WO2020159203A1 - Composition comprising streptonigrin and anticancer agent for preventing or treating brain tumor - Google Patents
Composition comprising streptonigrin and anticancer agent for preventing or treating brain tumor Download PDFInfo
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- WO2020159203A1 WO2020159203A1 PCT/KR2020/001307 KR2020001307W WO2020159203A1 WO 2020159203 A1 WO2020159203 A1 WO 2020159203A1 KR 2020001307 W KR2020001307 W KR 2020001307W WO 2020159203 A1 WO2020159203 A1 WO 2020159203A1
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- Prior art keywords
- streptonigrin
- brain tumor
- cancer
- bevacizumab
- combination
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Images
Classifications
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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Definitions
- the present invention relates to a composition or anticancer adjuvant for preventing, improving or treating brain tumors comprising streptonigreen and anticancer agents.
- Cancer cells can perform regular and elastic proliferation and suppression as needed, whereas cancer cells proliferate indefinitely, which is also called a tumor as a cell mass composed of undifferentiated cells. These cancer cells penetrate into surrounding tissues and metastasize to other organs of the body, causing serious pain and eventually death.
- a tumor as a cell mass composed of undifferentiated cells.
- These cancer cells penetrate into surrounding tissues and metastasize to other organs of the body, causing serious pain and eventually death.
- the number of cancer patients in Korea has continuously increased, increasing by about 44% in the last 10 years, and the market for anticancer drugs has also increased internationally, and has been reported to have a size of about 100 billion dollars per year.
- Anticancer drugs are chemotherapy drugs, which are first-generation anti-cancer drugs, and targeted anti-cancer drugs, which are second-generation anti-cancer drugs.
- immuno-cancer drugs have been developed as third-generation anti-cancer drugs and research is ongoing.
- the biggest problem in the treatment of cancer is the recurrence of cancer, which is why it is difficult to target a specific cancer due to various mutations in cancer, and resistance to anticancer drugs used in the treatment of recurrent cancer occurs. This is because the case is non-existent.
- a strategy to mix and treat the anti-cancer agent has been proposed.
- Transglutaminase (Transglutaminase 2, TGase2) is an enzyme that promotes the binding between the ⁇ -carboxamide group and various amines of a glutamine residue bound to a specific peptide, primarily promoting damage prevention, defense and repair Although it is known to play a major role in recent studies, recent studies have reported that abnormally excessive expression may contribute to the development of diseases such as neurodegenerative diseases, atherosclerosis, inflammatory diseases, and autoimmune diseases. There is a bar.
- TGase2 polymerizes and destabilizes p53 and thus disappears, and accordingly, it has been reported that TGase2 may have an anti-cancer effect on re-expressed kidney cancer through inhibition of TGase2.
- Republic of Korea Patent Publication No. 10-2016-0009146 provides a pharmaceutical composition for treating or preventing a disease caused by an increase in transglutaminase 2 activity including streptonigreen, pancreatic cancer, uterine cancer to the disease It is disclosed that breast cancer is included.
- the present inventors tried to provide a significantly increased anti-cancer effect by using streptonigreen and other anti-cancer drugs, and as a result, streptonigreen and temozolomide or bevacizumab (bevacizumab; avastin, avastin) were used in combination, respectively. It was confirmed that it exhibited an excellent anti-cancer effect when treated with brain tumor cells in combination with nigreen and radiation therapy, and the present invention was completed.
- an object of the present invention is to provide a method for preventing or treating brain tumor, comprising the step of administering Streptonigrin and an anticancer agent to a brain tumor patient.
- Another object of the present invention is to provide a method for preventing or treating brain tumor, comprising administering Streptonigrin to a brain tumor patient, characterized in that it is used in combination with radiation therapy.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating brain tumor, including streptonigreen and anticancer agent.
- the present invention provides a method for preventing or treating brain tumor comprising the step of administering Streptonigrin and an anticancer agent to a patient with a brain tumor.
- the anti-cancer agent may be temozolomide or bevacizumab.
