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Suppression of inhibitors

Inactive Publication Date: 2001-10-25
BRUNNER NIELS +7
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In certain circumstances it has not yet been established that a person has developed a malignant tumour, but it is considered highly likely that he or she is in the process of developing a malignant tumour or has developed a malignant tumour but the localization of the tumour has not yet been established.

Method used

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  • Suppression of inhibitors
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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0103] Prognostic value of PAI-1 in bronchiogenic adenocarcinomas.

[0104] In non small cell lung cancer the stage of disease, including tumour size and lymph node involvement, within the specific stages, have been reported to be among the strongest prognostic factors (62,63). Even though patients with bronchogenic adenocarcinoma are surgical radically resected (stage I and II), the 5 year survival is poor, with the 5 year survival being 40% in stage I and 10% in stage II (64). Thus a means to characterize and define patients with bronchogenic adenocarcinoma and poor prognosis is needed, to select sub-groups of radically resected patients for adjuvant chemotherapy. To our knowledge there is no such prognostic marker used in clinical practice today.

[0105] We have retrospectively studied the prognostic significance of uPA and PAI-1 levels as determined by ELISA in tumour extracts from patients with bronchogenic adenocarcinoma. The study includes 106 patients, all having had surgery with...

example 2

[0136] Predictive value of PAI-1 measurements in bronchiogenic adenocarcinomas.

[0137] As shown in Example 1, a proportion of lung cancer patients have high levels of PAI-1 in their tumours which predict a poor prognosis. Accordingly, patients with high PAI-1 levels will be candidates for a treatment aiming at inhibiting the binding of PAI-1 to uPA. This example describes a predictive assay to identify patients who potentially will benefit from such a treatment.

[0138] Material and Methods

[0139] Patients

[0140] Patients with bronchiogenic adenocarcinoma stage I or II referred for adjuvant therapy subsequent to radical resection of their lung tumours.

[0141] Tumour Extraction.

[0142] Tumour tissue from the patients with bronchogenic adenocarcinoma is stored at -80.degree. C. Tumour extracts are made by a procedure including pre-cooling the tissue in liquid nitrogen, mechanical pulverization, extraction with a buffer consisting 75 mM potassium acetate, 0.3 M NaCl, 0.1 M L-arginine, 10 mM E...

example 3

[0147] In situ Hybridization for PAI-1 mRNA and Immunostaining of PAI-1 Protein in Human Lung Cancer

[0148] Immunohistochemistry

[0149] Cryostat sections from 24 samples of pulmonary carcinoma were used for immunohistochemistry. These included 14 cases of squamous cell carcinoma, 5 cases of adenocarcinomas, 3 cases of mixed tumours (adenocarcinoma and squamous cell carcinoma) and 3 cases of large cell undifferentiated carcinoma. Adjacent normal mucosal tissue resected at time of surgery was obtained from 3 of the patients. Monoclonal anti-human PAI-1 antibodies (clones 1 and 2) were used for immunohistochemical stainings. An irrelevant monoclonal antibody (m-anti-TNP) was used as a negative control. The two monoclonal antibodies have previously been shown to be directed against two different epitopes on PAI-1. 5 .mu.m cryostat sections were subjected to a conventional APAAP (Alkaline Phosphatase-Anti-Alkaline Phosphatase) method as described previously (45).

[0150] In situ Hybridizatio...

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Abstract

The present invention relates to methods for inhibiting malignant tumour growth, invasion and / or metastasis in a patient, the method comprising suppressing the inhibitory activity of an inhibitor of a protease or of a non-proteolytic matrix-degrading enzyme (IPNME) in malignant tumour tissue or potential malignant tumour tissue. The suppression may be brought about by administering compounds interacting with the IPNME, but also administration of compounds interacting with transcription of genes encoding the IPNME is a possibility. The invention also relates to methods of selecting and identifying compounds in the therapeutical methods, as well of the use of such compounds in the treatment of malignancies.

Description

[0001] In order to invade and spread, cancer cells must degrade extracellular matrix proteins. This degradation is catalyzed by the concerted action of several enzymes including proteases and non-proteolytic matrix-degrading enzymes e.g. metalloproteases such as interstitial collagenases, type IV collagenases and stromelysins, aspartic proteases such as cathepsin D, other degradative enzymes such as heperanase, and serine proteases such as plasmin (1, 73-76). Plasmin is formed from its precursor, plasminogen, by two activators, tissue-type plasminogen activator (tPA) which is involved in thrombolysis, and urokinase-type plasminogen activator (uPA) which plays a central role in tissue remodelling, including cancer invasion. The activation of plasminogen is regulated by two specific plasminogen activator inhibitors (PAI-1 and PAI-2). Both uPA and PAI-1 are present in various types of cancer tissue, and it was recently found that high levels of uPA and PAI-1 in breast cancer tissue eac...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K38/49A61K38/55A61K38/57A61K39/395A61K45/00A61K48/00A61P35/00C07K16/38C12Q1/37G01N33/15G01N33/573G01N33/574
CPCA61K38/49A61K38/57A61K48/00C07K16/38G01N33/573G01N33/574G01N2333/47G01N2333/4704G01N2333/81A61P35/00
Inventor BRUNNER, NIELSROMER, JOHNELLIS, VINCENTPYKE, CHARLESGRONDAHL-HANSEN, JANPAPPOT, HELLE PEDERSENHANSEN, HEINE HOIDANO, KELD
Owner BRUNNER NIELS
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