WO2017209272A1 - Inhibiteur de métastases cancéreuses - Google Patents

Inhibiteur de métastases cancéreuses Download PDF

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WO2017209272A1
WO2017209272A1 PCT/JP2017/020569 JP2017020569W WO2017209272A1 WO 2017209272 A1 WO2017209272 A1 WO 2017209272A1 JP 2017020569 W JP2017020569 W JP 2017020569W WO 2017209272 A1 WO2017209272 A1 WO 2017209272A1
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phenyl
indol
cis
cancer
acetic acid
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PCT/JP2017/020569
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Japanese (ja)
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幸久 村田
小林　幸司
啓介 大森
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国立大学法人東京大学
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Definitions

  • the present invention relates to a cancer metastasis inhibitor.
  • cancer development and blood circulation are also observed in healthy subjects, but in normal subjects, normal inflammatory activity by the immune system is suppressed, and carcinogenesis and metastasis do not occur.
  • cancer patients cannot suppress carcinogenesis or metastasis because a mechanism for suppressing immunity against foreign substances (“immunity checkpoint”) works to reduce the inflammatory response to cancer.
  • immuno checkpoint a mechanism for suppressing immunity against foreign substances
  • malignant transformation of cancer depends largely on “reduction of inflammatory activity of host”, and in order to suppress it, the existence and mechanism of the above mechanism that regulates inflammatory activity of host against cancer is clarified, It needs to be applied to treatment.
  • Prostaglandin D 2 (PGD 2 ), one of the lipid mediators, is produced by PGD synthase (PGDS) that catalyzes the isomerization of PGH 2 to PGD 2 which is a common intermediate of PGs.
  • PGD synthase PGD synthase
  • Non-patent Document 1 PGD 2 produced by each enzyme acts on two types of receptors, DP (D prostanoid receptor) and CRTH2 (Chemoattractant receptor-homologous molecule on Th2 cells)
  • DP D prostanoid receptor
  • CRTH2 Cellular receptor-homologous molecule on Th2 cells
  • Non-Patent Documents 2 to 4 Non-Patent Documents 2 to 4.
  • the present inventor has focused on the pathophysiological action of prostaglandin D 2 (PGD 2 ), one of the lipid mediators, and has proved that PGD 2 is a powerful anti-inflammatory substance. While many other PGs promote inflammation, the inhibitory action of PGD 2 is very unique.
  • PGD 2 prostaglandin D 2
  • the present inventor has in subsequent studies, mice deficient or PGD 2 synthase or PGD 2 receptors, by administration of the inhibitor of PGD 2 synthase or PGD 2 receptor, the cancer metastasis is inhibited strongly I found
  • the present invention provides the following.
  • a cancer metastasis or recurrence inhibitor comprising a CRTH2 inhibitor as an active ingredient.
  • a cancer metastasis or recurrence inhibitor comprising a hematopoietic prostaglandin D synthase inhibitor as an active ingredient.
  • a cancer therapeutic agent comprising the cancer metastasis or recurrence inhibitor according to [1] or [2].
  • the cancer therapeutic agent according to [3] further comprising an anticancer agent.
  • a hematopoietic prostaglandin D synthase inhibitor for use in suppressing cancer metastasis or recurrence [7] A cancer therapeutic agent comprising the CRTH2 inhibitor according to [5] or the hematopoietic prostaglandin D synthase inhibitor according to [6]. [8] The cancer therapeutic agent according to [7], further comprising an anticancer agent. [9] Use of a CRTH2 inhibitor in the manufacture of a cancer metastasis or recurrence inhibitor. [10] Use of a CRTH2 inhibitor in the manufacture of a cancer therapeutic agent. [11] The use according to [10], wherein the cancer therapeutic agent further contains an anticancer agent.
  • [12] Use of a hematopoietic prostaglandin D synthase inhibitor in the manufacture of a cancer metastasis or recurrence inhibitor.
  • [13] Use of a hematopoietic prostaglandin D synthase inhibitor in the manufacture of a cancer therapeutic agent.
  • the cancer therapeutic agent further contains an anticancer agent.
  • a method for treating cancer comprising administering an effective amount of a CRTH2 inhibitor to a subject in need thereof.
  • the cancer treatment is prevention of metastasis or recurrence of cancer, or suppression of growth of metastasis cancer or recurrence cancer.
