WO2011030847A1 - Composition inductrice pour cellules souches hématopoïétiques - Google Patents

Composition inductrice pour cellules souches hématopoïétiques Download PDF

Info

Publication number
WO2011030847A1
WO2011030847A1 PCT/JP2010/065594 JP2010065594W WO2011030847A1 WO 2011030847 A1 WO2011030847 A1 WO 2011030847A1 JP 2010065594 W JP2010065594 W JP 2010065594W WO 2011030847 A1 WO2011030847 A1 WO 2011030847A1
Authority
WO
WIPO (PCT)
Prior art keywords
hematopoietic stem
stem cell
stem cells
composition according
composition
Prior art date
Application number
PCT/JP2010/065594
Other languages
English (en)
Japanese (ja)
Inventor
丘司 長澤
立樹 杉山
芳樹 尾松
Original Assignee
国立大学法人京都大学
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 国立大学法人京都大学 filed Critical 国立大学法人京都大学
Publication of WO2011030847A1 publication Critical patent/WO2011030847A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the present invention relates to a hematopoietic stem cell inducer composition.
  • Hematopoietic stem cells used for hematopoietic stem cell transplantation are usually those collected from donor bone marrow or peripheral blood. Although hematopoietic stem cells can be obtained from preserved umbilical cord blood, transplantation to adults has problems of insufficient number of cells and delayed recovery of hematopoiesis.
  • the donor When hematopoietic stem cells are collected from the bone marrow of the donor, the donor needs to be hospitalized for 1 week to 10 days, is highly invasive, such as being collected under general anesthesia, and the amount of bone marrow fluid collected is large, This puts a heavy burden on the donor.
  • Peripheral blood contains very few hematopoietic stem cells, so when transplanting peripheral blood hematopoietic stem cells, a stem cell mobilizing agent is administered to the donor in advance, and hematopoietic stem cells are induced from the bone marrow into the peripheral blood, and peripheral blood is collected. Done.
  • a stem cell mobilizing agent granulocyte stimulating factor (G-CSF) has already been put into practical use (Non-patent Document 1), and plurixafor (development name: AMD3100, an inhibitor of chemokine receptor CXCR4).
  • Non-patent Document 2 Trade name MOZOBIL, Genzyme
  • Patent Document 1 N-acetylneuraminic acid sulfate, N-acetylneuraminic acid homopolymer sulfate or a pharmaceutically acceptable salt thereof (Patent Document 1) and placenta A constituent cell pulverized product (Patent Document 2) and the like have been proposed.
  • the stem cell mobilization agent is pre-administered at the time of peripheral blood hematopoietic stem cell transplantation, the number of hematopoietic stem cells may not be ensured sufficiently, or apheresis may need to be repeated many times to ensure a sufficient number of hematopoietic stem cells. It is desired to increase the number of hematopoietic stem cells that can be collected during hematopoietic stem cell transplantation.
  • Nuclear receptor PPAR ⁇ is expressed before fetal mesoderm induction, in addition to adipocytes and vascular endothelial cells, fetal liver and adult bone marrow blood progenitor cells, adult peripheral blood leukocytes, It has been reported that it is expressed in the cell stroma of bone marrow (Non-patent Document 4).
  • Thiazolidine compounds such as troglitazone, pioglitazone, rosiglitazone, and the like are known as agonists of PPAR ⁇ receptors. There are various reports on the action of such thiazolidine compounds on hematopoietic stem cells.
  • Non-Patent Document 5 reports that troglitazone stops proliferation of myeloid leukemia-derived cells and hematopoietic stem cells in vitro at the G1 phase and inhibits hematopoietic stem cell proliferation.
  • Non-patent document 6 shows that administration of rosiglitazone increases granulocyte monocyte colony-forming cells (CFU-GM) in mice after administration of anticancer agents, but the effect on the number of CFU-GM even when administered to normal mice Report no.
  • Non-patent document 7 describes the presence of pioglitazone in hematopoietic progenitor cells such as granulocyte monocyte colony forming cells (CFU-GM), eosinophil colony forming cells (CFU-E), and erythroblast precursor cells (BFU-E).
  • CFU-GM granulocyte monocyte colony forming cells
  • CFU-E eosinophil colony forming cells
