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Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model
T Fujiwara1, D W Cai, R N Georges
1Department of Thoracic and Cardiovascular Surgery, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Background:
Mutations in the p53 tumor 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 tumors.
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 intratracheally with 2 x 10(6) H226Br cells (whose p53 gene has a homozygous mutation at codon 254) and treated beginning 3 days later with an intratracheal 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.
Insights
Restoring wild-type p53 function using a retroviral vector inhibited lung cancer cell growth in mice. This gene therapy approach shows promise for treating human lung cancers with p53 mutations.
Area of Science:
- Oncology
- Gene Therapy
- Cancer Biology
Background:
- Mutations in the p53 tumor suppressor gene (TP53) are prevalent in human lung cancers.
- Wild-type p53 is dominant over mutant forms, suggesting its restoration could suppress tumor growth.
Purpose of the Study:
- To evaluate the therapeutic efficacy of direct administration of a retroviral wild-type p53 (wt-p53) expression vector (LNp53B).
- To assess this therapy in an orthotopic human lung cancer model using immunodeficient mice.
Main Methods:
- H226Br lung cancer cells with a mutated p53 gene were used.
- These cells were inoculated into nu/nu mice, and treated intratracheally with the LNp53B retroviral vector.
- In vitro proliferation of infected cells was assessed via cell counting.
Main Results:
- Infection with LNp53B significantly inhibited H226Br cell proliferation in vitro.
- Direct administration of LNp53B suppressed tumor formation in 62%-100% of treated mice.
- The tumor suppressive effect was dependent on the retroviral vector concentration.
Conclusions:
- Direct delivery of a retroviral vector expressing wt-p53 can inhibit local in vivo growth of human lung cancer cells with abnormal p53.
- Gene-replacement strategies tailored to specific cancer mutations are warranted for developing novel adjunctive therapies and prevention strategies for lung cancer.