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The SERM, Arzoxifene, and the rexinoid, LG100268, cooperate to prevent estrogen receptor-positive and -negative breast cancer as well as colon cancer.

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Call No.	QP572.E85 R46 2004
Author	Rendi, Mara H.
Title	The SERM, Arzoxifene, and the rexinoid, LG100268, cooperate to prevent estrogen receptor-positive and -negative breast cancer as well as colon cancer.
Date	2004
Abstract	We have previously shown that the selective estrogen receptor modulator, Arzoxifene (Arz), and the rexinoid, LG100268 (268) synergistically prevent breast cancer in an ER+ breast cancer model. This study was designed to determine the mechanism of action of these drugs in estrogen receptor positive (ER+) breast cancer. We demonstrate here that the combination of Arz and 268 synergistically increases apoptosis in ER+ breast cancer cell lines and in ER+ breast tumors while the individual agents have no effect. In addition, we present a new model to explain the induction of apoptosis by these agents. We show that Arz induces TGF-β-mediated apoptosis while 268 inhibits the NF-κB and PI3K pro-survival pathways. We have also determined that Arz and 268 cooperate to prevent colon cancer and estrogen receptor negative (ER-) breast cancer in addition to ER+ breast cancer. For the colon cancer experiments, F344 male rats were injected with 15 mg/kg azoxymethane and subsequently fed control diet or diets containing Arz (6 mg/kg of diet), 268 (50 mg/kg of diet), or the combination. While Arz and 268 decreased tumor formation by 17.0% and 20.8% respectively, the combination inhibited tumor formation by 87.3% as compared with controls. For the ER- breast cancer experiments, MMTV- neu transgenic mice were fed control diets or diets containing Arz (6 mg/kg of diet), 268 (30 mg/kg diet), or the combination for 52 weeks. When 100% of control mice developed tumors, only 75% of mice receiving 268 alone and 37.5% mice receiving Arz alone developed tumors. Unexpectedly, mice receiving the combination diet did not develop any tumors. In addition to the in vivo results, the combination of Arz and 268 was found to synergize to promote apoptosis in both colon cancer and ER- breast cancer cell lines. Moreover, we demonstrate that Arz and 268 induce this apoptosis by a similar mechanism as in ER+ breast cancer; the induction of TGF-βmediated apoptosis by Arz and the inhibition of the NF-κB and PI3K pro-survival pathways by 268. This study further emphasizes the role of TGFβ and apoptotic agents in cancer chemoprevention and the importance of combination chemoprevention. Moreover, these data suggest that Arz and 268 may prevent several of the common epithelial cancers found clinically. As a result, these compounds should be considered for chemoprevention trials in humans as soon as possible.
Description	xv, 152 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Michael B. Sporn.
Subject	Estrogen -- Receptors -- Regulation. Selective estrogen receptor modulators. Receptor-ligand complexes. Breast -- Cancer -- Chemoprevention. Colon (Anatomy) -- Cancer -- Chemoprevention.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.37

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	The SERM, Arzoxifene, and the Rexinoid, LG100268, Cooperate to Prevent Estrogen Receptor-Positive and -Negative Breast Cancer as well as Colon Cancer A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Mara H. Rendi DARTMOUTH COLLEGE Hanover, New Hampshire June 3, 2004 Examining Committee ____________________________ (chair) Michael B. Sporn, M.D. ____________________________ Ethan Dmitrovsky, M.D. ____________________________ Michael Spinella, Ph.D. ____________________________ Anita Roberts, Ph.D. ____________________________ Carol Folt Dean of Graduate Studies

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The SERM, Arzoxifene, and the rexinoid, LG100268, cooperate to prevent estrogen receptor-positive and -negative breast cancer as well as colon cancer.

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