CHROMOSOME 3p21.3 GENES ARE TUMOR SUPPRESSORS

Abstract

Tumor suppressor genes play a major role in the pathogenesis of human lung cancer and other cancers. Cytogenetic and allelotyping studies of fresh tumor and tumor-derived cell lines showed that cytogenetic changes and allele loss on the short arm of chromosome 3 (3p) are most frequently involved in about 90% of small cell lung cancers and greater than 50% of non-small cell lung cancers. A group of recessive oncogenes, Fus1, 101F6, Gene 21 (NPRL2), Gene 26 (CACNA2D2), Luca 1 (HYAL1), Luca 2 (HYAL2), PL6, 123F2 (RaSSFI), SEM A3 and Beta* (BLU), as defined by homozygous deletions in lung cancers, have been located and isolated at 3p21.3.

1 .- 62 . (canceled) 
     
     
         63 . A method for suppressing growth of a tumor cell comprising contacting said cell with an expression cassette comprising:
 (a) an isolated polynucleotide encoding a human Gene 21 (NPRL2) polypeptide; and   (b) a heterologous promoter active in said tumor cell,   under conditions permitting the uptake of said polynucleotide by said tumor cell.   
     
     
         64 . The method of  claim 63 , wherein said tumor cell is derived from a tumor selected from the group consisting of brain tumor, lung tumor, liver tumor, spleen tumor, kidney tumor, lymph node tumor, small intestine tumor, blood cell tumor, pancreatic tumor, colon tumor, stomach tumor, cervix tumor, breast tumor, endometrial tumor, prostate tumor, testicle tumor, ovarian tumor, skin tumor, head and neck tumor, esophageal tumor, oral tissue tumor, and bone marrow tumor. 
     
     
         65 . The method of  claim 63 , wherein said polynucleotide is contained in a viral vector. 
     
     
         66 . The method of  claim 65 , wherein said viral vector is a retroviral vector, an adenoviral vector, an adeno-associated viral vector, a vaccinia viral vector, or a herpesviral vector. 
     
     
         67 . The method of  claim 66 , wherein said viral vector is an adenoviral vector. 
     
     
         68 . The method of  claim 63 , wherein said polynucleotide is contained in a liposome. 
     
     
         69 . A method of altering the phenotype of a tumor cell comprising contacting said cell with an expression cassette comprising:
 (a) an isolated polynucleotide encoding a human Gene 21 (NPRL2) polypeptide; and   (b) a heterologous promoter active in said tumor cell,   under conditions permitting the uptake of said polynucleotide acid by said tumor cell.   
     
     
         70 . The method of  claim 69 , wherein the phenotype is selected from the group consisting of proliferation, migration, contact inhibition, soft agar growth, cell cycling, invasiveness, tumorigenesis, and metastatic potential. 
     
     
         71 . The method of  claim 69 , wherein said promoter is a cytomegalovirus (CMV) promoter. 
     
     
         72 . A method of treating or inhibiting a cancer in a subject suffering therefrom comprising administering to said subject an expression cassette comprising:
 (a) an isolated polynucleotide encoding a human Gene 21 (NPRL2) polypeptide; and   (b) a heterologous promoter active in tumor cells of said subject,   whereby expression of said Gene 21 (NPRL2) polypeptide inhibits said cancer.   
     
     
         73 . The method of  claim 72 , wherein said subject is a human. 
     
     
         74 .- 83 . (canceled) 
     
     
         84 . The method of  claim 72 , wherein said cancer is selected from the group consisting of brain cancer, lung cancer, liver cancer, spleen cancer, kidney cancer, lymph node cancer, small intestine cancer, blood cell cancer, pancreatic cancer, colon cancer, stomach cancer, cervix cancer, breast cancer, endometrial cancer, prostate cancer, testicle cancer, ovarian cancer, skin cancer, head and neck cancer, esophageal cancer, oral tissue cancer, and bone marrow cancer. 
     
     
         85 . The method of  claim 72 , wherein said expression cassette is contained in a viral vector. 
     
     
         86 . The method of  claim 85 , wherein said viral vector is a retroviral vector, an adenoviral vector, an adeno-associated viral vector, a vaccinia viral vector, or a herpesviral vector. 
     
     
         87 . The method of  claim 86 , wherein said viral vector is an adenoviral vector. 
     
     
         88 . The method of  claim 72 , wherein said expression cassette is contained in a liposome. 
     
     
         89 . The method of  claim 72 , wherein said expression cassette further comprises a poly-A sequence. 
     
     
         90 . The method of  claim 89 , wherein said poly-A sequence is bovine growth hormone (BGH) poly-A sequence. 
     
     
         91 . The method of  claim 72 , wherein said expression cassette is administered intratumorally, in the tumor vasculature, local to the tumor, regional to the tumor, or systemically. 
     
     
         92 . The method of  claim 72 , further comprising administering a chemotherapuetic agent to said subject. 
     
     
         93 . The method of  claim 92 , wherein said chemotherapeutic comprises cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate. 
     
     
         94 . The method of  claim 72 , further comprising administering radiation to said subject. 
     
     
         95 . The method of  claim 94 , wherein said radiation is delivered local to a cancer site. 
     
     
         96 . The method of  claim 94 , wherein said radiation is whole body radiation. 
     
     
         97 . The method of  claim 94 , wherein said radiation comprises γ-rays, X-rays, accelerated protons, microwave radiation, UV radiation or the directed delivery of radioisotopes to tumor cells. 
     
     
         98 . The method of  claim 72 , further comprising administering a second anticancer gene to said subject. 
     
     
         99 . The method of  claim 98 , wherein said second anticancer gene is a tumor suppressor. 
     
     
         100 . The method of  claim 98 , wherein said second anticancer gene is an inhibitor of apoptosis. 
     
     
         101 . The method of  claim 98 , wherein said second anticancer gene is an oncogene antisense construct. 
     
     
         102 .- 117 . (canceled) 
     
     
         118 . The method of  claim 72 , wherein said heterologous promoter is a cytomegalovirus (CMV) promoter. 
     
     
         119 . The method of  claim 72 , wherein said tumor cells lack expression of a functional Gene 21 (NPRL2) polypeptide. 
     
     
         120 . The method of  claim 72 , wherein said tumor cells comprise hypermethylation of Gene 21 (NPRL2) gene promoter. 
     
     
         121 . The method of  claim 63 , wherein said expression cassette is contained in a lipid preparation. 
     
     
         122 . The method of  claim 69 , wherein said expression cassette is contained in a lipid preparation. 
     
     
         123 . The method of  claim 72 , wherein said expression cassette is contained in a lipid preparation. 
     
     
         124 . The method of  claim 121 , wherein said liposome is comprised of N-(1-[2,3-Dioleoyloxy]propyl)-N,N,N-trimethylammonium (DOTAP) and cholesterol. 
     
     
         125 . The method of  claim 122 , wherein said liposome is comprised of N-(1-[2,3-Dioleoyloxy]propyl)-N,N,N-trimethylammonium (DOTAP) and cholesterol. 
     
     
         126 . The method of  claim 123 , wherein said liposome is comprised of N-(1-[2,3-Dioleoyloxy]propyl)-N,N,N-trimethylammonium (DOTAP) and cholesterol.