Adenoviral vector-mediated gene transfer of IL-13Ralpha2 chain followed by IL-13 cytotoxin treatment offers potent targeted therapy for cytotoxin-resistant cancers.
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.
Saito
Makoto
M
Laboratory of Molecular Biology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Murata
Takashi
T
Watanabe
Ken
K
Kawakami
Koji
K
Suzuki
Motoyoshi
M
Koji
Takehiko
T
Puri
Raj K
RK
Kitazato
Kaio
K
Kobayashi
Nobuyuki
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003603:Cytotoxins / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D018793:Interleukin-13 / Q000627:therapeutic use*; D053661:Interleukin-13 Receptor alpha1 Subunit; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000628:therapy*; D018123:Receptors, Interleukin / Q000235:genetics*; D053660:Receptors, Interleukin-13; D014407:Tumor Cells, Cultured
D003603:Cytotoxins; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13