In vitro effect of cyclosporin A, mitomycin C and prednisolone on cell kinetics in cultured human umbilical vein endothelial cells.
BACKGROUND
Vascular endothelial cell damage plays an important role in microvascular thrombogenesis. In vivo administration of cyclosporin A or mitomycin C sometimes results in thrombotic microangiopathy in patients.


METHODS
The effects of cyclosporin A, mitomycin C and/or prednisolone on the cell cycle in cultured human umbilical vein endothelial cells were investigated to evaluate drug-induced endothelial cell damage and the protective effect of prednisolone on endothelial cells against the damage by cyclosporin A or mitomycin C in vitro.


RESULTS
The addition of cyclosporin A to cultures caused proliferation arrest in the G1-phase in a dose-dependent manner, while mitomycin C inhibited DNA synthesis, which resulted in cell cycle arrest and inhibition of BrdUrd incorporation in the S-phase. The administration of prednisolone also caused cell cycle arrest in the G1 by itself, and protected the cells from the damage caused by mitomycin C. The inhibitory effects of cyclosporin A and prednisolone on the cell cycle were reversible, while mitomycin C was not. The highly phosphorylated retinoblastoma protein expressed in human umbilical vein endothelial cells decreased in the presence of mitomycin C. Soluble thrombomodulin levels in the culture supernatant were elevated by the addition of cyclosporin A.


CONCLUSIONS
These effects of the drugs may cause the cell cycle arrest and the prolonged repair of damaged endothelial cells in patients.
Seki
Yoshinobu
Y
First Department of Internal Medicine, Niigata University Medical Hospital, 951-8510 Niigata, Asahimachi 1-757, Japan. y-seki@sbt.lamen.or.jp
Toba
Ken
K
Fuse
Ichiro
I
Sato
Naoaki
N
Niwano
Hiroe
H
Takahashi
Hoyu
H
Tanabe
Naohito
N
Aizawa
Yoshifusa
Y
D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D016685:Mitomycin / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D016685:Mitomycin; D016572:Cyclosporine; D011239:Prednisolone