Novel genotoxins that target estrogen receptor- and androgen receptor- positive cancers : identification of DNA adducts, pharmacokinetics, and mechanism

We 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.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2005

Author dc:creator

• Hillier, Shawn M. (Shawn Matthew)

Advisor dc:contributor.advisor

• John M. Essigmann.

• Chemistry.

Statement 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.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/32480

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/32480