  • a method for treating cancer comprising administering an effective amount of a hematopoietic prostaglandin D synthase inhibitor to a subject in need thereof.
  • the cancer treatment is prevention of metastasis or recurrence of cancer, or suppression of growth of metastasis cancer or recurrence cancer.
  • the method of [18] comprising administering the hematopoietic prostaglandin D synthase inhibitor and an anticancer agent.
  • a method for selecting a cancer therapeutic agent Administering a test substance to cells expressing CRTH2, and measuring the inhibitory action of the test substance on CRTH2 activation by prostaglandin D 2 ; Including the method.
  • a method for selecting a cancer therapeutic agent Administering a test substance to cells expressing hematopoietic prostaglandin D synthase; and measuring the expression or activity inhibitory action of hematopoietic prostaglandin D synthase; Including the method.
  • the CRTH2 inhibitor is an anti-CRTH2 antibody and at least one selected from the group consisting of compounds shown in the following (1) to (119) and pharmaceutically acceptable salts thereof: is there.
  • the hematopoietic prostaglandin D synthase inhibitor is at least one selected from the group consisting of antibodies to HQL-79, TFC-007, and hematopoietic prostaglandin D synthase. is there.
  • the H-PGDS inhibitor and CRTH2 inhibitor of the present invention can suppress cancer metastasis or recurrence and treat cancer.
  • H-PGDS inhibitor HQL-79 suppresses cancer metastasis.
  • the figure shows the number of metastatic cancer colonies in the lung.
  • CMC solvent (CMC) administration group
  • HQL HQL-79 administration group.
  • the figure shows the number of metastatic cancer colonies in the lung.
  • WT Wild type, CRTH2-/-: CRTH2 gene-deficient mouse. Cytokine expression levels in mice.
  • Flow cytometry of CD45 positive IFN- ⁇ producing cells Promotion of cancer metastasis by administration of anti-Gr-1 antibody.
  • Hematopoietic prostaglandin D synthase is one of prostaglandin D 2 (PGD 2 ) synthases and catalyzes isomerization of PGH 2 to PGD 2 . It has been suggested that PGD 2 synthesized by H-PGDS is closely involved in the development of allergic reactions.
  • the monomer structure is an N-terminal domain composed of 4 ⁇ -strands and 3 ⁇ -helices, and a C composed of 5 ⁇ -helices. It consists of two domains of the terminal domain, and the overall structure is similar to that of other GSTs, but it has been reported that the orientation of the side chain of Trp104 involved in activity has characteristics not found in other GST structures. (Cell, 90, pp.1085-1095, 1997).
  • CRTH2 (Chemoattractant receptor-homologous molecule on Th2 cells) is one of the receptors for PGD 2 and is also referred to as DP2 or GPR44. CRTH2 is classified as a receptor (GPCR) coupled to a Gi-type G protein, and its activation reduces the concentration of intracellular cAMP. CRTH2 is highly expressed in immune cells such as T cells, and it has been reported that these cells mediate the chemotaxis of PGD 2 to these cells. The PGD2-CRTH2 signal is thought to play an important role in allergic inflammation.
  • cancer means that cancer cells migrate to lymph nodes and other organs and proliferate there.
  • currence of cancer includes the case where the cancer reappears at the same site after the cancer has been removed from the living body and a certain period of time has elapsed, and the case where the cancer has metastasized.
  • Metalstatic cancer refers to cancer that has metastasized or is likely to have metastasized.
  • the type of “cancer” targeted by the present invention is not particularly limited, and examples include lung cancer, prostate cancer, pancreatic cancer, biliary tract cancer, breast cancer, melanoma, and preferably lung cancer.
  • the “cancer” targeted by the present invention may be primary cancer, metastatic cancer, or recurrent cancer.
  • H-PGDS or CRTH2 suppressed tumor metastasis.
  • Involvement of interferon ⁇ was found in the tumor metastasis suppressing effect by inhibiting H-PGDS or CRTH2 (see Examples described later).
  • These include tumor metastasis suppression mechanism via H-PGDS-PGD 2 -CRTH2 pathway, enhancement of cellular immunity (Th1 type) in the body, and cellular immunity (Th1 type) and humoral immunity (Th2 type) This suggests that it is based on the improvement of balance.
