Scientific Publications by FDA Staff

Int J Cancer 2005 Aug 10;116(1):1-8

Adenoviral vector-mediated gene transfer of IL-13Ralpha2 chain followed by IL-13 cytotoxin treatment offers potent targeted therapy for cytotoxin-resistant cancers.

Saito M, Murata T, Watanabe K, Kawakami K, Suzuki M, Koji T, Puri RK, Kitazato K, Kobayashi N

Kobayashi N, Nagasaki Univ, Grad Sch Biomed Sci, Lab Mol Biol Infect Agents, Dept Mol Microbiol & Immunol, 1-14 Bunkyomachi, Nagasaki 8528521, Japan Nagasaki Univ, Grad Sch Biomed Sci, Lab Mol Biol Infect Agents, Dept Mol Microbiol & Immunol, Nagasaki 8528521, Japan US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Lab Mol Tumor Biol, Bethesda, MD 20014 USA Yokohama City Univ, Sch Med, Dept Internal Med 1, Yokohama, Kanagawa 232, Japan Nagasaki Univ, Grad Sch Biomed Sci, Cell Biol & Histol Lab, Dept Dev & Reconstruct Med, Nagasaki 852, Japan

Previous studies demonstrated that IL-13Ralpha2 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-13Ralpha2 chain. To expand the IL-13 cytotoxin-mediated cancer targeting therapy, we combined cytotoxin treatment with gene transfer of IL-13Ralpha2 chain. We constructed a recombinant adenoviral vector carrying the human IL-13Ralpha2 gene (Ad-IL-13Ralpha2), which expresses high levels of IL-13Ralpha2 chain on infected cells. Human cancer cell lines A549 and HOS, which originally show no IL-13Ralpha2 expression and little sensitivity to IL-13 cytotoxin, were effectively converted to become sensitive to this cytotoxin after Ad-IL-13Ralpha2 infection. The CC(50) of IL-13 cytotoxin for Ad-IL-13Ralpha2-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-13Ralpha2 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-13Ralpha2 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-13Ralpha2 chain.