The antiangiogenesis effect of interleukin 12 during early growth of human pancreatic cancer in SCID mice.
Interleukin 12 (IL-12) is a heterodimeric cytokine that exerts a potent antitumor effect through its pleiotropic actions. It was recently reported that IL-12 has also a potent antiangiogenic effect through the induction of IFN-gamma, which triggers the production of chemokines such as IP-10 that has been shown to have antiangiogenesis properties. In this study we transfected the IL-12 gene into a human pancreatic adenocarcinoma cell line (PK-1). PK-1 cells transfected with the green fluorescence protein (gfp) gene were used as positive controls. The in vitro growth curve and in vivo tumor growth of transfectants (IL-12/PK-1 and gfp/PK-1) were compared with those of parental cells. The SCID mice used in this study were administered antiasialo GM-1 Ab (100 microg, i.p., twice weekly) to deplete the remaining immunoeffector cells, NK cells. Using a skinfold chamber model, we observed and recorded tumor angiogenesis by intravital microscopy. In vitro growth of IL-12/PK-1 and gfp/PK-1 cells was not different from that of wild-type PK-1 cells (wt/PK-1). However, IL-12 transfected PK-1 cells did not develop into tumors as did the wt/PK-1 cells after subcutaneous inoculation in antiasialo GM-1 Ab administered SCID mice. The growth of IL-12/PK-1 tumors was restored in mice treated with anti-IL-12 antibody. We found that IL-12/PK-1, in contrast to gfp/PK-1 and wt/PK-1, failed to initiate an angiogenic response, as observed in the skinfold chamber model. These results indicate that the antiangiogenesis effect of IL-12 alone, without immune system involvement, is sufficient to block the growth of human pancreatic cancer.
Sunamura
M
M
First Department of Surgery, Tohoku University School of Medicine, Sendai, Japan. msun-thk@umin.u-tokyo.ac.jp
Sun
L
L
Lozonschi
L
L
Duda
D G
DG
Kodama
T
T
Matsumoto
G
G
Shimamura
H
H
Takeda
K
K
Kobari
M
M
Hamada
H
H
Matsuno
S
S
D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology; D000818:Animals; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018664:Interleukin-12