Rick, I also came across a paper which is a comprehensive survey of recent PAI-2 research. This paper describes PAI-2 and identifies potential therapeutic and diagnostic applications. What's especially interesting about this paper is that the authors' company affiliation is given as Biotech Australia - the company which has a CIST license to develop PAI-2 therapeutics for the U.S. market.
The potential PAI-2 applications are very exciting. I'll try to excerpt some of the more interesting sections. The first of these (below) is on PAI-2 and cancer.
Rudy
Biological and Clinical Aspects of Plasminogen Activator Inhibitor Type 2.
Egbert K.O., Mark S. Baker, and Clive L. Bunn
Blood, Vol. 86, No. 11; Dec. 1, 1995
PAI-2: Inhibition of cancer cell invasion and metastasis:
A number of steps involved in metastasis are sensitive
to inhibition of urokinase plasminogen activator (u-PA)
activity either by PAIs or by inhibitory antibodies.
The recent availability of substantial amounts of
recombinant PAI-2 has allowed for this serpin to be
evaluated as a potential inhibitor of cell migration
and tumor cell invasion.
Exogenously added PAI-2 inhibited the plasminogen-dependent
degradation by cancer cells of the basement membrane
components collagen, proteoglycan, and glycoproteins.
Also, PAI-2 inhibited extracellular matrix degradation
by M24met human melanoma cells more effectviely
than tissue inhibition of metalloproteases type 2 (TIMP-
2), especially in the early stages. Suramin, a
polysulfonated naphthylurea compound, enhanced PAI-
2 production and suppressed u-PA production by human
renal cell carcinoma cells while inhibiting metastasis of
these tumor cells after renal subscapular implantation in
nude mice. The role of PAI-2 was further studied using
stably transfected HT-1080 clones. Expression of PAI-2
inhibited receptor bound u-PA activity and decreased
extracellular matrix degradation by the fibrosarcoma
cells. The PAI-2 expressing cells did not penetrate
multilayers of smooth muscle cells in vitro while
retaining tumorigenicity in nude mice. In agreement
with the idea that uncontrolled cell-surface plasminogen
activation contributes to the morphologic differences
between benign and malignant tumors, PAI-2
expressing HT-1080 transfectants displayed a thickened
collagenous-looking encapsulation, which was absent in
tumors formed from sham-transfected cells. A similar
tumor encapsulation was observed using TIMP-2
transfected cancer cells.
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Obviously, the efficacy of PAI-2 as an agent that might
decrease tumor growth and metastasis, possibly by
interfering with tumor angiogenesis, needs to be
analyzed more carefully. In particular, the observation
that PAI-2 decreased angiogenesis presumably through
inhibition of u-PA expressed by endothelial cells in
newly forming capillary sprouts should induce detailed
studies on the effect of PAI-2 on tumor angiogenesis. |