  • PGD 2 was produced in response to cancer metastasis stimuli and was found to be promising as a new molecule that regulates host inflammation and immune activity against cancer.
  • This discovery leads to the development of anti-metastatic or metastatic inhibitors that inhibit PGD 2 production and signal inhibition.
  • metastasis of cancer cells and micro cancer can be suppressed by controlling microenvironmental cells existing around the cancer cells by the H-PGDS inhibitor and the CRTH2 inhibitor.
  • the anticancer effect of the anticancer agent is enhanced by using these H-PGDS inhibitor and CRTH2 inhibitor in combination with a known anticancer agent. Inhibition of H-PGDS-CRTH2 signaling is thought to be particularly effective for metastatic cancer.
  • the present invention provides a cancer metastasis or recurrence inhibitor.
  • the cancer metastasis or recurrence inhibitor of the present invention contains a CRTH2 inhibitor as an active ingredient.
  • the cancer metastasis or recurrence inhibitor of the present invention contains an H-PGDS inhibitor as an active ingredient.
  • the present invention also provides use of a CRTH2 inhibitor or an H-PGDS inhibitor in the manufacture of a cancer metastasis or recurrence inhibitor.
  • the present invention also provides a CRTH2 inhibitor or an H-PGDS inhibitor for use in suppressing cancer metastasis or recurrence.
  • CRTH2 inhibitors include ramatroban, CAY10471, and Japanese Patent No. 4313819, Japanese Patent No. 5629403, Japanese Translation of PCT International Publication No. 2009-515191, Japanese Patent Publication No. 2009-533473, Japanese Patent No. 5278318, Japanese Patent Publication of Special Publication 2009. Examples thereof include compounds described in any one of -544721 and JP-A-2014-507449. All of the disclosures of each of the above patent documents, including compounds described as general formulas or specifically disclosed compounds, are hereby incorporated by reference.
  • CRTH2 inhibitors include the following compounds: (1) Ramatroban ((+)-(3R) -3-[[(4-fluorophenyl) sulfonyl] amino] -1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid, CAS 16649-85 -5); (2) 4- (3- ⁇ 3- [3- (diphenylmethyl) -6-oxopyridazin-1 (6H) -yl] propyl ⁇ phenoxy) butanoic acid; (3) 1- ⁇ 6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methyl-pyrimidin-4-yl ⁇ -pyrrolidine-3-carboxylic acid; (4) 2- (1- ⁇ 2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl ⁇ -piperidin-3-yl
  • the CRTH2 inhibitor exemplified above may be a free form compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • a pure form of a stereoisomer such as an enantiomer or diastereomer of the compound, a racemate or a mixture of any stereoisomers is used in the present invention. It can be used as a CRTH2 inhibitor.
  • CRTH2 inhibitors include antibodies against CRTH2 (anti-CRTH2 antibodies).
  • siRNA for CRTH2 mRNA is an example of a CRTH2 inhibitor.
  • the CRTH2 inhibitors exemplified above can be used alone or in combination of any two or more thereof.
  • the CRTH2 inhibitor used in the present invention is one or more selected from the group consisting of an anti-CRTH2 antibody and the compounds shown in the above (1) to (119) and pharmaceutically acceptable salts thereof. It is.
  • the CRTH2 inhibitors used in the present invention are not limited to those exemplified above.
  • CRTH2 inhibitors can be used.
  • the compounds represented by the above (1) to (119) can be obtained from Cayman Chemical, LKT Laboratories, Inc. Etc. can be purchased.
  • H-PGDS inhibitor for example, a tetrazole derivative represented by the general formula (1) described in JP-A-7-70112 can be used.
  • preferred H-PGDS inhibitors include HQL-79 (Japanese Patent Laid-Open No. 9-70112, 1- [3- (1H-tetrazol-5-yl) propyl] -4- (benzhydryloxy) piperidine) And TFC-007 (N- (4- (4- (morpholin-4-carbonyl) piperidin-1-yl) phenyl) -2-phenoxypyrimidine-5-carboxamide).
  • further H-PGDS inhibitors include BSPT, CBB, and PGD-042 described in Fig.
