This is a request for continuation of a program begun in 1979. Since isolation of gonadotropin releasing hormone (GnRH) in the early 1970s, basic and clinical discoveries have presented uses for GnRH analogs. Among these are treatments for endometriosis/fibroids, polycystic ovary disease, perimenopause, protection of the ovary and testes (i.e., during chemotherapy), assisted reproduction, precocious puberty, male and female birth control, prostatic, ovarian and mammary carcinomas, cryptorchidism, and other conditions. The first GnRH agonist was approved for use in the US in 1985 (Leuprolide (Lupron, TAP/Abbott)); Buserelin (Hoechst) was already in use in Europe at that time. Each of these molecules, and other agonists, continue to be available for international use. Due to patent expirations, they are now sold by various companies and in an array of formulations and delivery systems, adding to their potential utility and comprising a world-wide market in excess of $1.5 billion. Studies of GnRH action have provided a great deal of useful, basic information to the field of neuroendocrine peptides. Among the faciliatory features of GnRH and its analogs are ease of preparing GnRH analog radioligands, availability of model systems with measurable endpoints, the relative specificity of actions, size (i.e., TRH is very small and chemical modifications frequently destroy binding activity, while CRF and GHRH are large and analogs are relatively difficult to synthesize; GnRH is virtually impossible to denature), and availability of vectors encoding the GnRH receptor and many mutants (along with fluorescent probes) from a range of species and tissues. In addition, nearly 10,000 biologically active GnRH analogs are now described in the scientific and patent literature, providing an exquisite database for understanding structure-activity relations; these analogs include well-defined full agonists and full antagonists, many of which are metabolically stable or have other desirable characteristics. Improved understanding of the mechanism of action of this hormone will likely lead to opportunities for improved drugs (i.e., fewer side effects, orally active and cheaper) and more specific therapies. """"""""Non-traditional"""""""" approaches also have potential; approaches involving some of these are described in the present proposal.
The specific aims of this study will advance both our basic understanding and will identify new sites and approaches potentially amenable to therapeutic intervention. ? ?
Showing the most recent 10 out of 160 publications