  • BFU-E erythroblast precursor cells
  • Non-Patent Document 8 reports that administration of pioglitazone to a diabetic patient with coronary artery disease increases the number of vascular endothelial progenitor cells (CD34 + / Kinase insert domain receptor + ).
  • Non-Patent Document 9 reports that administration of pioglitazone to a type 2 diabetic patient increases CD34 positive cells (bone marrow-derived vascular endothelial progenitor cells) in peripheral blood. There is no unified view of the relationship between thiazolidine compounds and hematopoietic systems.
  • pioglitazone hydrochloride has already been used in the clinical setting for the treatment of diabetes as an insulin sensitizer (Patent Document 3 and Non-Patent Document 10). There is no report showing the effect of pioglitazone or a salt thereof on hematopoietic stem cells.
  • An object of the present invention is to provide a hematopoietic stem cell inducer.
  • the present invention provides a hematopoietic stem cell inducer for increasing the number of hematopoietic stem cells in a subject, comprising a thiazolidine compound having a nuclear receptor PPAR ⁇ agonist activity or a salt thereof as an active ingredient.
  • a thiazolidine compound having a nuclear receptor PPAR ⁇ agonist activity or salts thereof include pioglitazone, rosiglitazone, troglitazone and salts thereof, and particularly preferably include pioglitazone and salts thereof.
  • the hematopoietic stem cell inducer of the present invention is preferably used for induction of hematopoietic stem cells in donors of allogeneic hematopoietic stem cell transplantation or autologous hematopoietic stem cell transplantation.
  • Hematopoietic stem cell transplantation may be bone marrow transplantation or peripheral blood hematopoietic stem cell transplantation.
  • the hematopoietic stem cell inducing agent of the present invention is particularly suitable for peripheral blood hematopoietic stem cell transplantation in which it is difficult to secure the necessary number of cells. It is preferably used to increase the number of stem cells.
  • the hematopoietic stem cell inducer of the present invention When used for peripheral blood hematopoietic stem cell transplantation, it is preferable to use the hematopoietic stem cell inducer of the present invention in combination with a hematopoietic stem cell mobilizing agent.
  • the hematopoietic stem cell inducer of the present invention can also be used for the treatment of diseases accompanied by a decrease in hematopoietic stem cells.
  • the hematopoietic stem cell inducer of the present invention is further used for treatment of hematopoietic stem cell reduction in patients undergoing treatment in which hematopoietic stem cell reduction is induced, for example, patients undergoing chemotherapy or radiation therapy for cancer or autoimmune diseases.
  • treatment includes all management such as prevention, treatment, symptom reduction, symptom reduction, progression stoppage and the like.
  • the present invention also increases the number of hematopoietic stem cells in a subject, comprising administering an effective amount of a thiazolidine compound having a nuclear receptor PPAR ⁇ agonist activity or a salt thereof to a subject in need of increasing the number of hematopoietic stem cells. Provide a way to make it happen.
  • subjects that need to increase the number of hematopoietic stem cells include donors for allogeneic hematopoietic stem cell transplantation or autologous hematopoietic stem cell transplantation, and patients suffering from diseases associated with decreased hematopoietic stem cells and such Examples are patients who are highly likely to have a disease, patients undergoing chemotherapy for cancer or autoimmune disease, or cancer radiotherapy.
  • the present invention further relates to the use of a thiazolidine compound having a nuclear receptor PPAR ⁇ agonist activity or a salt thereof for producing a medicament for increasing the number of hematopoietic stem cells.
  • the number of hematopoietic stem cells in the bone marrow increases by administering the hematopoietic stem cell inducer composition of the present invention.
  • the number of hematopoietic stem cell inducer composition of the present invention can be increased at the time of peripheral blood hematopoietic stem cell transplantation. It becomes easy to secure a number of hematopoietic stem cells.