  • H-PGDS specific inhibitors for H-PGDS include, for example, International Publication WO2005 / 094805, International Publication WO2007 / 041634, International Publication WO2007 / 007778, JP2007-0511121A, International Publication WO2008 / 075172, International Publication WO2008 / 104869, International Publication WO2008 / 121670, International Publication WO2008 / 122787, International Publication WO2009 / 153720, International Publication WO2009 / 153721, International Publication WO2010 / 033777, International Publication WO2010 / 104024, and the like.
  • a compound described as a general formula or a specifically disclosed compound may be used. All of the disclosures of each of the above patent documents, including compounds described as general formulas or specifically disclosed compounds, are hereby incorporated by reference.
  • the H-PGDS inhibitor exemplified above may be a free form compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • a pure form of a stereoisomer such as an enantiomer or diastereomer of the compound, a racemate or a mixture of any stereoisomers is used in the present invention. It can be used as an H-PGDS inhibitor.
  • H-PGDS inhibitors include antibodies against hematopoietic prostaglandin D synthase (anti-H-PGDS antibodies).
  • anti-H-PGDS antibodies antibodies against hematopoietic prostaglandin D synthase
  • siRNA for H-PGDS mRNA is an example of an H-PGDS inhibitor.
  • the H-PGDS inhibitors exemplified above can be used either alone or in combination of any two or more.
  • the H-PGDS inhibitor used in the present invention is at least one selected from the group consisting of HQL-79, TFC-007, and anti-H-PGDS antibody.
  • the H-PGDS inhibitors used in the present invention are not limited to those exemplified above.
  • H-PGDS inhibitor A commercially available H-PGDS inhibitor can be used.
  • HQL-79 can be purchased from Cayman Chemical or the like.
  • the CRTH2 inhibitor or H-PGDS inhibitor which is an active ingredient of the cancer metastasis or recurrence inhibitor of the present invention, is a cancer metastasis in a patient who is receiving or undergoing cancer treatment. Or it can be used to prevent recurrence.
  • the CRTH2 inhibitor or H-PGDS inhibitor should be used to prevent cancer metastasis or recurrence in patients after undergoing surgery, radiation therapy or chemotherapy for cancer treatment. Can do.
  • the CRTH2 inhibitor or H-PGDS inhibitor can be used for cancer patients undergoing radiation therapy or chemotherapy.
  • the CRTH2 inhibitor or H-PGDS inhibitor may be administered to a patient having primary cancer and used to prevent metastasis or recurrence of the primary cancer. It may be used to administer to patients with carcinogenesis and suppress their growth or metastasis.
  • the present invention also provides a cancer therapeutic agent containing the cancer metastasis or recurrence inhibitor of the present invention.
  • the cancer therapeutic agent of the present invention contains the above-described CRTH2 inhibitor or H-PGDS inhibitor as an active ingredient.
  • the cancer therapeutic agent of the present invention may be used in combination with radiation therapy or other chemotherapy.
  • the cancer therapeutic agent of the present invention may further contain an anticancer agent.
  • an anticancer agent As an example of the said anticancer agent, a well-known anticancer agent can be mentioned without being specifically limited.
  • the type of anticancer agent to be combined can be appropriately selected by those skilled in the art according to the type of cancer to be applied and the patient's condition.
  • the cancer metastasis or recurrence inhibitor of the present invention and a cancer therapeutic agent comprise the above-mentioned CRTH2 inhibitor or H-PGDS inhibitor as an active ingredient.
  • a cancer therapeutic agent hereinafter collectively referred to as the pharmaceutical of the present invention
  • it may be a pharmaceutical composition containing the above-mentioned CRTH2 inhibitor or H-PGDS inhibitor together with other components.
  • the administration form of the medicament of the present invention may be either oral administration or parenteral administration.
  • the pharmaceutical dosage form is not particularly limited as long as it can be administered orally or parenterally.
  • Examples of the dosage form for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups.
  • Examples of dosage forms for parenteral administration include injection. Agents, drops, suppositories, inhalants, eye drops, nasal drops, and the like, but are not limited thereto.
  • the medicament of the present invention can be produced according to a method well known to those skilled in the art.
  • the active ingredient CRTH2 inhibitor or H-PGDS inhibitor can be prepared according to a conventional method by appropriately combining with a pharmaceutically acceptable carrier, other active ingredients, etc.
  • pharmaceutically acceptable carriers include, for example, excipients, disintegrants or disintegrants, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilizers, Examples include, but are not limited to, isotonic agents, pH adjusters, stabilizers, propellants, and adhesives.
