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Apoptosis Induction Mediated by Wild-Type p53 Adenoviral Gene Transfer in Squamous Cell Carcinoma of the Head and Neck¹

Departments of Head and Neck Surgery [T-J. L., M. W., D. L. T., G. L. C.] and Pathology [A. K. E., T. J. M., K. D. S.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Cancer gene therapy strategies for inducing apoptosis in solid tumors may allow contemporary medicine to reassess its management of these cancers. We demonstrated previously that overexpression of the wild-type p53 gene in squamous cell carcinoma of the head and neck cell lines via adenovirus-mediated gene transfer suppressed growth both in vitro and in vivo. Here, we characterize the mechanism of the growth suppression by the exogenous p53 gene as a consequence of programmed cell death (apoptosis). One of the cell lines used in this study, Tu-138, harbors a mutated p53 gene, whereas the other cell line, MDA 686LN, possesses a wild-type p53 gene. DNA fragmentation was detected by electrophoresis in both cell lines after infection with the wild-type p53 adenovirus, Ad5CMV-p53. With the use of the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling method, 4.4% of the remaining viable Tu-138 cell population was identified as apoptotic as early as 15 h after inoculation with Ad5CMV-p53. The percentage of apoptotic cells increased to 31% at 22 h. In contrast, only 10% of the viable MDA 686LN cells (wt-p53) had undergone apoptosis 30 h after Ad5CMV-p53 infection, although the percentage of apoptotic cells rapidly increased to 60% at 48 h after infection. For in vivo analysis of apoptosis, nude mice in which squamous cell carcinoma of the head and neck cell lines had been implanted s.c. had exogenous wt-p53 transiently introduced to the tumor cells via Ad5CMV-p53 2 days later. In situ end labeling clearly illustrated apoptosis in the tumor cells. These results suggest that wt-p53 plays an important role in the induction of apoptosis in human head and neck cancer cell lines and that selective induction of apoptosis in cancer cells can be further explored as a strategy for cancer gene therapy.

¹ This work was supported in part by American Cancer Society Career Development Award 93-9 (G. L. C.), M. D. Anderson Cancer Center Core Grant NIH-NCI-CA-16672, and a gift to the Division of Surgery from Tenneco and Exxon for the Core Laboratory Facility.

² To whom requests for reprints should be addressed, at M. D. Anderson Cancer Center, Department of Head and Neck Surgery, Box 69, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 4/ 6/95. Accepted 5/11/95.

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