Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

Abstract

Previous studies demonstrated that IL-13Ra2 chain-overexpressing cancer cells were highly sensitive to IL-13 cytotoxin (IL13-PE38QQR) and could be targeted by cytotoxin treatment. However, the majority of human tumors do not express high levels of IL-13Ra2 chain. To expand the IL-13 cytotoxin-mediated cancer targeting therapy, we combined cytotoxin treatment with gene transfer of IL-13Ra2 chain. We constructed a recombinant adenoviral vector carrying the human IL-13Ra2 gene (Ad-IL-13Ra2), which expresses high levels of IL-13Ra2 chain on infected cells. Human cancer cell lines A549 and HOS, which originally show no IL-13Ra2 expression and little sensitivity to IL-13 cytotoxin, were effectively converted to become sensitive to this cytotoxin after Ad-IL-13Ra2 infection. The CC 50 of IL-13 cytotoxin for Ad-IL13Ra2-infected A549 cells was <10 ng/ml, whereas the CC 50 for uninfected or control vector-infected cells was >500 ng/ml. We also examined the antitumor activity of IL-13 cytotoxin in an established xenograft model of cytotoxin-resistant human lung tumor. Only a single i.t. injection of Ad-IL-13Ra2 markedly enhanced the sensitivity of established tumors to IL-13 cytotoxin treatment; furthermore, this antitumor effect was significantly sustained for more than 1 month after the last treatment with IL-13 cytotoxin. Taken together, these results suggest the combination of adenoviral vector-mediated IL-13Ra2 gene transfer and IL-13 cytotoxin administration can be an effective targeting approach for several types of IL-13 cytotoxin-resistant cancers which show no or little expression of IL-13Ra2 chain. ' 2005 Wiley-Liss, Inc.

Specific Targeting of Human Interleukin (IL)-13 Receptor α2-Positive Cells with Lentiviral Vectors Displaying IL-13

“…Consistent with results reported previously (Saito et al, 2005), unmodified HOS cells and HOS-IL-13Ra2 cells in the absence of Dox did not reveal any IL-13Ra2-positive cells above background by FACS (Fig. 2A); however, in the presence of Dox, a substantial fraction of the cells were positive after staining with an anti-IL-13Ra2 antibody.…”

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

“…Interestingly, despite the marked refractoriness of naive A549 cells to IL-13-PE, the chimeric toxin clearly exacerbated the cytotoxic effect of silica particles on A549 cells, as shown by the MTT assay, suggesting that the cytotoxic activity exerted by IL-13-PE was probably apparent only after silica-induced cell activation and subsequent IL-13R expression. Notably, the A549 cell line, which constitutively shows no IL-13Ra2 chain expression and little sensitivity to IL-13-PE, became sensitive to the immunotoxin following IL-13Ra2 transfection (44). However, because the MTT assay is based on the measurement of mitochondrial enzyme activity, one cannot rule out the possibility that IL-13-PE reduces metabolic activity without affecting cell viability.…”

Mechanical Stretch and Angiotensin II Increase Interleukin-13 Production and Interleukin-13 Receptor .ALPHA.2 Expression in Rat Neonatal Cardiomyocytes

“…33,34 Among various cytokines, we focused on IL-13 in the present study because IL-13 is well known to promote fibrosis and apoptosis, and IL-13-IL-13R 2 reflects disease severity when the disease becomes chronic. 16,[18][19][20] Prevention of IL-13R 2 expression by gene interference, adenoviral vector or anti-IL-13R 2 antibody suppresses IL-13 toxicity; therefore, it is considered as a therapeutic target for fibrosis and cancer. 13,15,19,20 Cardiac fibrosis progresses during mechanical overload and angiotensin II stimuli, and plays a pivotal pathophysiological role in chronic heart failure by promoting left ventricular dysfunction.…”

“…16,[18][19][20] Prevention of IL-13R 2 expression by gene interference, adenoviral vector or anti-IL-13R 2 antibody suppresses IL-13 toxicity; therefore, it is considered as a therapeutic target for fibrosis and cancer. 13,15,19,20 Cardiac fibrosis progresses during mechanical overload and angiotensin II stimuli, and plays a pivotal pathophysiological role in chronic heart failure by promoting left ventricular dysfunction. However, the correlation between IL-13 and cardiac fibrosis is unclear.…”