  • the hematopoietic stem cell inducer composition of the present invention is administered to a subject having a reduced number of hematopoietic stem cells or a subject in which a decrease in hematopoietic stem cells is predicted to increase hematopoietic stem cells generated in the bone marrow of the subject. be able to. By such an action, it is possible to effectively prevent or treat diseases accompanied by a decrease in hematopoietic stem cells.
  • HSC Hematopoietic stem cell
  • Example 2 The result of having analyzed HSC fraction of the peripheral blood injection of the mouse
  • Example 3 C shows a control, P shows the result of a pioglitazone administration group.
  • the hematopoietic stem cell inducer composition of the present invention contains a thiazolidine compound having a nuclear receptor PPAR ⁇ agonist activity or a salt thereof as an active ingredient.
  • thiazolidine compounds having agonist activity of the nuclear receptor PPAR ⁇ include compounds disclosed as “thiazolidinedione derivatives” or “insulin resistance improvers” in JP-A-5-70633 and JP-A-2000-355550, for example. Is done.
  • 5- [4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidinedione (generic name: pioglitazone); 5-[[4-[(3, 4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (generic name: troglitazone); 5 -[[4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione (generic name: rosiglitazone); 5- [3- [4- (5-methyl-2 -Phenyl-4-thiazolylmethoxy) phenyl] propyl] -2,4-oxazolidinedione; 5- [4- (6-meth
  • Salts of thiazolidine compounds include pharmacologically acceptable salts such as salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids.
  • pharmacologically acceptable salts such as salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids.
  • Preferable examples of salts with inorganic bases include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with aluminum and ammonium.
  • Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
  • the thiazolidine compound or a salt thereof is preferably pioglitazone, troglitazone, rosiglitazone or a salt thereof, more preferably pioglitazone or a hydrochloride thereof, troglitazone, rosiglitazone or a maleate thereof, particularly preferably pioglitazone.
  • the hydrochloride salt is preferably pioglitazone, troglitazone, rosiglitazone or a salt thereof, more preferably pioglitazone or a hydrochloride thereof, troglitazone, rosiglitazone or a maleate thereof, particularly preferably pioglitazone.
  • the hydrochloride salt is preferably pioglitazone, troglitazone, rosiglitazone or a salt thereof, more preferably pioglitazone or a hydrochloride thereof, troglitazone, rosiglitazone or a maleate thereof, particularly preferably pio
  • Examples of the dosage form of the hematopoietic stem cell inducer composition of the present invention include oral agents such as tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions, and films. Moreover, it can be administered as parenteral agents such as injections, external preparations (eg, transdermal preparations), suppositories, pellets, nasal preparations and the like. Oral preparations are more preferably used.
  • Such a pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the hematopoietic stem cell inducer composition of the present invention contains a pharmacologically acceptable carrier in addition to a thiazolidinedione derivative having a nuclear receptor PPAR ⁇ agonist activity or a pharmaceutically acceptable salt thereof.
  • a pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids It is formulated as an agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used. As such components, those described in general textbooks of pharmaceutics can be appropriately used depending on the purpose.
  • Pioglitazone hydrochloride which is a preferred active ingredient of the hematopoietic stem cell inducer composition of the present invention, is currently marketed as an insulin resistance improving drug (Actos (registered trademark) Takeda Pharmaceutical Co., Ltd.), but the hematopoietic stem cell of the present invention.
  • an insulin resistance improving drug Actos (registered trademark) Takeda Pharmaceutical Co., Ltd.
  • the inducer composition such a commercially available drug may be used.
