Construction and analysis of new vector systems with improved interleukin-18 secretion in a xenogeneic human tumor model.
Interleukin (IL)-18 plays an important role in enhancing cellular immunity against cancer and bacteria. We constructed retroviral and adenoviral vectors that show improved secretion of bioactive murine IL-18 that could further enhance antitumor immunity in a murine model. Secretion of bioactive IL-18 was facilitated by fusing the leader sequences of prepro-parathyroid hormone (PTH) or IL-1 receptor antagonist (IL-1ra) to the 5; end of the mature murine IL-18 cDNA. Transfectants established by the retroviral vector carrying IL-1ra/IL-18 hybrid showed about 100-fold more IL-18 production and interferon (IFN)-gamma induction from splenocytes when compared with those carrying PTH/IL-18 hybrid. Repeated intraperitoneal injection of an adenoviral vector with IL-1ra/IL-18 hybrid ligated to IL-18 (Ad.IL-1ra.IL-18) successfully prevented establishment of human colon cancer cells in the abdominal cavity of mice. Treatment with Ad.IL-1ra.IL-18 was associated with significantly elevated levels of serum IL-18 and IFN- gamma. IL-18 administration also enhanced the cytostatic activity of peritoneal exudate cells against cancer cells. These improved viral vectors, which efficiently produce bioactive IL-18, could be used as a useful tool for cancer gene therapy.
Goto
Hiroyuku
H
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Osaki
Tadashi
T
Nishino
Kazumi
K
Tachibana
Isao
I
Takeda
Yoshito
Y
Yoneda
Tsutomu
T
Funakoshi
Toshiki
T
Kimura
Hiromi
H
Hayashi
Seiji
S
Tahara
Hideaki
H
D000256:Adenoviridae; D000818:Animals; D003110:Colonic Neoplasms / Q000628:therapy*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects*; D020382:Interleukin-18 / Q000378:metabolism / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D009368:Neoplasm Transplantation; D012680:Sensitivity and Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured
D020382:Interleukin-18; D007371:Interferon-gamma