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Cell Cycle Arrest and Inhibition of Tumor Cell Proliferation by the p16^INK4 Gene Mediated by an Adenovirus Vector¹

Section of Thoracic Molecular Oncology, Departments of Thoracic and Cardiovascular Surgery [X. J., D. N., W-W. Z., J. A. R.], Neuro-Oncology [A. P. K.], and Tumor Biology [J. A. R.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The p16^INK4 (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 p16^INK4 was expressed in an adenovirus-derived gene delivery system and introduced into lung cancer cell lines that do not express p16^INK4. Expression of the introduced p16^INK4 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 p16^INK4 is a tumor suppressor gene and is a candidate for cancer gene replacement therapy.

¹ This work was partially supported by National Cancer Institute and NIH (RO1 CA45187) Grants (J. A. R.); by gifts to the Division of Surgery from Tenneco and Exxon for the Core Laboratory Facility; by the M. D. Anderson Cancer Center Support Core Grant (CA16672); by a grant from the Mathers Foundation; and by a sponsored research agreement with Introgen Therapeutics, Houston, TX.

² Present address: Gene Therapy Unit, Baxter Healthcare Corporation, Baxter Technology Park, Route 120 and Wilson Road, Round Lake, IL 60073-0490.

³ To whom requests for reprints should be addressed, at M. D. Anderson Cancer Center, Department of Thoracic and Cardiovascular Surgery, Box 109, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 5/15/95. Accepted 6/16/95.

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