Method for reversing multiple resistance in animal cells

Abstract

The present invention is related to the use of a virus, preferably an adenovirus for reversing resistance in cells.

1 - 201 . (canceled) 
     
     
         202 . A method for restoring drug sensitivity in a subject having a tumor comprising drug resistant cells, wherein the drug resistance is induced by YB-1, the method comprising:
 administering an effective amount of an adenovirus to the subject, wherein the adenovirus replicates in the subject in a YB-1 dependent manner to restore drug sensitivity and wherein the adenovirus comprises an E1A protein lacking a functional CR3 region; and   further administering to said subject a pharmaceutically active agent and/or radiation, wherein the pharmaceutically active agent is a drug to which the drug resistant cells are resistant prior to restoration of drug sensitivity.   
     
     
         203 . The method of  claim 202 , wherein the E1A protein is incapable of transactivating adenovirus genes E1B, E2, E3, E4 or a combination thereof. 
     
     
         204 . The method of  claim 202 , wherein the adenovirus comprises an E1A protein lacking a CR3 region. 
     
     
         205 . The method of  claim 202 , wherein the adenovirus comprises a modification rendering the adenovirus E1B19k-minus. 
     
     
         206 . The method of  claim 202 , wherein the adenovirus is intratumorally administered. 
     
     
         207 . The method of  claim 202 , wherein the drug resistance is mediated by an ABC transporter, which expression is induced by YB-1. 
     
     
         208 . The method of  claim 207 , wherein the ABC transporter is selected from the group comprising MRP and MDR, in particular MDR-1. 
     
     
         209 . The method of  claim 202 , wherein the adenovirus is administered 1 to 3 days prior to the administration of the pharmaceutically active agent and/or the radiation. 
     
     
         210 . The method of  claim 209 , wherein the adenovirus is administered about 1 to 2 days prior to the administration of the pharmaceutically active agent and/or the radiation. 
     
     
         211 . The method of  claim 202 , wherein the pharmaceutically active agent is a cytostatic. 
     
     
         212 . The method of  claim 202 , wherein the adenovirus further comprises a nucleic acid coding for a transgene. 
     
     
         213 . The method of  claim 212 , wherein the transgene is selected from the group comprising a gene coding for a prodrug, a cytokine, an apoptosis-inducing protein, a tumor suppressor gene, a metalloproteinase inhibitor and an angiogenesis inhibitor. 
     
     
         214 . The method of  claim 212 , wherein the transgene is a sequence that targets a target molecule and is selected from the group comprising an siRNA, an aptamer, an antisense molecule, and a ribozyme. 
     
     
         215 . The method of  claim 202 , wherein the pharmaceutically active agent is selected from the group comprising a cytokine, a metalloproteinase inhibitor, an angiogenesis inhibitor, a cytostatic, a cell cycle inhibitor, a proteosome inhibitor, a recombinant antibody, an inhibitor of the signal transduction pathway and an inhibitor of a protein kinase. 
     
     
         216 . The method of  claim 202 , wherein the adenovirus comprises an additional modification rendering the adenovirus protein IX-minus.