Abstract

The main function of the Bioassay Core is to assist the other Projects to identify those retinoids that are the most suitable as probes to study the molecular mechanism of retinoid action and those that have the highest potential as chemotherapeutic agents against breast cancer. Three classes of retinoids that have inhibitory activity against breast cancer growth, will be evaluated: (1) retinoids inducing gene transcription from retinoid response elements; (2) retinoids indirectly repressing gene transcription from AP-1 sites located in the promoter regions of genes involved in cell proliferation; and (3) retinoids inducing apoptosis. The Core will have the tasks of (1) evaluating these compounds for binding affinity to recombinant retinoid receptors to determine agonist or antagonist activity or for the lack of retinoid binding to the receptors in the case of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2- naphthalenecarboxylic acid (AHPN) analogs to limit toxicity (2) determining by an antiangiogenesis assay in chick chorioallantoic membrane the ability of retinoids and AHPN analogs to inhibit vascularization of tumors, a process that promotes tumor growth and spread, to determine optimum candidates for the breast cancer xenograft experiments (3) conducting pharmacological/toxicological/metabolism studies in animals; and (4) systematically analyzing the results of these assays to select the optimum targets for mechanistic studies, lead optimization, further bioevaluation in the drug development process or recommendation for additional study by NCI. Pharmacological/tocixological/metabolism studies will include determination of candidate agent levels in plasma from treated mice to determine drug dosage for breast cancer xenograft inhibition studies toxicological assessment in mice; and determination of major metabolites and autometabolism potential. The NCI Decision Network method for setting selection criteria, marking rankings, and weighing assay results will be used to rank and then select the most promising retinoids as molecular probes or as therapeutic candidates.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA051993-07
Application #
6269434
Study Section
Project Start
1998-09-07
Project End
1999-01-15
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Sri International
Department
Type
DUNS #
City
Menlo Park
State
CA
Country
United States
Zip Code
94025

  Publications

Xia, Zebin; Cao, Xihua; Rico-Bautista, Elizabeth et al. (2013) Relative impact of 3- and 5-hydroxyl groups of cytosporone B on cancer cell viability. Medchemcomm 4:332-339
Dawson, Marcia I; Xia, Zebin (2012) The retinoid X receptors and their ligands. Biochim Biophys Acta 1821:21-56
Dawson, Marcia I; Xia, Zebin; Jiang, Tao et al. (2008) Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and J Med Chem 51:5650-62
Farhana, Lulu; Dawson, Marcia I; Leid, Mark et al. (2007) Adamantyl-substituted retinoid-related molecules bind small heterodimer partner and modulate the Sin3A repressor. Cancer Res 67:318-25
Dawson, Marcia I; Xia, Zebin; Liu, Gang et al. (2007) An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: effects of modifying its carboxylate group on apoptosis, proliferation, and J Med Chem 50:2622-39
Cavasotto, Claudio N; Liu, Gang; James, Sharon Y et al. (2004) Determinants of retinoid X receptor transcriptional antagonism. J Med Chem 47:4360-72
Dawson, M I (2004) Synthetic retinoids and their nuclear receptors. Curr Med Chem Anticancer Agents 4:199-230
Dawson, Marcia I; Harris, Danni L; Liu, Gang et al. (2004) Antagonist analogue of 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) family of apoptosis inducers that effectively blocks AHPN-induced apoptosis but not cell-cycle arrest. J Med Chem 47:3518-36
Farhana, Lulu; Dawson, Marcia I; Huang, Ying et al. (2004) Apoptosis signaling by the novel compound 3-Cl-AHPC involves increased EGFR proteolysis and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase activities. Oncogene 23:1874-84
Rishi, Arun K; Zhang, Liyue; Boyanapalli, Madanamohan et al. (2003) Identification and characterization of a cell cycle and apoptosis regulatory protein-1 as a novel mediator of apoptosis signaling by retinoid CD437. J Biol Chem 278:33422-35

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