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WO2004050125A1 - Inhibiteur de proliferation et/ou d'infiltration de cellules tumorales - Google Patents

Inhibiteur de proliferation et/ou d'infiltration de cellules tumorales Download PDF

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Publication number
WO2004050125A1
WO2004050125A1 PCT/JP2003/010631 JP0310631W WO2004050125A1 WO 2004050125 A1 WO2004050125 A1 WO 2004050125A1 JP 0310631 W JP0310631 W JP 0310631W WO 2004050125 A1 WO2004050125 A1 WO 2004050125A1
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WO
WIPO (PCT)
Prior art keywords
gene
collagen
cells
polynucleotide
tumor cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2003/010631
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English (en)
Japanese (ja)
Inventor
Kimi Honma
You Aso
Masaaki Terada
Takahiro Ochiya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Koken Co Ltd
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Koken Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Koken Co Ltd filed Critical Koken Co Ltd
Priority to AU2003262277A priority Critical patent/AU2003262277A1/en
Priority to JP2004556821A priority patent/JPWO2004050125A1/ja
Publication of WO2004050125A1 publication Critical patent/WO2004050125A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel antitumor agent, and more particularly, to an antitumor agent having a function of suppressing the growth and / or invasion of tumor cells. More specifically, an inhibitor of tumor cell growth and / or invasion comprising a composition for gene therapy containing a collagen gene and a homolog thereof, and a tumor cell growth and / or The present invention relates to a method for suppressing invasion, and a method for treating a tumor using the method.
  • Collagen a major component of extracellular matrix and abundant in vivo, has been studied for changes in the amount of collagen produced by cell carcinogenesis.
  • neuroblastoma Kuga et al.
  • hepatoblastoma Inagaki et al.
  • thyroid cancer Diohlma et al.
  • Non-Patent Document 1 Journal of the Nissho Gaijikai, Vol. 36, No. 2, April 2000 p 41-47
  • Non-Patent Document 2 Biochem. Biophys. Res.Commun. 1987 Oct 29; 148 (2 ): 8697
  • Non-Patent Document 3 Int.J. Cancer.2002 Mar 10; 98 (2): 186
  • An object of the present invention is to provide a novel antitumor agent, and to provide a means for gene therapy supporting a novel mechanism. That is, the present invention provides a means for controlling extracellular matrices for tumor cells, controlling cell proliferation and / or invasion, and treating cancer.
  • the present inventors have conducted intensive studies and found that, by introducing a collagen gene into tumor cells, it was possible to suppress the growth and / or invasion of tumor cells, thereby completing the present invention.
  • the present inventors have conducted intensive studies and found that, by introducing a collagen gene into tumor cells, it was possible to suppress the growth and / or invasion of tumor cells, thereby completing the present invention.
  • An agent for suppressing growth and / or invasion of tumor cells comprising a composition for gene therapy containing a collagen gene.
  • the amino acid sequence encoded by the gene of 1) or 2) has a mutation such as deletion, substitution, addition or insertion of one or several amino acids, and has an ability to suppress the growth and / or invasion of tumor cells. And a phase capture chain thereof
  • a polynucleotide represented by at least about 15 consecutive nucleotide sequences of the polynucleotide or the complementary strand thereof according to the above 1) to 3), and which has an ability to inhibit tumor cell growth and / or invasion;
  • composition for gene therapy is a recombinant vector.
  • the proliferation and / or invasion of a tumor cell which comprises introducing a collagen gene and a homolog thereof into a tumor cell in a living body using the inhibitor according to any one of the above items 1 to 9. How to control.
  • FIG. 1 shows an expression vector (PCXN2 / HC0L1A1).
  • FIG. 2 shows the established cell line expressing type I collagen ⁇ 1 chain (T98G / HCOL1A1).
  • FIG. 3 shows a comparison of proliferation between cells into which a collagen gene has not been introduced (control cells) and cells into which a collagen gene has been introduced.
  • FIG. 4 shows a comparison of the migratory and invasive properties of cells into which a collagen gene has not been introduced (control cells) and cells into which a collagen gene has been introduced.
  • control cells for ⁇ (comparison of migration), transwell was used, and for B (comparison of invasion), Matrigel chamber was used.
  • FIG. 5 shows a comparison of tumorigenicity in nude mice between cells into which a collagen gene has not been introduced (control cells) and cells into which a collagen gene has been introduced.
  • FIG. 6 shows a comparison of apoptosis induction between cells into which a collagen gene has not been introduced (control cells) and cells into which a collagen gene has been introduced.
  • collagen gene refers to a gene that broadly encodes collagen, and its fragment, mutant, and derivative can be used for tumor cell growth and proliferation.
