Novel multidrug resistance-associated polypeptide

Abstract

Compositions and methods are disclosed for improving the effectiveness of a chemotherapeutic regimen to eradicate multidrug-resistant transformed cells from the body of a mammal, preferably from the body of a human. The present disclosure capitalizes on the discovery of a novel multidrug-resistance associated protein (MRP), herein designated MRP-β. The disclosed compositions include MRP-β nucleic acids, including probes and antisense oligonucleotides, MRP-β polypeptides and antibodies, MRP-β expressing host cells, and non-human mammals transgenic or nullizygous for MRP-β. The disclosed methods include methods for attenuating aberrant MRP-β gene expression, protein production and/or protein function. In addition, methods are disclosed for identifying and using a modulator, such as an inhibitor, of MRP-β. Preferably, the modulator is a small molecule.

1 . A method of decreasing the activity of an MRP-β polypeptide, comprising contacting a nucleic acid molecule encoding the MRP-β polypeptide with an antisense oligonucleotide complementary to all or a portion of a nucleic acid molecule at least 70% identical to SEQ ID NO: 1 and encoding the polypeptide, wherein the MRP-β polypeptide functions to transport, expel, or sequester substances from an intracellular milieu, thereby decreasing the activity of the MRP-β polypeptide. 
     
     
         2 . The method of  claim 1 , wherein nucleic acid molecule is at least 80% identical to SEQ ID NO:1. 
     
     
         3 . The method of  claim 1 , wherein nucleic acid molecule is at least 90% identical to SEQ ID NO: 1. 
     
     
         4 . The method of  claim 1 , wherein nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 1. 
     
     
         5 . The method of  claim 1 , wherein nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 1 or the complement thereof. 
     
     
         6 . The method of  claim 1 , wherein nucleic acid molecule consists of the nucleotide sequence of SEQ ID NO: 1 or the complement thereof. 
     
     
         7 . The method of  claim 1 , wherein said MRP-β polypeptide is present on tumor cells from secretory epithelial tissue. 
     
     
         8 . The method of  claim 7 , wherein the secretory epithelial tissue is selected form the group consisting of respiratory tract, gastrointestinal tract, mammary, urogenital tract, paracrine, endocrine and neuroendocrine tissues. 
     
     
         9 . The method of  claim 1 , wherein the MRP-β polypeptide is present on tumor cells selected from the group consisting of sarcomas, carcinomas, and adenocarcinomas. 
     
     
         10 . The method of  claim 1 , wherein the MRP-β polypeptide is present on tumor cells selected from the group consisting of lung, colon, kidney, bladder, breast, ovarian, uterine, cervical, testicular, prostate and pancreatic tissue. 
     
     
         11 . The method of  claim 1 , wherein the antisense oligonucleotide decreases production of the MRP-β polypeptide. 
     
     
         12 . The method of  claim 1 , wherein the antisense oligonucleotide decreases biological function of the MRP-β polypeptide. 
     
     
         13 . The method of  claim 1 , wherein the antisense oligonucleotide is present in a vector. 
     
     
         14 . The method of  claim 1 , wherein the antisense oligonucleotide is present in a pharmaceutical composition. 
     
     
         15 . The method of  claim 1  wherein said MRP-β polypeptide comprises an amino acid sequence that is at least 85% identical to the amino acid sequence set forth as SEQ ID NO:2. 
     
     
         16 . The method of  claim 1 , wherein said MRP-β polypeptide comprises the amino acid sequence of SEQ ID NO:11.