THERAPEUTIC EFFECT OF A RETROVIRAL WILD-TYPE P53 EXPRESSION VECTOR INAN ORTHOTOPIC LUNG-CANCER MODEL

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 d ominant over the mutant; thus, restoration of wild-type p53 function i n lung cancer cells may suppress their growth as tumors. Purpose: We i nvestigated the therapeutic efficacy of direct administration of a ret roviral wild-type p53 (wt-p53) expression vector (LNp53B) in an orthot opic human lung cancer model in nu/nu mice. Methods: Proliferation of H226Br cells was determined by cell counting after infection with LNp5 3B in vitro. Irradiated (350 cGy) female BALB/c nu/nu mice were inocul ated 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 fo r 3 days. Results: Infection with LNp53B inhibited proliferation of H2 26Br 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 supernata nt with inactive vector. Conclusions: Direct administration of a retro viral vector expressing wt-p53 may inhibit local growth in vivo of hum an lung cancer cells with abnormal p53 expression. Implications: Devel opment of gene-replacement treatment strategies based on the type of m utations found in target cancers is warranted and may lead to the deve lopment of new adjunctive therapies and gene-specific prevention strat egies for lung cancer.