  • the collagen gene can suppress the growth and / or invasion of tumor cells according to the present invention, and easily prepares fragments, mutants, and derivatives thereof, and can also prepare a target substance. is there.
  • the origin of the collagen gene used in the present invention is not particularly limited, but is preferably the same as that of the tumor cell carrier. When a person is a carrier, it is preferably the same or homologous to a human.
  • the peptide chain encoded by the collagen gene is not particularly limited, but is large Type I, type II, type III, or types IV and XVIII which are considered to be involved in metastasis.
  • type I was selected as a suitable case.
  • type I collagen is composed of two types, ⁇ 1 chain and two chains, but it is not necessary to introduce two types of genes in the present invention, and it is possible to use either ⁇ 1 or ⁇ 2. Good, both, or their fragments, or their homologs.
  • the ⁇ 1 chain will be described as a preferable representative case.
  • the following homologues of the collagen gene of the present invention are also objects of the present invention, with the marker that intracellular introduction of the gene enables the growth and / or invasion of tumor cells.
  • polynucleotide according to 1) to 3 which is represented by at least about 15 consecutive nucleotide sequences of the polynucleotide or a complementary strand thereof and which has an ability to inhibit tumor cell growth and / or invasion.
  • PCR polymerase chain amplification
  • homologous amino acids polar amino acids, non-polar amino acids
  • Mutual substitution between amino acids, hydrophobic amino acids, hydrophilic amino acids, positively charged amino acids, negatively charged amino acids, aromatic amino acids, etc. is easily assumed.
  • the polynucleotide of the present invention and its complementary strand also include a polynucleotide that hybridizes under stringent conditions to its corresponding region.
  • Eve redidation conditions can be in accordance with, for example, Sambrook et al. [Molecular Cloning,, Laboratory Manual, 2nd Edition] Cold Spring Harbor Laboratory, (1989).
  • These polynucleotides need not necessarily be complementary sequences as long as they hybridize to the target polynucleotide.
  • the homology is at least about 40%, for example, about 70% or more, preferably about 80% or more, more preferably about 90% or more, and still more preferably about 95% or more.
  • polynucleotide of the present invention may be a polynucleotide or an oligonucleotide having a sequence of 10 or more nucleotides, preferably 15 or more, more preferably 20 or more corresponding to the designated base sequence region. And their complementary strands.
  • these polynucleotides can be provided by selecting using the activity of inhibiting the growth and / or invasion of the tumor as an index.
  • the polynucleotide of the present invention can be provided by selecting according to the present invention, using the ability to induce apoptosis of tumor cells as an index.
  • Recombinant vectors used for gene transfer can be prepared by any means known per se, for example, using lepicon, episomes, chromosomes, non-infectious viruses, etc. It is.
  • the recombinant vector is a bacterial plasmid-derived vector, a bacteriophage-derived vector, a transposon-derived vector, a yeast episomal-derived vector, an insertion element-derived vector, a yeast chromosome element-derived vector, a baculovirus-papovavirus SV40 Vectors derived from viruses such as vaccinia virus, adenovirus, fowlpox virus, pseudorabies virus, and retrovirus, and vectors derived from genetic elements of plasmid and batteriophage (cosmid and phagemid).
  • the vector is selected according to the type of the selected host, and comprises a gene sequence to be expressed and a gene sequence carrying information on replication and control as components.
  • the combination is classified into prokaryotic cells and eukaryotic cells, and a drug resistance marker gene, a promoter, a ribosome binding site, a terminator, a signal sequence, an enhancer, and the like can be used in combination by a method known per se.
  • the vector is not particularly limited as long as it can be expressed in eukaryotic cells.
  • pCXN2 is shown as a suitable expression vector, but is not limited thereto.
  • a method for integrating a gene into a vector a method known per se can be applied. For example, a method is used in which an appropriate restriction enzyme is selected and treated, the DNA is cleaved at a specific site, then mixed with a similarly treated DNA to be used as a vector, and religated with ligase.
  • the integration method into the chromosome for example, ribosome method, phosphoric acid solution method, electoral poration method, etc.
  • Transient ribosome method, calcium phosphate method, electroporation method, virus vector method, atelocollagen It may be a method such as a method.
  • the gene therapy composition comprising the vector containing the collagen gene of the present invention is generally administered parenterally to a subject.
  • the tumor cells are treated directly or by targeting techniques.
  • the dose is not particularly limited, but is appropriately adjusted depending on the size of the tumor cell.
