Interferon alpha and antisense k-ras rna combination gene therapy

Abstract

An antiproliferative effect of IFN-α gene transduction in pancreatic cancer cells. The invention relates to expression of IFN-α to effectively induce growth suppression and cell death in pancreatic cancer cells, an effect which appeared to be more prominent when compared with other types of cancers and normal cells. Another aspect of the invention relates to targeting the characteristic genetic aberration, K-ras point mutation, in pancreatic cancer, and that the expression of antisense K-ras RNA significantly suppresses the growth of pancreatic cancer cells. When these two gene therapy strategies are combined, the expression of antisense K-ras RNA significantly enhanced IFN-α-induced cell death (1.3-3.5 fold), and suppressed subcutaneous growth of pancreatic cancer cells in mice. The invention also relates to a method of suppressing pancreatic cancer cells using double strand RNA formed by antisense and endogeneous K-ras RNA in combination with the anti-tumor activity of IFN-α. The invention relates to the combination of IFN-α and antisense K-ras RNA as an effective gene therapy strategy against pancreatic cancer. The invention also relates to a method of treating pancreatic cancer cells disseminated throughout the body by administering the inventive combination to localized pancreatic cancer cell tumor. The invention also relates to inducing indirect immunological antitumor activity to provide systemic immunity against pancreatic cancer cells.

1 . A composition comprising interferon-alpha expressing vector and antisense K-ras expressing vector. 
   
   
       2 . A method of inducing systemic antitumor immunity in a human having cells having a K-ras gene point mutation, comprising:
 administering to pancreatic cancer cells via intratumoral administration a therapeutically effective amount of adenoviral vector comprising a DNA sequence encoding human IFN-α operably linked to a promoter;   wherein the pancreatic cancer cells to which the adenoviral vector is administered express the human IFN-α;   whereby expression of the human IFN-A induces systemic antitumor immunity in the human.   
   
   
       3 . The method of  claim 2 , wherein the promoter of the adenoviral vector is a beta-actin promoter fused to a cytomegalovirus enhancer element. 
   
   
       4 . The method of  claim 2 , wherein the adenoviral vector is administered in a dose ranging from about 5×10 8  to 25×10 8  pfu (plaque forming unit)/day/tumor weight (g). 
   
   
       5 . The method of  claim 2 , comprising activating direct tumor cytotoxicity, indirect immunological antitumor activity, or a combination thereof, by expression of the human IFN-α. 
   
   
       6 . The method of  claim 5 , wherein the indirect immunological antitumor activity comprises activation of natural killer cells. 
   
   
       7 . The method of  claim 5 , wherein the indirect immunological antitumor activity provides systemic immunity against pancreatic cancer. 
   
   
       8 . The method of  claim 2 , wherein metastasis of mammalian pancreatic cancer cells having a K-ras gene point mutation is suppressed.