Chronic obstructive pulmonary disease, characterised by a slowly progressive, irreversible airways limitation, is a major worldwide cause of chronic morbidity and mortality. The imbalance between human neutrophil elastase and endogenous antiproteases may cause excess human neutrophil elastase in pulmonary tissues, which may be considered a major pathogenic factor in chronic obstructive pulmonary disease. Great effort has been devoted to finding a method to restore the balance, resulting in the discovery of potent two-typed small-molecular-weight human neutrophil elastase inhibitors. In the application of chronic obstructive pulmonary disease therapy, the human neutrophil elastase inhibitors mainly focused upon include ONO-5046, MR-889, L-694,458, CE-1037, GW-311616 and TEI-8362 as the acyl-enzyme inhibitors; and ONO-6818, AE-3763, FK-706, ICI-200,880, ZD-0892 and ZD-8321 as the transition-state inhibitors. In this review, various problems that remain to be solved in the clinical use of human neutrophil elastase inhibitors are discussed.

01 Dec 2000·Journal of Surgical ResearchQ4 · MEDICINE

Elastase Activity Enhances the Adhesion of Neutrophil and Cancer Cells to Vascular Endothelial Cells

Q4 · MEDICINE

Article

Author: Muneyuki Shibata ; Akihiro Okabe ; Fumiaki Nozawa ; Takeshi Iwamura ; Masahiko Hirota ; Yoshio Haga ; Michio Ogawa

BACKGROUNDElastase activity in cancer cells has been reported to promote their metastasis. Hence, we analyzed the influence of elastase activity of cancer cells on their responsive adhesion to vascular endothelial cells.MATERIALS AND METHODSHuman pancreatic (S2-007, S2-013, S2-020, S2-028) and colonic (COLO205) cancer cell lines were used. S2-007, S2-013, and S2-020 possess high elastase activity, whereas S2-028 and COLO205 have low elastase activity. Adhesive reactions of these cancer cells and neutrophils to TNFalpha-activated HUVEC were analyzed. Bound cells onto HUVEC were counted after incubation for 10 min. The effects of suppression of elastase activity by ZD8321, a potent elastase inhibitor, and supplementation of human neutrophil elastase (NE) on the adhesive reactions were also analyzed. In addition, E-selectin expression on HUVEC and concentrations of soluble E-selectin in the medium were measured.RESULTSAdhesion of cells with high intracellular elastase activity to TNFalpha-activated HUVEC was suppressed by ZD8321. On the other hand, adhesion of cells with low elastase activity was enhanced by exogenous NE. Expression of E-selectin, a key molecule in leukocyte-endothelial cell interaction, on HUVEC was increased by NE. Soluble E-selectin concentration in the medium increased after the adhesive reaction between neutrophils and HUVEC. This increase was thought to be due to the shedding of cell surface E-selectin. Such responses were inhibited by ZD8321.CONCLUSIONElastase activity has a biological function of stimulating both the E-selectin expression on HUVEC and the resultant adhesive reaction of cancer cells with them. Inhibition of elastase activity is a potent strategy for controlling cancer metastasis.

01 Oct 2000·Current opinion in investigational drugs (London, England : 2000)

ZD-0892 AstraZeneca.

Article

Author: Ohbayashi, H

ZD-0892, a neutrophil elastase inhibitor, is under development by AstraZeneca as a potential treatment for chronic obstructive pulmonary disease (COPD) and peripheral vascular disease (PVD). It is in phase I clinical trials for these two indications [315489]. The compound was originally under investigation for the potential treatment of asthma, but development was discontinued for this indication [266604]. The compound is the follow-up to ZD-8321 (qv) [336599].

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lung Injury	Phase 2	US	AstraZeneca PLC	-
Bronchitis	Phase 2	US	AstraZeneca PLC	-
Respiratory Distress Syndrome, Adult	Phase 2	US	AstraZeneca PLC	-
Respiratory Distress Syndrome, Newborn	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Systemic Inflammatory Response Syndrome	Phase 2	US	AstraZeneca PLC	-

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