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Modulators of the abc transporter family and methods for their useModulators of the abc transporter family and methods for their use description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070275894, Modulators of the abc transporter family and methods for their use. Brief Patent Description - Full Patent Description - Patent Application Claims
INTRODUCTION [0001]This patent application is a continuation-in-part of U.S. application Ser. No. 10/575,577, filed Oct. 14, 2004, which claims the benefit of priority from U.S. Provisional Patent Application Ser. No. 60/511,609, filed Oct. 15, 2003, the teachings of which are herein incorporated by reference in their entirety. FIELD OF THE INVENTION [0003]A factor, confirmed using a proteomics approach to be a protein, which is secreted by Pseudomonas aeruginosa has now been identified as reducing plasma membrane expression of ATP-binding cassette (ABC) transmembrane proteins such as P-glycoprotein (Pgp or multidrug resistance protein (MDR)), multidrug resistance associated protein 2 (MRP2), Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), and other members of the ABC transporter family, whose functions include control of the transport of small molecules across cell membranes. Inhibition of the expression of these ABC transmembrane proteins in the plasma membrane by this newly identified factor or active fragments or mimetics thereof is expected to be useful in promoting delivery of therapeutics to the central nervous system, treating cancers that have developed resistance to conventional therapies due to over expression of multidrug resistance transporters, increasing the bioavailability of drugs and in inhibiting secretory diarrhea. Suppression of the inhibitory effects of this newly identified factor on expression of ABC transmembrane proteins, particularly CFTR expression, is expected to be useful in treatment of patients with cystic fibrosis and other diseases of the respiratory tract that are caused by infection with Pseudomonas aeruginosa. BACKGROUND OF THE INVENTION [0004]A family of proteins found on the surface of cells is known as the ATP-binding cassette (ABC) family of transmembrane proteins. Expression of these proteins affects the therapeutic accumulation of drugs in the central nervous system as well as in cancer cells and affects the absorption of therapeutic drugs by the gastrointestinal tract. This family of proteins includes, but is not limited to, the transmembrane ATP-dependent drug translocation protein P-glycoprotein (Pgp; Nooter, K. and Sonneveld, P. Leuk. Res. 1993 18:233-243; Biedler, J. L. Cancer Res. 1994 54:666-678; Kerbel et al. Cold Spring Harbor Symp. Quant. Biol. 1994 59:661-672; Broxterman et al. Curr. Opin. Oncol. 1995 7:532-540; and List, A. F. Leukemia 1996 10:937-942), also referred to as the Multi-drug Resistance Protein (MDR), whose over expression is L associated with multi-drug resistance (Demolombe, S. and Escande, D. TIPS 1996 17:273-275); and multidrug resistance associated protein 2 or MRP2, BCRP, MRP1, and the chloride channel Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). [0005]Pgp is expressed in a variety of normal tissues including liver, kidney and colon and in tumors arising from these tissues that usually over express Pgp as part of their multi-drug resistance (MDR) phenotype (Cole et al. Science 1992 258:1650-1654; Roninson, I. B. Biochem. Pharmacol. 1992 43:95-102; Arceci, R. J. Blood 1993 81:2215-2222; and Merkel et al. J. Clin. Oncol. 1989 7:1129-1136). Pgp can also be over expressed in tumors from tissues that do not normally express this protein, such as breast and ovarian tissues (Arceci, R. J. Blood 1993 81:2215-2222; and Ihnat et al. Clin. Cancer Res. 1997 3:1339-1346). The mechanism of Pgp upregulation in tumors in vivo is still unclear, but can occur de novo as in acute myologenous leukemia (AML) (Gregorcyk et al. Ann. Surg. Oncol. 1996 3:8-14; Koh et al. Yonsei Medical Journal 1992 33:137-142; Dalton, W. S. and Sikic, B. I. J. NIH Res. 1994 6:54-58; Cole et al. Science 1992 258:1650-1654; Demolombe, S. and Escande, D. TIPS 1996 17:273-275; Schneider et al. British J. Cancer 1989 60:815-818; Fojo et al. Proc. Natl. Acad. Sci. USA 1987 84:265-269; Roninson, I. B. Biochem. Pharmacol. 1992 43:95-102; Arceci, R. J. Blood 1993 81:2215-2222; and Merkel et al. J. Clin. Oncol. 1989 7:1129-1136) or can be acquired over the course of cancer treatment as in breast and ovarian cancer (Merkel et al. J. Clin. Oncol. 1989 7:1129-1136; Ihnat et al. Clin. Cancer Res. 1997 3:1339-1346; Hamilton, J. W. and Wetterhahn, K. E. Mol. Carcinogens 1989 2:274-286; and McCaffrey et al. Mol. Carcinogens 1994 10:189-198). [0006]MDR1 gene transcription and MDR1 mRNA expression can be induced by certain DNA damaging agents, including chemotherapeutic drugs such doxorubicin, alkylating agents such as methyl methanesulfonate, and genotoxic chemical carcinogens that induce bulky DNA adducts such as aflatoxin B1 and 2-acetylaminofluorene. [0007]MRP1, MRP2, and BCRP are also members of the ABC family of transmembrane proteins involved in the transport of small therapeutic drugs and other molecules across cell membranes. [0008]CFTR, another member of the ABC family of transport proteins is a cAMP-regulated chloride channel that mediates transepithelial chloride transport in the airways, intestine, pancreas, testis and other tissues. Cystic fibrosis, a lethal genetic disease, is caused by mutations in the CFTR gene, the most common of which is AF508. Intestinal CFTR contributes to the massive fluid and electrolyte losses in secretory diarrhea (Al-Awqati, Q. J. Clin. Invest. 