Antiproliferative effects of interferon-alphaCon1 on ovarian clear cell adenocarcinoma in vitro and in vivo.
OBJECTIVE
We examined the antiproliferative effect of IFN-alphaCon1 and its mechanism on ovarian clear cell adenocarcinoma in vitro and in vivo.


METHODS
(a) The effects of IFN-alphaCon1 on growth, morphology, cell cycle, and type I IFN-alpha receptor (IFNAR-2) expression were examined on two ovarian clear cell adenocarcinoma cell lines (KOC-5C and KOC-7C) in vitro. (b) KOC-5C or KOC-7C cells were transplanted into nude mice, and changes in tumor volume, tumor weight, apoptosis, necrosis, and microvessel density were investigated. The expression of angiogenesis factors was examined in the serum and the developed tumors.


RESULTS
Both cell lines expressed IFNAR-2 mRNA, but its protein was detected only in KOC-7C. In KOC-7C cells, antiproliferative effects were observed in a time- and dose-dependent manner and cell division was blocked at the S phase. The KOC-7C tumors showed decreases in tumor volume and weight; a decreasing tendency in basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and interleukin (IL)-8 protein expression in the tumor; a significant decrease in bFGF and IL-8 protein expression in the serum, and of microvessel density; and significant increase in apoptosis and necrosis in the tumor. In the KOC-5C tumors, these in vitro and in vivo changes were not apparent, and the antiproliferative effects of IFN-alphaCon1 were not obvious.


CONCLUSIONS
IFN-alphaCon1 suppresses tumor proliferation by inducing apoptosis, blocking the cell cycle, and inhibiting tumor angiogenesis. Our findings show that the clinical efficacy of IFN-alphaCon1 can be predicted by examining IFNAR-2 expression on tumor cells, and the efficacy of IFN-alphaCon1 treatment can be evaluated by measuring serum bFGF and IL-8 levels.
Takemoto
Yumi
Y
Department of Pathology, Kurume University School of Medicine, Research Center of Innovative Cancer Therapy of the 21st Century COE Program for Medical Science, Kurume University, Kurume, Fukuoka, Japan. hyumi@med.kurume-u.ac.jp
Yano
Hirohisa
H
Momosaki
Seiya
S
Ogasawara
Sachiko
S
Nishida
Naoyo
N
Kojiro
Sakiko
S
Kamura
Toshiharu
T
Kojiro
Masamichi
M
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007370:Interferon Type I / Q000627:therapeutic use*; D016898:Interferon-alpha; D016209:Interleukin-8 / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008833:Microcirculation; D009336:Necrosis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000998:Antiviral Agents; C507964:IFNAR1 protein, human; C508034:Ifnar2 protein, mouse; D007370:Interferon Type I; D016898:Interferon-alpha; D016209:Interleukin-8; D008565:Membrane Proteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D053633:Receptor, Interferon alpha-beta; C050739:interferon alfacon-1