Show simple item record

dc.contributor.advisorJohn M. Essigmann.en_US
dc.contributor.authorHillier, Shawn M. (Shawn Matthew)en_US
dc.contributor.otherMassachusetts Institute of Technology. Dept. of Chemistry.en_US
dc.date.accessioned2006-03-29T18:48:22Z
dc.date.available2006-03-29T18:48:22Z
dc.date.copyright2005en_US
dc.date.issued2005en_US
dc.identifier.urihttp://hdl.handle.net/1721.1/32480
dc.descriptionThesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005.en_US
dc.descriptionVita.en_US
dc.descriptionIncludes bibliographical references.en_US
dc.description.abstractWe have designed and synthesized novel molecules capable of selectively killing tumor cells that aberrantly express steroid hormone receptors. Many human breast cancers express high levels of the estrogen receptor (ER), and most prostate cancers express the androgen receptor (AR). We reasoned that the potential genotoxic effect of DNA adducts would be increased in target cells if these adducts were camouflaged by their association with receptor proteins. This association could shield the DNA adducts from repair proteins and thus increase the toxicity towards a tumor cell. Furthermore, these hormone receptors are transcription factors and an interaction between the protein and the DNA adduct could disrupt cellular signaling events, thus leading to further toxicity. We have synthesized bifunctional agents that contain an aniline mustard linked to ligands for tumor specific hormone receptors. To target ER(+) breast cancers, an aniline mustard was linked to estradiol at the 7[alpha] position (E2-7[alpha]), and to target AR(+) prostate cancer, the aniline mustard was linked to estradien-3-one at the 11[beta] position (11[beta]). Competitive binding experiments show that E2-7[alpha] and 11[beta] compete well with the natural ligands for the ER and AR, respectively. Clonal survival studies have shown that hormone receptor expressing malignant cell lines are more sensitive to our compounds than a corresponding receptor deficient line. [¹⁴C]-E2-7[alpha] and [¹⁴C]- 11[beta] have been formulated in Cremophor-EL and exhibit good bioavailability and stability when injected into mice intraperitoneally. E2-7[alpha] inhibits the growth of ER(+) HeLa cells and 11[beta] inhibits the growth of AR(+) LNCaP cells, both in xenograft mouse models.en_US
dc.description.abstract(cont.) The compounds are well tolerated by mice after the therapeutic regimens. Stable DNA adducts have been isolated and detected by electrospray mass spectrometry and accelerator mass spectrometry has provided us with a means of quantifying the number of DNA adducts formed in vivo. E2-7[alpha] DNA adducts are repaired, in part, by nucleotide excision repair but the adducts persist longer in ER(+) cells than in ER(-) ones. Melphalan adducts, however, are repaired with equal rates in both cell lines. This result provides evidence in support of the repair shielding hypothesis and suggests that it may be a contributing mechanism to the increased toxicity observed for the ER(+) cell line in the clonal survival study.en_US
dc.description.statementofresponsibilityby Shawn M. Hillier.en_US
dc.format.extent2 v. (315 leaves)en_US
dc.format.extent18186825 bytes
dc.format.extent18209072 bytes
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsM.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.urihttp://dspace.mit.edu/handle/1721.1/7582
dc.subjectChemistry.en_US
dc.titleNovel genotoxins that target estrogen receptor- and androgen receptor- positive cancers : identification of DNA adducts, pharmacokinetics, and mechanismen_US
dc.typeThesisen_US
dc.description.degreePh.D.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistry
dc.identifier.oclc61773066en_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record