  • hematopoietic stem cells are pluripotent cells that can differentiate into all blood cells.
  • the hematopoietic stem cell inducer composition of the present invention is suitably used for increasing the number of hematopoietic stem cells in a transplant donor in transplantation of hematopoietic stem cells.
  • the composition of the present application is suitably used for both allogeneic hematopoietic stem cell transplant donors and patients who are autologous hematopoietic stem cell transplant donors.
  • the term “hematopoietic stem cell transplant donor” or “donor” is used to include both allogeneic and autologous donors.
  • the dose and administration schedule of the hematopoietic stem cell inducer composition of the present invention are not limited, and may be appropriately set depending on the purpose of inducing hematopoietic stem cells and the age, weight, sex, etc. of the administration target.
  • administration to a hematopoietic stem cell transplant donor it may be appropriately set depending on the donor's age, weight, sex, general health status, bone marrow transplant or peripheral blood hematopoietic stem cell transplant, desired hematopoietic stem cell amount, and the like.
  • decisions should be made to meet the overall treatment plan.
  • the daily dose of pioglitazone or a salt thereof is 0.1-100 mg, preferably 1-50 mg, The dose is preferably administered once a day or in multiple doses so that the dose is 45 mg or less.
  • the administration period is not limited and may be determined as appropriate. For example, administration may be performed for 2 to 80 days.
  • the number of hematopoietic stem cells in the bone marrow increases by administering the hematopoietic stem cell inducer composition of the present invention to a bone marrow transplant or peripheral blood hematopoietic stem cell transplant donor.
  • the number of hematopoietic stem cells in the bone marrow increases, in the case of bone marrow transplantation, it is expected that the amount of bone marrow fluid collected from the donor can be reduced and the burden on the donor can be reduced.
  • the number of hematopoietic stem cells in peripheral blood can be increased by administering the hematopoietic stem cell inducer composition of the present invention and then administering the hematopoietic stem cell mobilizing agent.
  • hematopoietic stem cell mobilizing agent refers to a substance having an effect of mobilizing hematopoietic stem cells in bone marrow into peripheral blood.
  • Hematopoietic stem cell mobilization agents are not limited to known ones, and those that will be developed in the future as hematopoietic stem cell mobilization agents may be used in combination with the pharmaceutical composition of the present invention.
  • hematopoietic stem cell mobilizing agent granulocyte colony-stimulating factor (G-CSF), plerixafor hydrochloride, N-acetylneuraminic acid sulfate, N-acetylneuraminic acid homopolymer sulfate or pharmaceuticals thereof
  • G-CSF granulocyte colony-stimulating factor
  • plerixafor hydrochloride N-acetylneuraminic acid sulfate
  • N-acetylneuraminic acid homopolymer sulfate or pharmaceuticals thereof examples of such a salt are acceptable, (Patent Document 1), pulverized placenta-constituting cells (Patent Document 2) and the like, but are not limited thereto.
  • one or two or more hematopoietic stem cell mobilizing agents may be used in combination.
  • the dose and administration schedule of the hematopoietic stem cell mobilizing agent may be appropriately determined according to the age, weight, sex, general health status, desired hematopoietic stem cell amount, etc. of the donor.
  • G-CSF When G-CSF is used, it may be administered according to the current clinical protocol. As a typical example, about 10 ⁇ g / kg / day of G-SCF per donor body weight is divided into once or twice a day. Subcutaneous administration may be continued every day for 4 to 6 days, and then peripheral blood may be collected.
  • the dose and administration period of G-CSF may be lower than those currently used in clinical practice as hematopoietic stem cells increase with the hematopoietic stem cell inducer of the present invention.
  • prelixaphor or other hematopoietic stem cell mobilizing agent it may be adjusted based on the known usage and dose of each hematopoietic stem cell mobilizing agent.
