© 1994 by Oxford University Press
Journal of the National Cancer Institute, Vol. 86, No. 19, 1458-1462,
October 5, 1994
© 1994 Oxford University Press
Therapeutic Effect of a Retroviral Wild-Type p53 Expression Vector in an Orthotopic Lung Cancer Model
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center Houston
Departments of Tumor Biology and Surgical Oncology, The University of Texas M. D. Anderson Cancer Center Houston
Section of Thoracic Molecular Oncology. Department of Thoracic and Cardiovascular Surgery; and Department of Tumor Biology, The University of Texas M. D. Anderson Cancer Center
Correspondence to: Jack A. Roth, M.D. Department of Thoracic and Cardiovascular Surgery, Box 109. The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd. Houston, TX 77030.
BACKGROUND:: Mutations in the p53 tumour suppressor gene (also known as TP53) are common in human lung cancers. The wild-type form of p53 is dominant over the mutant; thus, restoration of wild-type p53 function in lung cancer cells may suppress their growth as tumours. Purpose: We investigated the therapeutic efficacy of direct administration of a retroviral wild-type p53 (wt-p53) expression vector (LNp53B) in an orthotopic human lung cancer model in nu/nu mice. Methods: Proliferation of H226Br cells was determined by cell counting after infection with LNp53B in vitro. Irradiated (350 CGy) female BALB/C nu/nu mice were inoculated in-tratracheally with 2 x 106 H226Br cells (whose p53 gene has a homozygous mutation at codon 254) and treated beginning 3 days later with an in-tratracheal instillation of LNp53B retroviral supernatant for 3 days. Results: Infection with LNp53B inhibited proliferation of H226Br cells in vitro. Thirty days after tumor cell inoculation, 62%–80% of the control mice showed macroscopic tumors of the right main stem bronchus. LNp53B suppressed H226Br tumor formation in 62%–100% of mice, and the effect was abrogated by dilution of the retroviral supernatant with inactive vector. Conclusions: Direct administration of a retroviral vector expressing wt-p53 may inhibit local growth in vivo of human lung cancer cells with abnormal p53 expression. Implications: Development of gene-replacement treatment strategies based on the type of mutations found in target cancers is warranted and may lead to the development of new adjunctive therapies and gene-specific prevention strategies for lung cancer. (J Natl Cancer Inst 86: 1458–1462, 1994)
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