2002 110(11):1599-601; Kunzelman et al. Physiol. Rev. 2002 82(1):245-89). [0009]The ability to modulate the expression of these proteins has broad applications in a variety of clinical situations including, but not limited to, prevention of multidrug resistance in cancer, delivery of therapeutics to the central nervous system, inhibition of secretory diarrhea, and treatment of cystic fibrosis. SUMMARY OF THE INVENTION [0010]An object of the present invention is to provide a composition comprising an isolated factor confirmed, using a proteomics approach to be a protein, or an active fragment thereof, derived from the bacterium Pseudomonas aeruginosa that reduces expression of ABC transmembrane proteins in the plasma membrane. [0011]Another object of the present invention is to provide a composition comprising a mimetic of the isolated factor, or an active fragment thereof, derived from the bacterium Pseudomonas aeruginosa that reduces expression of ABC transmembrane proteins in the plasma membrane for use in combination therapies for CNS disorders, infections and diseases and cancers exhibiting multidrug resistance. [0012]Another object of the present invention is to provide a method for modulating plasma membrane expression of an ABC transmembrane protein in a cell comprising administering to the cell of the isolated factor, or active fragment thereof, derived from Pseudomonas aeruginosa or a mimetic thereof that modulates plasma membrane expression of ABC transmembrane proteins. [0013]Another object of the present invention is to provide a method for delivering a small molecule therapeutic agent to the central nervous system of a subject which comprises administering to the subject the isolated factor or active fragment thereof derived from Pseudomonas aeruginosa or a mimetic thereof that reduces expression of ABC transmembrane proteins in the plasma membrane so that expression of ABC transmembrane proteins which prevent small molecules from accumulating in the central nervous system is inhibited in the subject and administering to the subject the small molecule therapeutic agent. [0014]Another object of the present invention is to provide a method for treating cancer in a subject which comprises administering to the subject the isolated factor or active fragment thereof derived from Pseudomonas aeruginosa or a mimetic thereof that reduces plasma membrane expression of ABC transmembrane proteins so that expression of ABC transmembrane proteins which confer drug resistance in cancer cells is inhibited in the subject and administering to the subject an anti-cancer agent. This method of treating cancer is particularly useful in cancers that have become resistant to therapy due to overexpression of ABC transmembrane proteins and/or to cancers of the central nervous system. [0015]Another object of the present invention is to provide a method for treating secretory diarrhea in a subject which comprises administering to the subject the isolated factor or active fragment thereof derived from Pseudomonas aeruginosa or a mimetic thereof that reduces plasma membrane expression of ABC transmembrane proteins, and in particular intestinal CFTR expression, so that massive fluid and electrolyte losses in secretory diarrhea are inhibited. [0016]Another object of the present invention is to provide agents and methods for identifying agents which inhibit or suppress this Pseudomonas aeruginosa and active fragments thereof and their inhibitory effects on expression of ABC transmembrane proteins, particularly CFTR expression. [0017]Another object of the present invention is to provide a method for increasing the bioavailability of drugs by reducing the membrane expression of ABC transporters in the intestine, kidney and liver. [0018]Yet another object of the present invention is to provide compositions and methods for treating or alleviating symptoms of a subject suffering from cystic fibrosis via administration of a composition comprising an agent which inhibits or suppresses this Pseudomonas aeruginosa factor and its inhibitory effects on expression of ABC transmembrane proteins, particularly CFTR expression. DETAILED DESCRIPTION OF THE INVENTION [0019]A factor, confirmed using a proteomics approach to be a protein, which is secreted by clinical isolates of the bacterium Pseudomonas aeruginosa has now been identified that reduces or otherwise modulates the plasma membrane expression of CFTR as well as P-glycoprotein (i.e. Pgp or multidrug resistance protein (MDR)), MRP2, MRP1, BCRP and other members of the ABC transmembrane protein family, whose functions include the transport of small molecules, including but not limited to ions, across cell membranes. More specifically, members of the ABC transporter family function by preventing therapeutics including but not limited to anti-cancer therapeutics and antibiotics from accumulating in the central nervous system, and by conferring the observed "drug resistance" of numerous cancers. [0020]The factor of the present invention that reduces or otherwise modulates the plasma membrane expression of the ABC transmembrane protein family is secreted by P. aeruginosa during the stationary phase. This factor has been found to be heat-labile and its activity is extended in the presence of protease inhibitors. The factor is retained by a membrane with a reported molecular weight cut-off of greater than 30 kDa. The factor of the present invention remains in solution in the presence of 70% ammonium sulfate and it interacts with the anion exchange resin at pH 6.5. Thus, the factor was believed to be a protein. The factor was partially purified with ion exchange chromatography, ammonium sulfate precipitation, and gel filtration. Continue reading about Modulators of the abc transporter family and methods for their use... Full patent description for Modulators of the abc transporter family and methods for their use Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Modulators of the abc transporter family and methods for their use patent application. 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