  • Other active ingredients include, but are not limited to, the anticancer agents described above.
  • the dosage of the pharmaceutical agent of the present invention is not particularly limited, and various factors that should normally be taken into consideration, such as patient weight, age or condition, type of disease, purpose of prevention or treatment, type of active ingredient, route of administration, administration schedule, etc. It can be determined appropriately by those skilled in the art.
  • the pharmaceutical of the present invention can be used in the range of about 0.01 to 1,000 mg per day for an adult, and the dosage can be appropriately selected by those skilled in the art. It is not limited to.
  • Examples of the administration target of the medicament of the present invention include humans and non-human mammals, preferably humans. These administration subjects can be cancer patients and those with a history of cancer, and more preferably those who need metastasis or recurrence suppression of cancer. Examples of such persons include surgery after cancer treatment, patients after receiving radiation therapy or chemotherapy, cancer patients receiving radiation therapy or chemotherapy, and the like.
  • the cancer may be primary cancer, metastatic cancer, or recurrent cancer.
  • the present invention provides a method for treating cancer, comprising inhibiting the activity of CRTH2 or H-PGDS in a subject in need thereof.
  • the treatment of cancer in the method of the present invention includes prevention of metastasis or recurrence of cancer and suppression of growth of metastasis or recurrence cancer.
  • examples of means for inhibiting the activity of CRTH2 or H-PGDS in a subject include administration of the above-mentioned CRTH2 inhibitor or H-PGDS inhibitor to the subject.
  • the present invention provides a method for treating cancer comprising administering to a subject in need thereof an effective amount of a medicament of the present invention.
  • the medicament of the present invention administered by the cancer treatment method of the present invention may be the above-mentioned CRTH2 inhibitor or H-PGDS inhibitor itself, but contains the CRTH2 inhibitor or H-PGDS inhibitor. It may be a pharmaceutical composition.
  • administration of the medicament of the present invention can be used in combination with radiation therapy or other chemotherapy.
  • the cancer treatment method of the present invention may comprise administering the CRTH2 inhibitor or H-PGDS inhibitor and an anticancer agent. Examples of usable anticancer agents are as described above.
  • the effective amount of the medicament of the present invention can be appropriately determined by those skilled in the art according to various factors that should be normally considered.
  • the present invention provides a method for selecting a cancer therapeutic agent using as an index the inhibitory action of CRTH2 activation or the inhibitory action of H-PGDS expression or activity.
  • the method for selecting a cancer therapeutic agent of the present invention comprises administering a test substance to cells expressing CRTH2, and measuring the inhibitory effect of the test substance on CRTH2 activation by PGD 2. including.
  • the method for selecting a cancer therapeutic agent of the present invention comprises administering a test substance to a cell that expresses H-PGDS, and inhibiting the expression or activity of the test substance by H-PGDS. Measuring.
  • the method may be an in vivo method or an in vitro method.
  • Examples of cells that express CRTH2 include Th2 cells and immune cells such as eosinophils and basophils.
  • Examples of cells that express H-PGDS include mast cells, dendritic cells, macrophages, and epithelial cells.
  • the kind of the test substance is not particularly limited, and may be a natural product or a synthetic product, and may be a single substance, a composition or a mixture.
  • the mode of administration of the test substance to the cells can be any form depending on the test substance and the type of cell to which it is administered.
  • the test substance may be added to the medium in which the cells are cultured, or the test substance may be applied directly to the cultured cells.
  • the test substance may be administered to the living body of an animal having CRTH2 or H-PGDS expressing cells.
  • Examples of a method for detecting CRTH2 activation by PGD 2 in cells include evaluation of signal activity using cells. For example, there is a method for detecting a decrease in intracellular cAMP concentration caused by the activity of Gi-type GPCR.
  • Examples of methods for detecting H-PGDS expression in cells include conventional PCR methods, in situ hybridization, tissue immunostaining using antibodies, FACS (fluorescence activated cell sorting), and the like.
  • Examples of the method for detecting the activity of H-PGDS include a method for measuring the production amount of PGD 2 and its metabolites, and a method for evaluating the conversion efficiency of PGH 2 as a substrate of PGD 2 using a label. .
  • the inhibitory action of the CRTH2 activation by the test substance is measured.
