PMID- 18045968
OWN - NLM
STAT- MEDLINE
DCOM- 20080521
LR  - 20211020
IS  - 0006-4971 (Print)
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 111
IP  - 4
DP  - 2008 Feb 15
TI  - Prophylactic thrombolysis by thrombin-activated latent prourokinase targeted to 
      PECAM-1 in the pulmonary vasculature.
PG  - 1999-2006
AB  - A recombinant prodrug, single-chain urokinase-type plasminogen activator (scuPA) 
      fused to an anti-PECAM-1 antibody single-chain variable fragment (anti-PECAM 
      scFv/scuPA) targets endothelium and augments thrombolysis in the pulmonary 
      vasculature.(1) To avoid premature activation and inactivation and to limit 
      systemic toxicity, we replaced the native plasmin activation site in 
      scFv/low-molecular-weight (lmw)-scuPA with a thrombin activation site, generating 
      anti-PECAM scFv/uPA-T that (1) is latent and activated by thrombin instead of 
      plasmin; (2) binds to PECAM-1; (3) does not consume plasma fibrinogen; (4) 
      accumulates in mouse lungs after intravenous injection; and (5) resists PA 
      inhibitor PAI-1 until activated by thrombin. In mouse models of pulmonary 
      thrombosis caused by thromboplastin and ischemia-reperfusion (I/R), scFv/uPA-T 
      provided more potent thromboprophylaxis and greater lung protection than 
      plasmin-sensitive scFv/uPA. Endothelium-targeted thromboprophylaxis triggered by 
      a prothrombotic enzyme illustrates a novel approach to time- and site-specific 
      regulation of proteolytic reactions that can be modulated for therapeutic 
      benefit.
FAU - Ding, Bi-Sen
AU  - Ding BS
AD  - Department of Pharmacology, Institute for Translational Medicine and 
      Therapeutics, University of Pennsylvania, Philadelphia, USA.
FAU - Hong, Nankang
AU  - Hong N
FAU - Murciano, Juan-Carlos
AU  - Murciano JC
FAU - Ganguly, Kumkum
AU  - Ganguly K
FAU - Gottstein, Claudia
AU  - Gottstein C
FAU - Christofidou-Solomidou, Melpo
AU  - Christofidou-Solomidou M
FAU - Albelda, Steven M
AU  - Albelda SM
FAU - Fisher, Aron B
AU  - Fisher AB
FAU - Cines, Douglas B
AU  - Cines DB
FAU - Muzykantov, Vladimir R
AU  - Muzykantov VR
LA  - eng
GR  - HL076406/HL/NHLBI NIH HHS/United States
GR  - HL076206/HL/NHLBI NIH HHS/United States
GR  - R01 CA083121/CA/NCI NIH HHS/United States
GR  - P01 HL076406/HL/NHLBI NIH HHS/United States
GR  - R01 HL076206/HL/NHLBI NIH HHS/United States
GR  - CA83121/CA/NCI NIH HHS/United States
GR  - P01 HL079063/HL/NHLBI NIH HHS/United States
GR  - HL071174/HL/NHLBI NIH HHS/United States
GR  - HL079063/HL/NHLBI NIH HHS/United States
GR  - R01 HL071174/HL/NHLBI NIH HHS/United States
GR  - HL71175/HL/NHLBI NIH HHS/United States
GR  - R01 HL071175/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20071128
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Platelet Endothelial Cell Adhesion Molecule-1)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 9001-32-5 (Fibrinogen)
RN  - EC 3.4.21.5 (Thrombin)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
RN  - U5NH2JV64T (saruplase)
SB  - IM
MH  - Animals
MH  - Endothelium, Vascular/drug effects/*physiology
MH  - Fibrinogen/metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Platelet Endothelial Cell Adhesion Molecule-1/metabolism/*physiology
MH  - Protein Binding
MH  - Pulmonary Circulation/*physiology
MH  - Recombinant Fusion Proteins/metabolism
MH  - Recombinant Proteins/metabolism/pharmacology
MH  - Thrombin/*physiology
MH  - *Thrombolytic Therapy
MH  - Tissue Distribution
MH  - Urokinase-Type Plasminogen Activator/genetics/metabolism/*physiology
PMC - PMC2234048
EDAT- 2007/11/30 09:00
MHDA- 2008/05/22 09:00
PMCR- 2009/02/15
CRDT- 2007/11/30 09:00
PHST- 2007/11/30 09:00 [pubmed]
PHST- 2008/05/22 09:00 [medline]
PHST- 2007/11/30 09:00 [entrez]
PHST- 2009/02/15 00:00 [pmc-release]
AID - S0006-4971(20)44594-X [pii]
AID - 2007/103002 [pii]
AID - 10.1182/blood-2007-07-103002 [doi]
PST - ppublish
SO  - Blood. 2008 Feb 15;111(4):1999-2006. doi: 10.1182/blood-2007-07-103002. Epub 2007 
      Nov 28.