  • any known method may be employed for collecting hematopoietic stem cells from a donor.
  • bone marrow transplantation bone marrow fluid is collected from a donor and, if necessary, the one from which impurities are removed with a mesh or filter is used for transplantation. If necessary, red blood cells or plasma components may be removed from the bone marrow fluid.
  • contamination with cancer cells or the like is predicted, such as in autologous transplantation, it is preferable to remove the cancer cells or transplant after further purifying the hematopoietic stem cell fraction with a surface marker or the like.
  • CD34 As a surface marker that can be used for purification of hematopoietic stem cells, CD34 is exemplified, and it is known that hematopoietic stem cells are CD34 positive. Other markers may be used as long as hematopoietic stem cells can be purified.
  • peripheral blood from a donor is subjected to extracorporeal circulation (apheresis) using a continuous blood component separation device to isolate a mononuclear cell fraction in the peripheral blood, and the remaining blood is returned to the donor.
  • the isolated mononuclear cell fraction may be further purified as necessary.
  • any of the conventionally known methods may be adopted, but for example, purification may be performed based on a surface marker such as CD34.
  • purification may be performed based on a surface marker such as CD34.
  • known means such as a flow cytometer, an immunomagnetic bead method using an anti-CD34 antibody, and an immune avidin bead method may be used.
  • the hematopoietic stem cells obtained from a donor using the composition of the present invention are suitably used for treatment of various diseases that can be treated by hematopoietic stem cell transplantation.
  • diseases include, but are not limited to, non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, acute myeloid leukemia, neuroblastoma, rhabdomyosarcoma, brain tumor ( Autologous diseases such as collagenous disease, and so on. Examples thereof include amyloidosis.
  • Diseases for which allogeneic hematopoietic stem cell transplantation is effective include acute myeloid leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, multiple myeloma, chronic myelogenous leukemia, chronic lymphocytic leukemia, kidney Malignant tumors such as cell cancer, pancreatic cancer, colon cancer, breast cancer and aplastic anemia, paroxysmal nocturnal hemoglobinuria, severe combined immunodeficiency, Fanconi anemia, Diamond-Blackfan anemia, sickle cell disease, Wiskott-Aldrich syndrome Examples include marble bone disease, inborn metabolic diseases and autoimmune diseases.
  • the composition of the present invention is also useful for the treatment of diseases accompanied by a decrease in hematopoietic stem cells.
  • Diseases with decreased hematopoietic stem cells include chronic inflammation, malignant tumor, severe infection, autoimmune disease, diabetes, sickle cell disease, uremia, myelodysplastic syndrome, Fanconi anemia, aplastic anemia, chronic liver injury And renal failure, myelopathic thrombocytopenia, idiopathic thrombocytopenic purpura and the like.
  • the compositions of the present invention are further usefully used to increase the number of hematopoietic stem cells in the bone marrow of patients undergoing cancer chemotherapy, cancer radiotherapy, autoimmune disease chemotherapy, or autoimmune disease radiation therapy. It is done.
  • the dosage of the hematopoietic stem cell inducer composition of the present invention is not limited, and may be appropriately set depending on the age, weight, sex, etc. of the administration subject.
  • the daily dose of pioglitazone or a salt thereof is 0.1 to 100 mg, preferably 1 to 50 mg, more preferably 45 mg or less. Dosage once to several times a day.
  • mice Hematopoietic stem cell inducing ability of pioglitazone hydrochloride 15-25 week old mice were used. Feed was prepared by mixing pioglitazone hydrochloride (Takeda Pharmaceutical Co., Ltd.) into a standard chow for mice for 0.7 mg / g solid feed for 8 weeks. The control group was fed the same chow diet except that it did not contain pioglitazone hydrochloride. Four mice were used for each group.