  • the inhibitory action of the H-PGDS expression or activity by the test substance is measured.
  • the measurement is performed by comparison with a control.
  • CRTH2 activation or H-PGDS expression or activity by PGD 2 is detected in the same procedure as described above in CRTH2 or H-PGDS expression cells (control cells) not administered with the test substance.
  • the test substance is measured for CRTH2 activation, or inhibition of H-PGDS expression or activity.
  • the test substance when the detection value for CRTH2 activity or H-PGDS expression or activity in a cell administered with a test substance is lower than that of a control cell, the test substance exhibits an inhibitory effect on CRTH2 activation or H-PGDS expression or activity.
  • the test substance having an inhibitory effect on CRTH2 activation or H-PGDS expression or activity can function as a CRTH2 inhibitor or an H-PGDS inhibitor and can therefore be selected as a candidate for a cancer therapeutic agent.
  • the cancer therapeutic agent selected in the present invention is a cancer metastasis or recurrence inhibitor.
  • the test substance is an antibody.
  • the test substance is selected from any library of antibodies, preferably selected from a library of anti-CRTH2 antibodies or anti-H-PGDS antibodies.
  • anti-CRTH2 antibody having an inhibitory action on the activation of CRTH2 by PGD 2 or an anti-H-PGDS antibody having an inhibitory action on the activity of H-PGDS is detected by the procedure according to the present invention described above.
  • the detected antibody can be selected as a candidate for a cancer therapeutic agent, preferably a cancer metastasis or recurrence inhibitor.
  • H-PGDS gene-deficient mice H-PGDS-/-
  • L-PGDS gene-deficient mice L-PGDS gene-deficient mice
  • CRTH2 gene-deficient mice CRTH2-/-
  • DP gene-deficient mice CRTH2- / -
  • B16 melanoma or Lewis lung carcinoma (both RIKEN BRC Cell Materials Development Office -CELL BANK-) was used.
  • a suspension of cancer cells (200,000 cells / 100 ⁇ L) (Dulbecco's Modified Eagle's Medium) was injected into the tail vein of mice.
  • CRTH2 inhibitor (30 mg / kg)
  • H-PGDS inhibitor 50 mg / kg are dissolved in 0.5% carboxymethylcellulose solution twice a day for 14 days after B16 melanoma injection. Administered intraperitoneally.
  • the anti-IFN- ⁇ antibody (200 ⁇ g) was administered once abdominally by dissolving in physiological saline once 3 hours after B16 melanoma injection.
  • the anti-Gr-1 antibody (100 ⁇ g) was intraperitoneally administered twice a day from the day before B16 melanoma injection, dissolved in physiological saline for 14 days.
  • Fourteen days after the injection of cancer cells the mice were euthanized, the lungs were removed and cut into lung lobes, and the number of colonies of metastatic cancer was counted visually under a stereomicroscope.
  • Bone marrow transplantation Bone marrow cells were collected from the upper arm, femur or tibia of donor mice and transplanted into recipient mice (3-4 weeks old) irradiated with ⁇ rays (2 million cells / 100 ⁇ L). Recipient mice 6 weeks after transplantation were used for the experiment.
  • the specimen was blocked with phosphate buffered saline containing 0.05% triton and 3% normal donkey serum, and the primary antibodies were anti-CD45 rat antibody (Millipore), anti-CD31 rat antibody (Biocare Medical), anti-antibody E-cadherin rat antibody (Biolegend) and anti-H-PGDS rabbit antibody (Cayman Chemical) were used.
  • As the secondary antibody a fluorescence-labeled anti-rat antibody (Invitrogen) or anti-rabbit antibody (Invitrogen) was used. The fluorescence observation was performed using a fluorescence microscope (Eclipse E800, Nikon). Fluorescence for CD45, CD31, E-cadherin and H-PGDS was detected at 617 nm, 617 nm, 617 nm, and 525 nm, respectively.
  • Example 1 Suppression of Cancer Metastasis by H-PGDS Inhibition 1 Suppression of Melanoma Metastasis in H-PGDS-/-Mice According to Method C), wild-type mice (WT), H-PGDS-/-mice, and L-PGDS- /-Mice were injected with B16 melanoma (2 ⁇ 10 5 ) and the number of metastatic cancer colonies in the lung was evaluated 14 days later.
