Tumor-specific promoter

Abstract

A DNA comprising a 609 bp base sequence from −559 to +50 when the first base sequence of exon 1 of the midkine gene, a human retinoic acid-responsive growth/differentiation factor was set as +1, or a DNA comprising a 251 bp base sequence from −213 to +38 when the transcription initiation point of the c-erbB-2 gene belonging to the EGF receptor family and having a tyrosine kinase activity was set as +1 has a tumor-specific transcription activity, and the promoter activity thereof is high, and therefore is very important as a tumor-specific promoter for use in the suicide gene therapy that combines the use of a gene for a drug metabolizing enzyme and a prodrug for cancer therapy, the gene therapy of cancer using an expression vector that contains a gene encoding a cytokine, and the gene therapy of cancer using an oncolytic virus.

1 . A tumor-specific promoter that has a base sequence from any base starting from at positions 1-127 to a base at position 251 in the base sequence set forth in SEQ ID NO: 9.  
     
     
         2 . A tumor-specific promoter that hybridizes to a base sequence from any base at positions 1-127 to a base at position 251 in the base sequence set forth in SEQ ID NO: 9 under a stringent condition.  
     
     
         3 . (canceled)  
     
     
         4 . The tumor-specific promoter according to  claim 1  or  2 , wherein said tumor is breast cancer, ovarian cancer, gastric cancer or esophageal cancer.  
     
     
         5 . A tumor-specific promoter comprising SEQ ID NO:  9 .  
     
     
         6 . A vector comprising the tumor-specific promoter according to any of claims  1 ,  2  or  5 .  
     
     
         7 . The vector according to  claim 6 , wherein a gene encoding a drug metabolizing enzyme was ligated downstream of said tumor-specific promoter and wherein said enzyme converts a prodrug to an active form.  
     
     
         8 . The vector according to  claim 7  wherein said gene encoding a drug metabolizing enzyme and said prodrug are selected from the group consisting of the thymidine kinase gene of herpes simplex virus and gancyclovir or acyclovir, the cytosine deaminase gene and 5-fluorocytosine, the thymidine kinase gene of varicella-zoster virus and 6-methoxypurine arabinoside, the  E. coli  gpt gene and 6-thioxanthine, the cytochrome P450 2B1 gene and cyclophosphamide, the human deoxycytidine kinase gene and cytosine arabinoside, the  E. coli  UPRT gene and 5-fluorouracil, and the  E. coli  deoD gene and 6-methylpurine-2′-deoxyribonucleoside.  
     
     
         9 . An oncolytic virus vector comprising the tumor-specific promoter according to any of claims  1 ,  2  or  5  wherein a virus gene necessary for the propagation of the virus is operably linked to said tumor-specific promoter so that the virus propagates specifically in tumor cells or tumor tissues.  
     
     
         10 . A method of treating a tumor in a subject, comprising administering a vector to said subject, wherein said vector comprises the tumor-specific promoter according to any one of claims  1 ,  2  or  5 , said promoter is operably linked to a nucleotide sequence coding for a drug metabolizing enzyme, and additionally administering a prodrug to said subject, wherein said enzyme converts said prodrug to an active form in said subject.  
     
     
         11 . The method according to  claim 10 , wherein said nucleotide sequence coding for said enzyme and said prodrug are selected from the group consisting of the thymidine kinase gene of herpes simplex virus and gancyclovir or acyclovir, the cytosine deaminase gene and 5-fluorocytosine, the thymidine kinase gene of varicella-zoster virus and 6-methoxypurine arabinoside, the  E. coli  gpt gene and 6-thioxanthine, the cytochrome P450 2B1 gene and cyclophosphamide, the human deoxycytidine kinase gene and cytosine arabinoside, the  E. coli  UPRT gene and 5-fluorouracil, and the  E. coli  deoD gene and 6-methylpurine-2′-deoxyribonucleoside.  
     
     
         12 . The method according to  claim 10 , wherein said tumor is selected from the group consisting of breast tumor, ovarian tumor, gastric tumor or esophageal tumor.  
     
     
         13 . A method of treating in a subject, comprising administering an oncolytic virus to said subject, wherein said virus comprises the tumor-specific promoter according to any one of claims  1 ,  2  or  5 , and a gene of said oncolytic virus necessary for viral propagation is operably linked to said promoter so that said virus propagates specifically in said tumor.  
     
     
         14 . The method according to  claim 13 , wherein said tumor is selected from the group consisting of breast tumor, ovarian tumor, gastric tumor or esophageal tumor.