  • a vector containing a collagen gene is administered to a tumor cell lg in an amount of 20 to 440 ⁇ ⁇ , preferably about 40 to 110 / xg.
  • the administration timing is more efficient during the growth phase of the tumor cells, but is not particularly limited.
  • the tumor targeted by the present invention is not particularly limited, but a tumor whose collagen production is reduced by malignant tumors such as neuroblastoma, hepatoblastoma, and thyroid cancer is preferable.
  • malignant tumors such as neuroblastoma, hepatoblastoma, and thyroid cancer.
  • collagen gene transfer was particularly effective for Darioplastoma cells (T98G) and breast cancer cells (MCF-7).
  • T98G Glioblastoma cells (ATCC-derived cell line purchased from Dainippon Pharmaceutical Co., Ltd.) were used as tumor cells.
  • the gene to be introduced into the cell is a human type I procollagen single chain gene, and a full-length cDNA having a propeptide at both ends of the helical region is inserted under the CAG promoter of the expression vector pCXN2 for expression.
  • a vector (pCXN2 / HCOLlAl) was constructed (FIG. 1).
  • PCXN2 / HCOL1A1 was introduced into T98G cells by the liposome method using the gene transfer reagent Lipofectamine 2000 reagent (GIBCO).
  • the calorie content is about 50% confluent cells (approximately 4 l.OxlO) in a petri dish (diameter 10cm).
  • 20 ⁇ l of Lipofectamine 2000 reagent and 10 ⁇ g of pCXN2 / HCOLlAl were used.
  • the selective drug G418 for the drug resistance marker (Neo R) is added to the culture solution to a final concentration of 800 ⁇ // ⁇ 1, and the colonies of cells with the stable phenotype are added. Was formed and collected.
  • the recovered cells were further cultured and subjected to cell immunostaining with an anti-type I collagen chain antibody to confirm their expression, and a type I collagen-1 chain-expressing cell line (T98G / HCOL1A1) was established (Fig. 2 ).
  • the transmigration and invasiveness were examined by Transwell Atsushi.
  • the migratory activity was compared by counting the number of cells that passed through the membrane after adding 2.5 to 10 5 cells to an 8-micron pore size transwenore (Becton Deutskinson) and culturing for 24 hours. .
  • the migratory activity of the transfected cells was reduced to 30% of the control cells.
  • the invasiveness was compared by adding 2.5 to 10 5 cells to one Matrigel chamber (Betaton 'Dickinson), culturing for 24 hours, and counting the number of cells passing through the cells.
  • the invasiveness of the transfected cells was 1/10 or less of the control cells (Fig. 4). Test example 3
  • Each cell was implanted subcutaneously in a nude mouse to examine its tumorigenicity.
  • the tumor grew rapidly after 50 days.
  • the group transplanted with collagen gene-transfected cells no tumor growth was observed and tumorigenicity was lost (Fig. 5).
  • Darioblastoma cells T98G
  • breast cancer cells MCF-7: ATCC-derived cell line purchased from Dainippon Pharmaceutical Co., Ltd.
  • the introduced gene and the method of introducing the gene were performed in the same manner as in Example 1 except for the following.
  • the difference from Example 1 is that the amount of gene transfer reagent used was 20 ⁇ l of Lipofectamine 2000 reagent and 17.5 ⁇ g of pCXN2 / HCOLlAl for tumor cells, and Lipofectamine 2000 was used for tumor cells used as a control.
  • the reagent was 20 ⁇ 20 and pCXN2 lO.O ⁇ g.
  • the cells are passaged to another dish, and the selection drug G418 is adjusted to a final concentration of 600 ⁇ g / ml.
  • the culture solution was added to form a cell colony, which was collected.
  • the cells collected by the above method were used to determine the percentage of colonies in which pCXN2 / HCOLlAl-introduced tumor cells were introduced relative to control cells in which pCXN2 was introduced.
  • Both glioblastoma cells (T98G) and breast cancer cells (MCF-7) had a colony generation rate of 25% in tumor cells into which a collagen gene had been introduced. From the above results, it was found that the introduction of collagen gene into Darioblastoma cells (T98G) and breast cancer cells (MCF-7) has a remarkable cell growth inhibitory effect. Industrial applicability.
  • the introduction of a collagen gene into tumor cells by the method of the present invention has been confirmed to have an effect of significantly suppressing tumor cell invasion and / or metastasis, and can be a useful antitumor means.
  • a collagen gene has been confirmed to have an effect of significantly suppressing tumor cell invasion and / or metastasis, and can be a useful antitumor means.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un agent antitumoral et des moyens de thérapie génique impliquant un mécanisme nouveau. Le but consiste à mettre en oeuvre des moyens de régulation de la matrice extracellulaire concernant les cellules tumorales et de réguler la prolifération et/ou l'infiltration des cellules afin de traiter ainsi le cancer. Plus particulièrement, on trouve qu'il est possible d'empêcher la prolifération et/ou l'infiltration des cellules de tumeur par introduction d'un gène de collagène dans les cellules de tumeur.
PCT/JP2003/010631 2002-12-03 2003-08-22 Inhibiteur de proliferation et/ou d'infiltration de cellules tumorales Ceased WO2004050125A1 (fr)