  • FIG. FIG. 1A is a photograph of a lung with typical metastatic cancer
  • FIG. 1B shows the number of metastatic cancer colonies in the lung.
  • L-PGDS gene-deficient mice (L-PGDS-/-) no significant reduction in cancer metastasis was observed.
  • FIG. 2A shows a photograph of a lung with typical metastatic cancer
  • FIG. 2B shows the number of metastatic cancer colonies in the lung.
  • H-PGDS inhibitor HQL-79 50 mg / kg
  • CMC solvent (carboxymethylcellulose
  • FIG. 5 shows an immunostained image of a lung tissue section.
  • the left side of FIG. 5 shows a stained image of the tissue and the center of FIG. 5 shows a stained image of H-PGDS.
  • FIG. 5 right H-PGDS was localized in the epithelium and vascular endothelium of the lung.
  • Example 2 Suppression of Cancer Metastasis by CRTH2 Inhibition 1 Suppression of Melanoma Metastasis in CRTH2 ⁇ / ⁇ Mice Lung metastasis of B16 melanoma was evaluated using PGD 2 receptor DP and CRTH2 gene-deficient mice. According to method C), WT, CRTH2-/-and DP-/-mice were injected with B16 melanoma (2 ⁇ 10 5 ) and the number of metastatic cancer colonies in the lung was evaluated 14 days later. The results are shown in FIG. FIG. 6A shows a photograph of a lung having typical metastatic cancer, and FIG. 6B shows the number of metastatic cancer colonies.
  • Example 3 Suppression of Cancer Metastasis by Inhibition of H-PGDS-CRTH2 Signal via IFN- ⁇ 1) Quantification of Cytokine Expression Level
  • Cytokine expression levels were evaluated. According to method C), B16 melanoma (2 ⁇ 10 6 ) were injected into WT, CRTH2 ⁇ / ⁇ and H-PGDS ⁇ / ⁇ mice. One day later, the lungs were removed, and the mRNA expression level of cytokines involved in metastasis was quantified using realtime-PCR.
  • Cytokines include IFN- ⁇ (interferon- ⁇ ), IL-4 (interleukin-4), IL-12 (interleukin-12) and their subunits IL-12p35 and IL-12p40, TNF ⁇ (tumor necrosis factor ⁇ ) And iNOS (inducible nitric oxide synthase).
  • Total RNA was extracted from the extracted lung tissue using the acid guanidinium thiocyanate-phenol-chloroform extraction method. From the extracted RNA, cDNA was prepared by performing reverse transcription reaction with reverse transcriptase (ReverTra Ace) using TaKaRa PCR Thermal Cycler MP TP3000.
  • Realtime-PCR was performed using an Aria Mx Real-Time PCR system (Agilent Technologies) according to the attached instructions.
  • the 18rRNA gene was used as an internal standard.
  • IFN- ⁇ producing cells in lung tissues were examined by flow cytometry.
  • flow cytometry 3 hours after administration of B16 melanoma, the lung tissue was perfused and excised, and the lung tissue was digested with Dulbecco's Modified Eagle's Medium solution containing 2 mg / mL collagenase at 37 ° C. for 1 hour. Then, it was treated with a labeled antibody at 4 ° C. for 30 minutes, and analyzed with a BD Accuri TM C6 Flow Cytometer (BD Biosciences). The results are shown in FIG. Many of the CD45 positive IFN- ⁇ producing cells in the lung were CD11b positive / Gr-1 positive (CD11b + Gr-1 + ).

Abstract

La présente invention porte sur la suppression du cancer par inhibition du signal H-PGDS-CRTH2. La présente invention porte également sur un agent permettant de supprimer des métastases cancéreuses ou une récurrence cancéreuse, ledit agent comprenant un inhibiteur de CRTH2 en tant qu'ingrédient actif. La présente invention porte également sur un agent permettant de supprimer des métastases cancéreuses ou une récurrence cancéreuse, ledit agent comprenant un inhibiteur de la prostaglandine D synthétase hématopoïétique (H-PGDS) en tant qu'ingrédient actif. La présente invention porte également sur un procédé permettant de cribler un agent thérapeutique pour le cancer selon lequel un effet inhibiteur sur l'activation de CRTH2 ou un effet inhibiteur sur l'expression ou l'activité de H-PGDS est utilisé en tant qu'index.
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