Administration of plasmid/lipid complexes to the lung airways for the treat
ment of metastatic pulmonary diseases represents a new strategy of gene the
rapy. In this study we present evidence that intratracheal administration o
f a plasmid encoding murine IL-12 complexed with N-(1-(2,3-dioleyloxy)propy
l)-N,N,N-trimethylammonium chloride:cholesterol inhibits the growth of lung
metastases, using a renal cell carcinoma model, Instillation of pIL-12/lip
id complexes resulted in expression of biologically active IL-12 (170-240 p
g/ml) and IFN-gamma (100-190 pg/ml) in the bronchoalveolar lavage fluid. A
significantly reduced number of lung metastases (26 +/- 24) was observed in
mice instilled with IL-12/lipid complexes 24 hr after tumor challenge, whe
reas more than 250 metastatic foci were counted in lungs of untreated mice.
Moreover, IL-12/lipid inhibited the growth of 3-day-old established metast
ases when compared with empty plasmid/lipid or IL-12 plasmid in saline. Mic
e receiving IL-12 gene therapy survived significantly longer (median surviv
al of 43 days) than untreated mice (median survival of 31 days) or mice tre
ated with control plasmid/lipid complexes (median survival of 35 days), The
se data demonstrate that a nonviral IL-12 gene therapy employing synthetic
cationic lipids as a delivery system can be used to inhibit the development
of lung metastases, Thus, this method provides support for the use of IL-1
2/lipid complexes to control the growth of pulmonary metastases and represe
nts a potentially safer alternative to IL-12 protein immunotherapy.