Improvements in cancer treatment and cancer treatment efficacy prediction by blocking and detecting protease inhibitors

A protease inhibitor, inhibitor technology, applied in the field of cancer treatment, can solve problems such as apoptosis and loss of differentiation of breast epithelial cells

Inactive Publication Date: 2007-05-30
UNIVERSITY OF COPENHAGEN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] First, proteolytic degradation of the extracellular matrix leads to loss of mammary epithelial cell differentiation as well as to apoptosis in vitro and in vivo

Method used

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  • Improvements in cancer treatment and cancer treatment efficacy prediction by blocking and detecting protease inhibitors
  • Improvements in cancer treatment and cancer treatment efficacy prediction by blocking and detecting protease inhibitors
  • Improvements in cancer treatment and cancer treatment efficacy prediction by blocking and detecting protease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Establishment and determination of cell lines from genetically deleted animals

[0150] According to the present invention, in order to study the importance of specific gene products for the sensitivity of cancer to anti-tumor therapy, cell lines were established from wild-type and gene-deficient animals. These cell lines can then be used in screening systems to study the link between various anti-tumor treatments and cell death, as well as to identify blockers of the anti-apoptotic function of protease inhibitors.

[0151] This example describes the establishment and characterization of an immortal fibrosarcoma cell line from a mouse deficient in the PAI-1 gene.

[0152] mouse

[0153] Mice were placed on a 12-h day / night cycle and fed with normal chow. The generation of PAI-1- / - mice has been previously described (Carmeliet P et al., Dec 1993, J Clin Invest 92(6):2746-55). Mapping PAI-1 gene-mapped mice with META TM / Bom-nu(=META TM / Bomnu / nu) (Brünner N et al....

Embodiment 2

[0192] Testing the Chemosensitivity of Fibrosarcoma Cell Lines Using a Colony Formation Assay

[0193] A number of protease inhibitors have been described to protect cells from apoptosis. Because many types of antineoplastic treatments kill cells by inducing apoptosis, it can be expected that cell lines lacking expression of protease inhibitors will be more sensitive to antineoplastic treatments that induce apoptosis.

[0194] This example describes the detection of chemosensitivity of wild-type and PAI-1 gene-deficient cell lines to various cytotoxic drugs.

[0195] cell line

[0196] The cell lines described in Example 1 were used. The cells were at passage 35 (wild type cells) and passage 50 (cells lacking PAI-1 gene).

[0197] Colony Formation Assay

[0198] Drug (35 μl) and cells (0.35 ml) were mixed, and a mixture of 3.15 ml agar and medium was added thereto (agar: boil 990 mg Bacto agar and 30 ml PBS for 60 minutes; medium: heat M199 and FCS 10% to 37°C; mixtur...

Embodiment 3

[0225] Effect of PAI-1 Gene Deletion on Etoposide Toxicity in Vivo (VP-16)

[0226] When a cytotoxic drug is administered systemically to a cancer patient, both cancer cells and normal cells elsewhere in the body are also affected by the drug's toxic effects. If cells are sensitized to the toxic effects of a drug, such sensitization will potentially affect cancer cells as well as normal cells.

[0227] In this example, we show that although sensitivity to cytotoxic drugs is enhanced in cancer cells lacking PAI-1 expression, this is not the case when toxicity is studied in normal cells.

[0228] In vivo toxicity test

[0229] We investigated sensitivity in intact mice by comparing sensitivity in body weight loss between PAI-1+ / + and - / - mice.

[0230] Further, blood was sampled at the nadir (day 3 (WBC)) and day 5 expected from hematological evaluation. The experimental drug used in this study was etoposide.

[0231] Mouse: META TM / Bom nu / nu; PAI-1+ / + and PAI-1- / -. Siz...

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Abstract

Disclosed is a method for improving cancer therapy that relies on induction of apoptosis in malignant cells. It has been found that docking of protease inhibitors PAI-1 and TIMP-1 renders malignant cells expressing these inhibitors more sensitive to apoptosis, whereas non-malignant cells do not change their sensitivity to apoptosis induction. It is therefore possible to increase the effect of various anti-cancer treatments in a rational manner and to predict whether or not an apoptosis-inducing cancer treatment will be effective in a patient or not. The invention also provides for methods of identifying agents that inhibit the apoptosis sensitivity modulating effects of protease inhibitors and to methods of identifying anti-cancer compounds that are not dependent on an apoptosis inducing mechanism which can be modulated by protease inhibitors.

Description

field of invention [0001] The present invention relates to the field of cancer treatment. In particular, the invention relates to methods of increasing the sensitivity of malignant cells, but not non-malignant cells, to various anticancer drugs and treatments. In particular, the invention relates to improvements in treating cancer patients and in predicting the efficacy of cancer treatment. Background of the invention [0002] apoptosis [0003] Apoptosis or programmed cell death is a cellular suicide mechanism that enables multicellular organisms to maintain tissue homeostasis and eliminate cells that threaten the animal's survival. Abnormalities in apoptosis have been observed in a variety of diseases, such as neurodegenerative diseases where excessive cell death occurs and cancers where apoptosis is inhibited. [0004] Apoptosis can be triggered by a variety of stimuli, including the activation of cell surface death receptors (Fas, TRAIL-R1 / R2, TNF-R1, etc.), anticanc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K39/00G01N33/53A61P35/00A61K38/02A61K39/395G01N33/574
CPCG01N2333/81G01N2510/00G01N33/574A61P35/00A61P43/00
Inventor 马里亚·温尼·罗默乌尔里克·阿克塞尔·拉泽曼肯尼思·弗朗西斯·霍夫兰德彼得·布尔·延森玛丽昂·埃伦·迈耶·范格尔德约翰内斯·阿尔贝特·福肯斯安内-索菲耶·施罗尔·拉斯穆森尼尔斯·奥厄·布伦纳佩妮莱·奥特泽恩·厄舍
Owner UNIVERSITY OF COPENHAGEN
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