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AU2003262277A AU2003262277A1 (en) 2002-12-03 2003-08-22 Inhibitor of proliferation and/or infiltration of tumor cells
JP2004556821A JPWO2004050125A1 (ja) 2002-12-03 2003-08-22 腫瘍細胞の増殖及び／又は浸潤の抑制剤

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JP2002/351599 2002-12-03

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8765709B2 (en) 2004-11-12 2014-07-01 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
US9080215B2 (en) 2007-09-14 2015-07-14 Asuragen, Inc. MicroRNAs differentially expressed in cervical cancer and uses thereof
US9365852B2 (en) 2008-05-08 2016-06-14 Mirna Therapeutics, Inc. Compositions and methods related to miRNA modulation of neovascularization or angiogenesis
US9644241B2 (en) 2011-09-13 2017-05-09 Interpace Diagnostics, Llc Methods and compositions involving miR-135B for distinguishing pancreatic cancer from benign pancreatic disease
US10047388B2 (en) 2004-05-28 2018-08-14 Asuragen, Inc. Methods and compositions involving MicroRNA

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999049885A2 (fr) * 1998-03-27 1999-10-07 University Of Kansas Medical Center Utilisation de domaines isoles de collagene du type iv pour modifier des interactions cellulaires et tissulaires
JP2000511511A (ja) * 1996-04-22 2000-09-05 ハエモペップ ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング 腫瘍成長阻害及び毛細管増殖のための生物学的活性タンパク質、コラーゲンフラグメントＨＦ―ＣＯＬＬ―１８／５１４ｃｆ
WO2000054801A1 (fr) * 1999-03-17 2000-09-21 Entremed, Inc. Compositions et procedes d'utilisation de ligands recepteurs du type ldl pour le traitement du cancer et de maladies angiogeniques
JP2002173446A (ja) * 2000-08-30 2002-06-21 Morisuke Yokoyama 健康食品等の飲食物・医薬品

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000511511A (ja) * 1996-04-22 2000-09-05 ハエモペップ ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング 腫瘍成長阻害及び毛細管増殖のための生物学的活性タンパク質、コラーゲンフラグメントＨＦ―ＣＯＬＬ―１８／５１４ｃｆ
WO1999049885A2 (fr) * 1998-03-27 1999-10-07 University Of Kansas Medical Center Utilisation de domaines isoles de collagene du type iv pour modifier des interactions cellulaires et tissulaires
WO2000054801A1 (fr) * 1999-03-17 2000-09-21 Entremed, Inc. Compositions et procedes d'utilisation de ligands recepteurs du type ldl pour le traitement du cancer et de maladies angiogeniques
JP2002173446A (ja) * 2000-08-30 2002-06-21 Morisuke Yokoyama 健康食品等の飲食物・医薬品

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10047388B2 (en) 2004-05-28 2018-08-14 Asuragen, Inc. Methods and compositions involving MicroRNA
US8765709B2 (en) 2004-11-12 2014-07-01 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
US8946177B2 (en) 2004-11-12 2015-02-03 Mima Therapeutics, Inc Methods and compositions involving miRNA and miRNA inhibitor molecules
US9447414B2 (en) 2004-11-12 2016-09-20 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
US9506061B2 (en) 2004-11-12 2016-11-29 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
US9080215B2 (en) 2007-09-14 2015-07-14 Asuragen, Inc. MicroRNAs differentially expressed in cervical cancer and uses thereof
US9365852B2 (en) 2008-05-08 2016-06-14 Mirna Therapeutics, Inc. Compositions and methods related to miRNA modulation of neovascularization or angiogenesis
US9644241B2 (en) 2011-09-13 2017-05-09 Interpace Diagnostics, Llc Methods and compositions involving miR-135B for distinguishing pancreatic cancer from benign pancreatic disease
US10655184B2 (en) 2011-09-13 2020-05-19 Interpace Diagnostics, Llc Methods and compositions involving miR-135b for distinguishing pancreatic cancer from benign pancreatic disease

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AU2003262277A1 (en) 2004-06-23

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