  • the mice were killed and bone marrow cells were washed out from the femur and tibia to obtain a bone marrow single cell suspension.
  • the resulting bone marrow cell suspension is known as CD45, CD3 ⁇ , B220, c-Kit, CD48, Gr-1, CD11b, CD34, CD150, Sca-1, Ter119, Lin, C03, C011b, Br-1 antibodies. Staining was performed by the method (M. Osawa et al., Science 273, 242 (1996)).
  • the obtained cells were analyzed by flow cytometry (BD FACSAria (BD Biosystems)), and CD34 ( ⁇ ) CD48 ( ⁇ ) c-Kit (+) Sca-1 (+) Lin ( ⁇ ) cells in bone marrow cells.
  • the fraction fraction was measured. It is known that about 40% of this cell fraction is hematopoietic stem cells (HSC) in mice.
  • HSC hematopoietic stem cells
  • the antibodies used are as follows: CD45 (30-F11), CD3 ⁇ (145-2C11), B220 (RA3-6B2), c-Kit (2B8), CD48 (HM48-1), Gr-1 (RB6-8C5), CD11b (M1 / 70) CD34 (RAM34), CD150 (TC15-12F12.2), Sca-1 (E13-1617.7, D7), Ter119 (Ter119)
  • the number of hematopoietic stem cells in the bone marrow was significantly increased in the mice administered with the composition of the present invention compared to the control mice.
  • Hematopoietic stem cells were induced into peripheral blood using pioglitazone hydrochloride and G-CSF. 15-25 week old mice were used.
  • a feed containing pioglitazone hydrochloride was administered for 8 weeks. Thereafter, the mice were fed with food containing no pioglitazone hydrochloride, and G-CSF was subcutaneously administered once a day for 5 days at 100 ng / g / day.
  • Control mice were fed a diet containing no pioglitazone hydrochloride for 8 weeks, and then G-CSF was administered according to the same protocol as in the test group.
  • mice peripheral blood was collected, and a mononuclear cell fraction was obtained by hemolysis. This was stained in the same manner as in Example 1, and hematopoietic stem cell fraction CD34 was obtained by flow cytometry. The proportion of ( ⁇ ) CD48 ( ⁇ ) c-Kit (+) Sca-1 (+) Lin ( ⁇ ) cells was examined. Three mice were used for each group. The results are shown in FIG.
  • the hematopoietic stem cell fraction in the peripheral blood of mice administered with pioglitazone hydrochloride increased compared to the control group.
  • Hematopoietic stem cell induction into peripheral blood was performed using pioglitazone hydrochloride and AMD3100 (prerixafor). 15-25 week old mice were used.
  • a feed containing pioglitazone hydrochloride was administered for 8 weeks. Thereafter, the feeding to the mice was changed to one containing no pioglitazone hydrochloride, and 5 mg / kg of AMD3100 was subcutaneously administered.
  • Control mice were fed a diet containing no pioglitazone hydrochloride for 8 weeks and then administered AMD3100 in the same protocol as the test group.
  • One hour after administration of AMD3100 mouse peripheral blood was collected, and a mononuclear cell fraction was obtained by hemolysis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition inductrice pour cellules souches hématopoïétiques, qui contient un composé thiazolidine ou ses sels avec une activité agoniste du récepteur nucléaire PPARγ, et qui sert à accroître le nombre des cellules souches hématopoïétiques chez un sujet. Ladite composition inductrice pour cellules souches hématopoïétiques peut accroître le nombre des cellules souches hématopoïétiques pour une greffe de moelle osseuse, et augmente également le nombre des cellules souches hématopoïétiques du sang périphérique en combinaison avec un mobilisateur de cellules souches hématopoïétiques. Ladite composition inductrice pour cellules souches hématopoïétiques est utile pour augmenter le nombre des cellules souches hématopoïétiques d'un donneur de cellules souches hématopoïétiques, et peut être utilisée pour tout donneur de greffe de cellules souches hématopoïétiques autologues et de greffe de cellules souches hématopoïétiques allogènes. En outre, la composition inductrice pour cellules souches hématopoïétiques est également utile dans le traitement d'états associés à une diminution des cellules souches hématopoïétiques et le traitement de patients soumis à une chimiothérapie ou à une radiothérapie.
PCT/JP2010/065594 2009-09-10 2010-09-10 Composition inductrice pour cellules souches hématopoïétiques WO2011030847A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009-209437 2009-09-10
JP2009209437 2009-09-10

