MRP-Related Transporter Genes Involved in Erectile Dysfunction Signaling Pathway, Drug Resistance and Connective Tissue Homeostasis
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Tumors often develop resistance to the drugs used to treat them. Resistance to chemotherapeutic drugs is considered to be the most significant reason why anticancer agents are not more effective in treating common malignancies. A particularly serious form of resistance is associated with expression of MRP-related transporters because they simultaneously confer resistance to a broad spectrum of drugs. A great need exists for therapeutic compounds that will inhibit these transporters and thus potentially increase the potency of anticancer agents
Fox Chase researchers have isolated four MRP-related (Multidrug Resistance-associated Protein) genes, termed MRP3 (MOAT-D), MRP4 (MOAT- B), MRP5 (MOAT-C), and MRP6 (MOAT-E). This family of transporters exports many pharmaceutical compounds from cells. As a result, MRP1, MRP3, MRP4, and MRP5 all confer resistance to anticancer agents. In addition, MRP4 and MRP5 confer resistance to certain drugs used in the treatment of AIDS. MRP5 and possibly MRP4 are capable of exporting cGMP from cells. This is the pathway targeted by Viagra and other pharmaceuticals that impact cGMP signaling. MRP6 is involved in connective tissue homeostasis, as its loss is known to result in the hereditary human disease pseudoxanthoma elasticum, an illness that involves skin, eyes and blood vessels.
It is anticipated that these discoveries will have diagnostic, drug development, drug characterization and research reagent applications. Companies that are developing therapeutic agents may want to determine if these transporters influence the cellular or physiological distribution of their products. We anticipate that biotechnology and pharmaceutical companies will be interested in developing inhibitors of MRP1, MRP3, MRP4 and MRP5 that might improve currently available cancer therapies. Inhibitors of MRP4 and MRP5 might be developed with the view that they would increase intracellular levels of anti-HIV drugs. Inhibitors of MRP4 and MRP5 designed to elevate cGMP levels may be useful in alleviating erectile dysfunction.
We are interested in establishing a collaboration with a company that includes both sponsorship of this research as well as licensing for further commercial development.
A US patent application has been filed. (December 08, 2000)