- the streptonigreen and anticancer agent may be included in a molar concentration ratio of 1:1 to 1:100000.
- the streptonigreen and anti-cancer agent may be administered simultaneously or sequentially.
- the composition may be used in combination with radiation therapy.
- the present invention also provides a method for preventing or treating brain tumor, comprising administering Streptonigrin to a brain tumor patient, characterized in that it is used in combination with radiation therapy.
- the present invention also provides pharmaceutical compositions for use in the prevention or treatment of brain tumors, including Streptonigrin and anticancer agents.
- the anti-cancer agent may be temozolomide or bevacizumab.
- the streptonigreen and anticancer agent may be included in a molar concentration ratio of 1:1 to 1:100000.
- the anti-cancer adjuvant may be used in combination with radiation therapy.
- the anti-cancer effect can be exhibited by using the transglutaminase (TGase2) inhibitory effect of streptonigreen, and when used in combination with the anticancer agent, the anticancer effect is significantly increased. No studies or descriptions of synergistic effects have been disclosed.
- TGase2 transglutaminase
- the growth or growth of the cancer cell line is inhibited to generate a significant anti-cancer effect, thereby preventing or treating cancer. It is effective as a composition.
- the anti-cancer effect of the streptonigreen can be significantly increased when used in combination with radiation therapy.
- the present invention can provide a method for preventing or treating brain tumor, comprising the step of administering Streptonigrin and an anticancer agent to a brain tumor patient.
- the streptonigreen is a transglutaminase 2 inhibitor produced by Streptomyces floculus, and refers to an antibiotic that causes chromosome cleavage.
- the anti-cancer agent of the present invention is temozolomide or bevacizumab.
- the temozolomide is a chemotherapeutic drug for oral administration. In particular, it controls the alkylation to methylation occurring at a guanine residue in DNA, thereby causing an anticancer effect.
- the bevacizumab (bevacizumab; avastin) is a drug used to treat various cancers or specific ophthalmic diseases such as colorectal cancer, which may slow the growth of tumors but affect the survival rate of patients with glioblastoma multiform. It is said to have not gone crazy.
- the streptonigreen and anticancer agent of the present invention is preferably administered in a molar concentration ratio of 1:1 to 100000, more preferably in a molar concentration ratio of 1:10 to 1:10000, most preferably Preferably it is administered in a molar concentration ratio of 1:50 to 1:1000.
- Brain tumors which occur when abnormal cells form inside the brain, can occur in various parts of the brain and can be benign or malignant, primary (primary) or secondary (secondary) Can.
- Common primary tumors include gliomas, meningiomas, pituitary adenomas, or nerve sheath tumors.
- Primary tumors mainly occurring in adults are astrocytomas such as meningiomas or glioblastoma multiform (GBM), and primary tumors occurring in children are malignant medulloblastomas.
- the composition of the present invention may have a prophylactic or therapeutic effect on all types of brain tumors, but may preferably have a significant effect on glioblastoma multiforme brain tumors.
- the Streptonigrin and anticancer agent of the present invention may be administered simultaneously or sequentially.
- the treatment method of the present invention can be used in combination with conventional anti-cancer treatment methods such as chemotherapy, radiation therapy, surgical therapy or immune cell therapy, but is preferably used in combination with radiation therapy.
- the combination includes co-administration, or continuous administration in order, as a single pharmaceutical formulation used as a separate formulation when performing radiation therapy or mixed with other therapeutic agents such as radiotherapy or immunotherapy required for radiation therapy.
- the radiation therapy may mean known radiation therapy such as X-ray deep treatment, radium therapy, mass irradiation of cobalt 60, ultra-high-pressure radiation therapy, and radioisotope content therapy.
- the radiation therapy is preferably irradiated with 1Gy to 100Gy low-level radiation, more preferably 2Gy to 50Gy low-level radiation, most preferably 3Gy to 10Gy low-level radiation, but not limited thereto. .
