1304 Protein & Peptide Letters, 2010, Vol. 17, No. 10
Markowska et al.
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Evolving role of uPA/uPAR system in human cancers. Cancer
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showed concentration-dependent activity. The most interest-
ing compounds seem to be 4 with IC50 value 2.9 ꢀM for
MDA-MB-231 cells and compound 11, which was the most
selective inhibitor of urokinase and showed a cytotoxic ef-
fect in concentration 5.2 ꢀM for MDA-MB-231 cells. All
potential inhibitors are slightly more cytotoxic to MDA-MB-
231 cells than the examined amiloride. Originally, amiloride
was an antidiuretic agent, and it was later found that it inhib-
its uPA with Ki = 7ꢀM and has an antitumor activity in vivo
[16]. Further development of amiloride was limited by the
lack of selectivity and weak solubility.
[8]
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[11]
[12]
[13]
The examined compound did not influence MCF-7 can-
cer cells. It was found that the proteolytic activity of uPA is
closely connected with cell-surface events at the breast can-
cer cell. MCF-7 cells have low uPAR/uPA-expressing and
low plasminogen-binding, whereas MDA-MB-231 cells have
high uPAR/uPA expressing and high plasminogen-binding
[19]. Thus, the influence of the synthesized compounds on
the cytotoxic effect of MCF-7 cells could be insignificant.
Okada, Y.; Tsuda, Y.; Teno, N.; Wanaka, K.; Bohgaki, M.; Hiji-
kata-Okunomiya, A.; Naito, T.; Okamoto, S. Development of
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constant ([K.sub.i]) and the concentration of inhibitor which causes
50 per cent inhibition ([I.sub.50]) of an enzymatic reaction. Bio-
chem. Pharmacol., 1973, 22, 3099-3106.
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Zeslawska, E.; Jacob, U.; Schweinitz, A.; Coombs, G.; Bode, W.;
Madison, E.J. Crystals of urokinase type plasminogen activator
complexes reveal the binding mode of peptidomimetic inhibitors.
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Schweinitz, A.; Steimetzer, T.; Banke, I.J; Arlt, M.J.E.; Stürze-
becher, A.; Schuster, O.; Geissler, A.; Giersiefen, H.; Zesꢂawska,
E.; Jacob, U.; Krꢃger, A.; Stꢃrzebecher, J. Design of novel and se-
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The toxicity to erythrocytes was investigated using pig’s
red blood cells. The results show that the concentration up to
1000 ꢀg/ml of the synthesized peptides did not lyse erythro-
cytes.
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Received: February 10, 2010
Revised: June 07, 2010
Accepted: June 14, 2010