Division of Bioengineering and Environmental Health, 2000. en_US
dc.description Includes bibliographical references (leaves 43-47). en_US
dc.description.abstract Although one million new breast cancer cases arise each year worldwide, therapies to treat the disease are limited. Conventional treatments including the chemotherapeutic agent, Tamoxifen, have had only limited success, often showing uncomfortable side effects. Our group has proposed a new scheme for a rational drug design. This scheme utilizes recent findings on the mechanism of cisplatin, the drug found to cure in excess of 93% of all testicular cancer cases. Cisplatin forms DNA adducts that are toxic. The toxicity of these adducts is enhanced by the recruitment of proteins that bind to the adducts and impede adduct repair. This thesis was an attempt to duplicate this "repair shielding" mechanism with another cytotoxin. Specifically, this toxin will be programmed to kill breast cancer cells. Breast cancer cells often overexpress the estrogen receptor protein. By synthesizing a drug that not only binds and damages the DNA but also binds the abundant proteins in the cells, thereby blocking the damaged site from DNA repair proteins, a selective treatment of cancer cells can be achieved. In this study, the human estrogen receptor (hER) and the ligand binding domain of the hER genes were cloned into baculovirus expression vectors, establishing a system where a large quantity of the proteins can be expressed. The proteins expressed in insect cells were purified in one step, using the FLAG-epitope, yielding homogeneous proteins. The proteins were tested for binding to p-estradiol and were confirmed to be functional in ligand binding. They were also tested for their ability to bind the novel drugs synthesized to bind both the protein and the DNA. It was found that the ligand binding domain of the hER was capable of binding the drugs adducted to the DNA. In an effort to elucidate the mechanism of the protein-drug-DNA complex formation, an association experiment was carried out, which showed that the drug more readily bound to the protein than to DNA. However, a significant amount of the drug-protein complex still bound the DNA, if the ratio of the protein to the drug did not exceed 1.5. en_US
dc.description.statementofresponsibility by Annie S. Lee. en_US
dc.format.extent 69 leaves en_US
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. en_US
dc.rights.uri http://dspace.mit.edu/handle/1721.1/7582 en_US
dc.subject Division of Bioengineering and Environmental Health. en_US
dc.title Molecular mechanism of interactions between estrogen receptor and estrogen receptor selective genotoxins en_US
dc.type Thesis en_US
dc.description.degree S.M. en_US
dc.contributor.department Massachusetts Institute of Technology. Division of Bioengineering and Environmental Health. en_US
dc.identifier.oclc 47862348 en_US


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