- 1Gy to 100Gy low-level radiation more preferably 2Gy to 50Gy low-level radiation, most preferably 3Gy to 10Gy low-level radiation, but not limited thereto.
- the present invention can provide a method for preventing or treating brain tumor, comprising the step of administering Streptonigrin to a brain tumor patient, characterized in that it is used in combination with radiation therapy.
- the radiation therapy, combination, and streptonigreen are the same as the concepts used in the prevention or treatment method, so the description is replaced by the description.
- the present invention can provide a pharmaceutical composition for use in the prevention or treatment of brain tumors, including Streptonigrin and anticancer agents.
- the streptonigreen and anti-cancer agent is the same as the concept used in the prevention or treatment method, so the description is replaced by the description.
- the anti-cancer agent of the present invention is temozolomide or bevacizumab.
- the temozolomide is a chemotherapeutic drug for oral administration. In particular, it controls the alkylation to methylation occurring at a guanine residue in DNA, thereby causing an anticancer effect.
- the bevacizumab is a drug used for the treatment of various cancers or specific ophthalmic diseases such as colorectal cancer, and is known to slow the growth of tumors but does not affect the survival rate of patients with glioblastoma multiform.
- the streptonigreen and anti-cancer agent of the present invention is preferably included in a molar concentration ratio of 1:1 to 100000, more preferably in a molar concentration ratio of 1:1 to 10000, and most preferably It is preferably included in a molar concentration ratio of 1:50 to 1:1000.
- the pharmaceutical composition of the present invention can be used in combination with conventional anti-cancer treatment methods such as chemotherapy, radiation therapy, surgical therapy or immune cell therapy, but is preferably used in combination with radiation therapy.
- the combination includes co-administration, or continuous administration in order, as a single pharmaceutical formulation used as a separate formulation when performing radiation therapy or mixed with other therapeutic agents such as radiotherapy or immunotherapy required for radiation therapy.
- the radiation therapy may mean known radiation therapy such as X-ray deep treatment, radium therapy, mass irradiation of cobalt 60, ultra-high-pressure radiation therapy, and radioisotope content therapy.
- the radiation therapy is preferably irradiated with 1Gy to 100Gy low-level radiation, more preferably 2Gy to 50Gy low-level radiation, most preferably 3Gy to 10Gy low-level radiation, but not limited thereto. .
- 1Gy to 100Gy low-level radiation more preferably 2Gy to 50Gy low-level radiation, most preferably 3Gy to 10Gy low-level radiation, but not limited thereto.
- the pharmaceutical composition of the present invention may be various oral or parenteral formulations.
- buffers e.g. saline or PBS
- antioxidants e.g. bacteriostatic agents
- chelating agents e.g. EDTA or glutathione
- fillers e.g., extenders, binders
- adjuvants e.g., Aluminum hydroxide
- suspending agents thickener wetting agents, disintegrating agents or surfactants, diluents or excipients.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in one or more compounds, such as starch (corn starch, wheat starch, rice starch, potato Starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl -It is prepared by mixing cellulose or gelatin. For example, tablets or dragees can be obtained by blending the active ingredient with a solid excipient and then grinding it and adding a suitable adjuvant to the granule mixture.
- starch corn starch, wheat starch, rice starch, potato Starch, etc.
- calcium carbonate sucrose, lactose, dextrose, sorbitol, mannitol, xylitol,
- lubricants such as magnesium stearate, talc and the like are used in addition to simple excipients.
- Liquid preparations for oral administration include suspending agents, intravenous solutions, emulsions or syrups, etc.
- simple diluents such as water and liquid paraffin
- various excipients such as wetting agents, sweeteners, flavoring agents or preservatives, are included.
- cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and may further include an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, and a preservative. .
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized preparations or suppositories.
- non-aqueous solvent and suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
- injectable ester such as ethyl oleate
- a base for suppositories witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
- composition of the present invention may be administered orally or parenterally, and for parenteral administration, external application to the skin; Injections that are injected intraperitoneally, rectal, intravenous, intramuscular, subcutaneous, intrauterine dura mater or cerebrovascular; Alternatively, nasal inhalants may be formulated according to methods known in the art.
