Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model

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 × 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)