Comparative thrombolytic properties of single-chain forms of urokinase-
type plasminogen activator
DC Stump, JM Stassen, E Demarsin and D Collen
The specific thrombolytic properties of urokinase and three molecular forms
of single-chain urokinase-type plasminogen activator (scu-PA) were compared
in a human plasma milieu in vitro and in an experimental thrombosis model
in rabbits. These scu-PA molecules included Mr 54,000 scu-PA from human
urine (urinary scu-PA), scu-PA from conditioned media of a human lung
adenocarcinoma cell line (CALU-3,ATCC,HTB-55) (cellular scu-PA) and an Mr
32,000 proteolytic derivative of cellular scu-PA (scu- PA-32k). All four
molecular forms induced significant lysis of a 125I- labeled human plasma
clot immersed in citrated human plasma at concentrations between 50 and 200
IU/mL. None of the four showed absolute fibrin-specificity, but at
equivalent lytic dose the three single-chain forms appeared to cause less
fibrinogen degradation and alpha 2-antiplasmin consumption than two-chain
urokinase. In addition, the fibrinolytic potential of the three
single-chain forms was largely maintained during pre-incubation in plasma
for up to 48 hours whereas that of urokinase was completely inhibited.
Intravenous (IV) infusion of cellular scu-PA or scu-PA-32k into rabbits
with a 125I-labeled thrombus in the jugular vein caused significant
dose-dependent lysis at concentrations ranging from 8,700 to 35,000 and
from 9,000 to 36,000 IU/kg respectively. Clot lysis was accompanied by
minor alpha 2- antiplasmin consumption or fibrinogen breakdown. In
contrast, urokinase induced lysis at doses between 20,000 and 200,000
IU/kg, but at higher doses was associated with significant systemic
activation of the fibrinolytic system. It is concluded that scu-PA obtained
from CALU-3 cell cultures has identical thrombolytic properties to that
obtained from urine. In addition, the scu-PA-32k proteolytic derivative has
the same fibrin-specific thrombolytic properties as the intact molecule.
Cellular scu-PA and scu-PA-32k may therefore constitute more readily
available alternatives for clot-selective thrombolytic therapy in man.
Volume 69,
Issue 2,
pp. 592-596,
02/01/1987
Copyright © 1987 by The American Society of Hematology
