Suppression of angiogenesis and therapy of human colon cancer liver metastasis by systemic administration of interferon-alpha.
The purpose of this study was to determine whether systemic administration of interferon-alpha (IFN-alpha) can inhibit liver metastasis produced in nude mice by human colon cancer cells. KM12L4 (IFN-alpha-sensitive) or KM12L4 IFN(R) (IFN-alpha-resistant) cells were injected into the spleen of nude mice. Seven days later, the mice were treated with subcutaneous (s.c.) injections of IFN-alpha (70,000 units/week) at different dosing schedules (1, 2, or 7 times/week). Significant inhibition of tumor growth, vascularization and expression of basic fibroblast growth factor (bFGF) or matrix metalloproteinase-9 (MMP-9) mRNA and protein occurred in mice given daily injections of IFN-alpha. Kinetic analysis of therapy showed that daily s.c. administrations of 10,000 units of IFN-alpha induced apoptosis in liver metastasis-associated endothelial cells, followed by inhibition of tumor cell division and apoptosis of tumor cells. These data suggest that the antiangiogenic activity of IFN-alpha-2a depends on frequent administration of the optimal biologic dose.
Ozawa
S
S
Departments of Cancer Biology and Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Shinohara
H
H
Kanayama
H O
HO
Bruns
C J
CJ
Bucana
C D
CD
Ellis
L M
LM
Davis
D W
DW
Fidler
I J
IJ
D000818:Animals; D017209:Apoptosis; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007370:Interferon Type I / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007700:Kinetics; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D007370:Interferon Type I; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D020784:Matrix Metalloproteinase 8