Cytokine gene transfer using (multiple) intratumoral
injections can induce
tumor regression in several animal models, but this administration technique limits the use for human gene therapy. In the present studies we describe
tumor growth inhibition of established limb
sarcomas after a single isolated limb perfusion (ILP) with recombinant adenoviral vectors harboring the rat
IL-3 beta gene (IG.Ad.CMV.rIL-3 beta). In contrast, a single intratumoral injection or
intravenous administration did not affect
tumor growth. Dose-finding studies demonstrated a dose-dependent response with a loss of antitumor effect below 1 x 10(9) IU of IG.Ad.CMV.rIL-3 beta. Perfusions with adenoviral vectors bearing a weaker promoter (MLP promoter) driving the rIL-3 beta gene did not result in antitumor responses, suggesting that the rIL-3 beta-mediated antitumor effect depends on the amount of rIL-3 beta
protein expressed by the infected cells. Furthermore, it was shown by direct comparison that ILP with IG.Ad.CMV.rIL-3 beta in the ROS-1
osteosarcoma model is at least as efficient as the established
therapy with the combination of
TNF-alpha and
melphalan. Treatment with IG.Ad.CMV.rIL-3 beta induced a transient dose-dependent
leukocytosis accompanied by an increase in peripheral blood levels of
histamine. Leukocyte infiltrations were also histopathologically demonstrated in
tumors after perfusion. These results demonstrate that ILP with recombinant adenoviral vectors carrying the
IL-3 beta transgene inhibits
tumor growth in rats and suggest that
cytokine gene therapy using this administration technique might be beneficial for clinical
cancer treatment.