ESTROGEN RECEPTOR-DIRECTED THERAPY WITH AUGER ELECTRONS

点击翻译按钮获取中文摘要

The long term goal of this research is to establish the feasibility and applicability of steroid receptor-directed therapy using Auger electron emitting nuclides covalently attached to specific receptor binding ligands to treat cancers containing the appropriate steroid hormone receptors. The approach proposed is based on 1) the known ability of the steroid receptors to form high affinity complexes with the receptor ligands and to bring them into intimate association with regions of DNA in the nucleus, 2) the ability to synthesize bromo- and iodo-ligands which retain high affinity for the steroid receptors, 3) the availability of nuclides of bromine and iodine which decay by emission of Auger electrons, and 4) the highly effective DNA-lytic radiation of Auger electrons emitted in DNA. While endocrine therapies are highly effective in those estrogen receptor positive cancers, such as breast, and endometrial carcinomas, which respond, only about half, at best, of the receptor positive cancer patients obtain remissions following such treatment. And certain cancers, such as ovarian cancers, which often contain estrogen receptor (ER) seldom respond to endocrine treatment. The limitations of current endocrine therapies agree that they require that the growth of the cancer depends on the hormone, and furthermore are cytostatic in nature. On the other hand steroid receptor-directed therapy with Auger electron emitting, receptor- binding ligands would be expected to depend only upon the presence of the receptor in the cell nucleus and, by causing double stranded DNA breads, should kill the cells. Preliminary results in our laboratory have shown that the 4.4 hr half-life nuclide Br-80m, when incorporated into DNA is radiotoxic, and that both steroidal and non-steroidal estrogens containing this nuclide are taken up by ER+ tissues in animals. Our specific aims are therefore: 1) to evaluate in cell culture and animal models the use of radio-iodinated estrogens for the imaging and treatment of ER+ cancers; 2) to establish the feasibility, quantitative features and application of the Auger electron emission of Br-80m labeled estrogens for treatment of ER+ cancers; 3) to elucidate the molecular effects of Auger electrons emanating from steroid receptor-directed ligands upon the steroid receptor proteins and on the DNA to which the receptors are bound; and to explore other approaches to the use of Auger electron emitting nuclides for therapy. Bromine-80m will be produced by the Se-80 (p,n) reaction and attached to the desired ligands by electrophilic substitution of tributyltin derivatives. Similar reactions with commercially available l-123 will provide the analogous radioiodoligands. Specific binding of the radiohalogenated ligands to ER will be determined by titration assays (Scatchard plots), competitive binding and sedimentation analysis using monoclonal antibodies to the steroid receptors. The specific target tissue uptake will be determined by administration of the radioligands to animals in the absence and presence of unlabeled estrogen, and imaging or assay of tissue content of the nuclide, as appropriate. Radiotoxicity will be assessed in steroid receptor positive and negative cells in vitro and in tumors in animals, and compared with the assayed uptake of ligand by the target and nontarget cells of radiohaloestrogen and ER, respectively. Basic studies will measure the radiolytic effects of receptor-directed ligands on the receptor proteins and on associated DNA in model systems.