Cell Cycle Arrest and Inhibition of Tumor Cell Proliferation by the pl6WK4 Gene Mediated by an Adenovirus Vector1

The p/<5INK4(MTS1 ) gene has many features of a tumor suppressor gene. It maps to 9p21, a region of frequent loss of heterozygosity in a variety of tumor types. It encodes an inhibitor of cyclin-dependent kinase 4, and its homozygous deletion is common in tumor-derived cell lines. To examine its tumor suppressive function and its potential in cancer gene replacement therapy, wild-type p76INK4 was expressed in an adenovirusderived gene delivery system and introduced into lung cancer cell lines that do not express p7tì'NK4. Expression of the introduced pl6tNK4 blocked tumor cell entry into S phase of the cell cycle and inhibited tumor proliferation both in vitro and in vivo. These observations strongly support that p/6'INK4 is a tumor suppressor gene and is a candidate for cancer gene replacement therapy.