The p53-independent tumoricidal activity of an adenoviral vector encoding a p27-p16 fusion tumor suppressor gene.
We describe here that DE1-adenovirus vectors (AV) expressing a p27-p16 fusion molecule, termed W9, induce tumor cell apoptosis when overexpressed in a wide range of tumor cell types. However, in primary human cells derived from a variety of normal tissues, AV-W9 induced minimal apoptosis. In tumor cells AV-W9 demonstrated 5- to 50-fold greater tumoricidal activity than either of the parental molecules p16 and p27. In these studies, AV-W9 elicited apoptosis independent of the p53 and Rb status of the tumor cells. In several murine tumor models AV-W9 demonstrated p53-independent antitumor activity. It completely prevented tumor formation in two ex vivo models, whereas the parental molecules resulted in partial protection. Furthermore, AV-W9 induced tumor regression or suppressed tumor growth when introduced intratumorally into preestablished tumors in mice. This effect may be mediated through tumor cell apoptosis or antiangiogenic activity of AV-W9. Thus, this novel chimeric molecule is more potent and capable of killing a broader spectrum of tumors than the parental p16 and p27 molecules independent of the tumor cell p53 and phenotype and represents a powerful new therapeutic agent for cancer gene therapy.
Patel
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SD
Cell Genesys Incorporated, 324 Lakeside Drive, Foster City, California 94404, USA.
Tran
A C
AC
Ge
Y
Y
Moskalenko
M
M
Tsui
L
L
Banik
G
G
Tom
W
W
Scott
M
M
Chen
L
L
Van Roey
M
M
Rivkin
M
M
Mendez
M
M
Gyuris
J
J
McArthur
J G
JG
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D001011:Aorta / Q000378:metabolism; D017209:Apoptosis; D018797:Cell Cycle Proteins; D002460:Cell Line; D002469:Cell Separation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D017304:Annexin A5; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27