Publications (1)

Publication Number Publication Date
WO2011030847A1 true WO2011030847A1 (fr) 2011-03-17

Family

ID=43732515

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/065594 WO2011030847A1 (fr) 2009-09-10 2010-09-10 Composition inductrice pour cellules souches hématopoïétiques

Country Status (1)

Country Link
WO (1) WO2011030847A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016040313A3 (fr) * 2014-09-08 2016-06-02 Dana-Farber Cancer Institute, Inc. Méthodes de traitement du cancer
US11116819B2 (en) 2013-02-28 2021-09-14 President And Fellows Of Harvard College Methods and compositions for mobilizing stem cells

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006104177A (ja) * 2004-10-08 2006-04-20 Takashi Shioda 末梢血中に、造血幹細胞を動員するための肝細胞増殖因子（ｈｇｆ）の使用と、この使用を目的とした医薬品

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006104177A (ja) * 2004-10-08 2006-04-20 Takashi Shioda 末梢血中に、造血幹細胞を動員するための肝細胞増殖因子（ｈｇｆ）の使用と、この使用を目的とした医薬品

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BENKO, I. ET AL.: "Rosiglitazone-induced protection against myelotoxicity produced by 5-fluorouracil", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 477, 2003, pages 179 - 182 *
DJAZAYERI, K. ET AL.: "Accelerated recovery of 5-fluorouracil-damaged bone marrow after rosiglitazone treatment", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 522, no. 1-3, 17 October 2005 (2005-10-17), pages 122 - 129, XP005116975 *
ERIKO NAGASAWA ET AL.: "Dai 66 Kai The Japanese Society of Hematology Sokai - Dai 46 Kai", THE JAPANESE SOCIETY OF CLINICAL HEMATOLOGY SOKAI DOJIKI KAISAI PROGRAM SHOROKUSHU, 2004, pages 348 *
ERIKO NAGASAWA ET AL.: "Dai 68 Kai The Japanese Society of Hematology - Dai 48 Kai", THE JAPANESE SOCIETY OF CLINICAL HEMATOLOGY GODO SOKAI PROGRAM SHOROKUSHU, 2006, pages 251 *
GREINIX H T, WOREL N: "New agents for mobilizing peripheral blood stem cells", TRANSFUSION AND APHERESIS SCIENCE, vol. 41, no. 1, August 2009 (2009-08-01), pages 67 - 71, XP026395931 *
SAIKI, M. ET AL.: "Pioglitazone inhibits the growth of human leukemia cell lines and primary leukemia cells while sparing normal hematopoietic stem cells", INTERNATIONAL JOURNAL OF ONCOLOGY, vol. 29, no. 2, August 2006 (2006-08-01), pages 437 - 443 *
TAKAKO SUGISAWA ET AL.: "Pioglitazone no Masshoketsu CD34 Yosei Saibosu ni Oyobosu Koka no Kento", DAI 50 KAI JAPAN DIABETES SOCIETY NENJI GAKUJUTSU SHUKAI YOKOSHU, 2007, pages S-254 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11116819B2 (en) 2013-02-28 2021-09-14 President And Fellows Of Harvard College Methods and compositions for mobilizing stem cells
WO2016040313A3 (fr) * 2014-09-08 2016-06-02 Dana-Farber Cancer Institute, Inc. Méthodes de traitement du cancer

Similar Documents

Publication Publication Date Title
JP6215394B2 (ja) エクスビボ培養されたナチュラルキラー細胞の集団
Andrews et al. Multiple myeloma: the bone marrow microenvironment and its relation to treatment
JP4481828B2 (ja) 骨髄異形成症候群を治療および管理するための免疫調節化合物の使用方法およびそれを含む組成物
JP5199253B2 (ja) カテコールアミン受容体の調節
RU2536242C2 (ru) Угнетение опухолей с помощью плацентарного перфузата человека и выделенных из плаценты человека вспомогательных натуральных клеток-киллеров
US8075921B2 (en) Rapamycin-resistant T cells and therapeutic uses thereof
JP2011207906A (ja) 異常ヘモグロビン症及び貧血症の治療及び管理のための方法及び組成物
MX2009001272A (es) Terapia de combinacion.
KR20110127111A (ko) 중간엽 줄기 세포의 용도
KR20170042598A (ko) 항체와 조합된 면역조절 화합물을 이용하여 다발성 골수종을 치료하는 방법
WO2017042944A1 (fr) Agent thérapeutique ou méthode de traitement pour la leucémie lymphoïde aiguë (lla) à chromosome philadelphie positif (ph+)
KR20210072039A (ko) 면역절제 요법
KR20170106980A (ko) 이식 후에 조혈 줄기 세포의 생착 효능을 증가시키는데 사용하기 위한 조성물
AU2017300738A1 (en) Combination of a BCL-2 inhibitor and a MCL-1 inhibitor, uses and pharmaceutical compositions thereof
JP2017527572A (ja) 造血幹細胞医療において有用な方法および化合物
KR20050093759A (ko) 혈소판 및 조혈 줄기세포의 생산을 증가시키는 방법
CN115282165A (zh) 来自胎盘的自然杀伤细胞
JP2024088717A (ja) 治療に使用する細胞組成物を生成するためのガンマ・デルタｔ細胞のホーミング及び保持の方法
WO2011030847A1 (fr) Composition inductrice pour cellules souches hématopoïétiques
US20230172984A1 (en) CLEARANCE OF SENESCENT CELLS BY ACTIVATION OF iNKT CELLS
EP3302710A1 (fr) Agents mobilisateurs et leurs utilisations
WO2020092650A1 (fr) Compositions et méthodes pour inhiber l'épuisement des lymphocytes t
US20200306302A1 (en) Treating and inhibiting leukemia with nk-92 cells
JP2020520237A (ja) 移植に適した臍帯細胞画分の選択と使用
EP2946008A1 (fr) Méthodes de mobilisation de cellules souches hématopoïétiques

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10815441

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10815441

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP