Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI-p53 complexes.

Abstract

Lung metastases are a frequent complication of osteosarcoma and a treatment that would reduce the severity of this complication would be of great benefit to patients. We have used a formulation consisting of polyethyleneimine (PEI) and a p53 gene administered in aerosol to treat established lung micrometastases as a model of human osteosarcoma in nude mice. The SAOS-LM6 cell line, a metastatic derivative of the p53 null SAOS-2 line, expresses high levels of p53 protein after in vitro transfection with PEI-p53 complexes as determined by ELISA, and transfection with both p53wt and the p53 variant, p53-CD(1-366) in vitro, results in a marked inhibition of SAOS-LM6 cell proliferation. Aerosol delivery of plasmid DNA containing either the p53 gene or a p53-CD(1-366) variant gene formulated with PEI to mice resulted in highly significant reductions in the numbers and size of tumors (P<.001), the total number of tumor foci in the lungs (P<.001) and the size of individual tumor nodules in treated animals compared to untreated, PEI only-treated and PEI-CAT-treated control animals. The different tissues examined did not reveal any signs of toxicity or inflammation after repeated exposure to PEI-DNA. The aerosol delivery of PEI-based formulations of p53 or synthetic p53 variant genes represents a promising new strategy for the treatment of established human osteosarcoma lung metastases. The noninvasive nature of aerosol delivery coupled with low toxicity also make this therapeutic approach potentially appropriate for combination therapy with either radio- or chemotherapy.