A novel antiangiogenic effect for telomerase-specific virotherapy through host immune system.
Soluble factors in the tumor microenvironment may influence the process of angiogenesis; a process essential for the growth and progression of malignant tumors. In this study, we describe a novel antiangiogenic effect of conditional replication-selective adenovirus through the stimulation of host immune reaction. An attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1 genes, could replicate in and cause selective lysis of cancer cells. Mixed lymphocyte-tumor cell culture demonstrated that OBP-301-infected cancer cells stimulated PBMC to produce IFN-gamma into the supernatants. When the supernatants were subjected to the assay of in vitro angiogenesis, the tube formation of HUVECs was inhibited more efficiently than recombinant IFN-gamma. Moreover, in vivo angiogenic assay using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice showed that tumor cell-induced neovascularization was markedly reduced when the chambers contained the mixed lymphocyte-tumor cell culture supernatants. The growth of s.c. murine colon tumors in syngenic mice was significantly inhibited due to the reduced vascularity by intratumoral injection of OBP-301. The antitumor as well as antiangiogenic effects, however, were less apparent in SCID mice due to the lack of host immune responses. Our data suggest that OBP-301 seems to have antiangiogenic properties through the stimulation of host immune cells to produce endogenous antiangiogenic factors such as IFN-gamma.
Ikeda
Yoshihiro
Y
Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Kojima
Toru
T
Kuroda
Shinji
S
Endo
Yoshikatsu
Y
Sakai
Ryo
R
Hioki
Masayoshi
M
Kishimoto
Hiroyuki
H
Uno
Futoshi
F
Kagawa
Shunsuke
S
Watanabe
Yuichi
Y
Hashimoto
Yuuri
Y
Urata
Yasuo
Y
Tanaka
Noriaki
N
Fujiwara
Toshiyoshi
T
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy / Q000821:virology; D000256:Adenoviridae / Q000201:enzymology* / Q000276:immunology; D000257:Adenoviridae Infections / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology; D005260:Female; D005822:Genetic Vectors / Q000276:immunology; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D019098:Telomerase / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D019098:Telomerase