Author: Park, H W ; Kim, K-A ; Son, D-S ; Lee, E ; Lee, J M ; Weiner, L M ; Lee, S B ; Oh, Y M ; Murray, J C ; Wang, S ; Jeong, Y ; Song, Y-J ; Zhou, Y ; Ahn, T ; Kim, B ; Yoo, H-s ; Song, P H ; Choi, J

Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting that FGFR and integrin β3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.

01 Dec 2002·Analytica Chimica Acta

Kinetics of the post-column complexation reaction of Cu(II) with N-formylmethionyl chemoattractant and chemotactic peptides

Author: F. Shi ; S.J. Woltman ; S.G. Weber

The N-formylmethionyl peptides comprise an important class of peptides that activate neutrophils to attack microbial invaders.The post-column reaction of Cu(II) with peptides following their separation leads to electroactive complexes that are detectable with electrochem. detection.The need to minimize post-column band spreading puts constraints on the time allowed for the complexation reaction to occur.For most peptides, the reaction rate is rapid, however, for peptides without a free terminal amine the reaction rate is slower.In order for this detection scheme to be sensitive to so-called N-blocked peptides, the rate law and the influence of buffers need to be understood.The kinetics of the complexation of Cu(II) with several N-blocked chemoattractant and chemotactic peptides are similar.One N-blocked peptide, N-f-MLF, has been studied in detail.Two parallel paths have been found for the complexation reaction.The reaction at the amide terminus is first order in [peptide] and [OH^-].The reaction at the carboxylate terminus is first order in [peptide], [Cu(II)], and total carbonate at constant pH.The response of the rate as pH is changed reveals that bicarbonate ion is the active species.

01 Jun 2000·StrokeQ1 · MEDICINE

Integrin α _IIb β ₃ Inhibitor Preserves Microvascular Patency in Experimental Acute Focal Cerebral Ischemia

Q1 · MEDICINE

Article

Author: Tschopp, Juerg F. ; Koziol, James A. ; Abumiya, Takeo ; Pierschbacher, Michael D. ; Copeland, Brian R. ; del Zoppo, Gregory J. ; Mazur, Curt ; Fitridge, Robert

Background and Purpose —Platelets become activated and accumulate in brain microvessels of the ischemic microvascular bed after experimental focal cerebral ischemia. The binding of glycoprotein IIb/IIIa (integrin α IIb β 3 ) on platelets to fibrinogen is the terminal step in platelet adhesion and aggregation. This study tests the hypothesis that inhibition of platelet-fibrin(ogen) interactions may prevent microvascular occlusion after experimental middle cerebral artery occlusion (MCA:O). Methods —TP9201 is a novel Arg-Gly-Asp (RGD)-containing integrin α IIb β 3 inhibitor. Microvascular patency after 3-hour MCA:O and 1-hour reperfusion within the ischemic and nonischemic basal ganglia was compared in adolescent male baboons who received high-dose TP9201 (group A: IC 80 in heparin, n=4), low-dose TP9201 (group B: IC 30 in heparin, n=4), or no treatment (group C: n=4) before MCA:O. Results —After MCA:O, microvascular patency decreased significantly in group C. However, in the ischemic zones of groups A and B compared with group C, patencies were significantly greater in the 4.0- to 7.5-μm-diameter (capillary) and 7.5- to 30.0-μm-diameter vessels (2 P <0.05). A dose-dependent increase in hemorrhagic transformation was seen in group A (3 of 4 animals) compared with group B (1 of 4 animals), and no hemorrhage was visible in group C (χ 2 analysis for trend, P <0.05). Conclusions —Platelet activation contributes significantly to ischemic microvascular occlusion. Occlusion formation may be prevented by this RGD–integrin α IIb β 3 inhibitor at a dose that does not produce clinically significant parenchymal hemorrhage. The effect of microvascular patency on neuron recovery can now be tested.

100 Deals associated with TP-9201

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Indication	Highest Phase	Country/Location	Organization	Date
Angina, Unstable	Phase 1	-	Integra LifeSciences Holdings Corp.	-
Angina, Unstable	Phase 1	-	Integra LifeSciences Holdings Corp.	-
Angina, Unstable	Phase 1	United States	Telios Pharmaceuticals, Inc.	-
Angina, Unstable	Phase 1	United States	Telios Pharmaceuticals, Inc.	-
Reperfusion Injury	Phase 1	United States	Telios Pharmaceuticals, Inc.	-
Stroke	Phase 1	United States	Telios Pharmaceuticals, Inc.	-
Vascular restenosis	Phase 1	-	Integra LifeSciences Holdings Corp.	-
Vascular restenosis	Phase 1	United States	Telios Pharmaceuticals, Inc.	-
Vascular restenosis	Phase 1	-	Integra LifeSciences Holdings Corp.	-
Vascular restenosis	Phase 1	United States	Telios Pharmaceuticals, Inc.	-

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