- suitable carriers for injections include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycols, etc.), mixtures thereof and/or solvents or vegetable media comprising vegetable oils Can. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with ethanol amine or sterile water for injection, isotonic solutions such as 10% ethanol, 40% propylene glycol and 5% dextrose. Etc. can be used.
- PBS phosphate buffered saline
- the injection may further include various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- the injection may additionally include an isotonic agent such as sugar or sodium chloride in most cases.
- the compounds used according to the invention may be pressurized packs or, using suitable propellants, such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray from a nebulizer.
- the dosage unit can be determined by providing a valve that delivers a metered amount.
- gelatin capsules and cartridges used in inhalers or insufflators can be formulated to contain a powder mixture of a compound and a suitable powder base such as lactose or starch.
- the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
- a pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the patient's disease type, severity, drug activity, drug sensitivity, and administration time , The route of administration and rate of excretion, duration of treatment, factors including co-drugs, and other factors well known in the medical field.
- the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple.
- the total effective amount of the composition of the present invention can be administered to a patient in a single dose, and can be administered by a fractionated treatment protocol that is administered for a long time in multiple doses. . Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.
- the dosage of the pharmaceutical composition of the present invention may vary depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and disease severity.
- the daily dosage is preferably from 0.01 to 50 mg per kg of body weight per day, more preferably, based on the streptonigrin, temozolomide or bevacizumab (bevacizumab; avastin) of the present invention when administered parenterally.
- the dosage can be divided into 1 to several times to be administered in an amount of 0.01 to 10 mg.
- the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.
- the present invention can also provide an anti-cancer adjuvant comprising Streptonigrin and an anti-cancer agent.
- the anticancer adjuvant refers to all forms for enhancing the anticancer effect of the anticancer agent or suppressing or improving side effects of the anticancer agent.
- the anti-cancer adjuvant of the present invention may be administered in combination with various types of anti-cancer agents or anti-cancer adjuvants. Treatment can be performed.
- the route of administration of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue.
- the anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, orally, pulmonarily, or rectally, as desired, but is not limited thereto.
- the anti-cancer adjuvant may be administered by any device capable of transporting the active substance to the target cell.
- the anticancer adjuvant may be preferably formulated as an anticancer adjuvant by including one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration.
- Carriers, excipients or diluents that may be included in the anticancer treatment adjuvants of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- the anticancer adjuvant may be a formulation for oral or parenteral administration, and the description of the formulation is replaced by a description of the formulation of the pharmaceutical composition.
- the inhibitory effect on the brain tumor cell line is superior compared to the case of being used alone, thus preventing or preventing brain tumors. It can be effectively used as a treatment method or a pharmaceutical composition.
- the streptonigrin and temozolomide or bevacizumab (avastin) can be administered simultaneously or sequentially, and the streptonigrin has a significant inhibitory effect on the brain tumor cell line when combined with radiation therapy. May increase.
- a brain tumor cell line (83NS) in a solvent (vehicle), streptonigrin (Streptonigrin), temozolomide (TMZ), radiation therapy (Radiation 5Gy), streptonigrin and temozolomide in combination (Streptonigrin+TMZ) or strepto
- a solvent vehicle
- streptonigrin Streptonigrin
- temozolomide TTZ
- radiation therapy Randomtion 5Gy
- streptonigrin and temozolomide in combination (Streptonigrin+TMZ) or strepto
- the combination of nigrin and radiation therapy (Streptonigrin+RT)
- the growth of brain tumor cell lines is shown.
- the growth inhibitory effect on the brain tumor cell line was significantly increased when streptonigrin and temozolomide were used in combination, and similar levels of the brain tumor cell growth were also observed when the combination of streptonigrin and radiation therapy was used. It was confirmed that the inhibitory effect appeared.
- Figure 2 the solvent (vehicle), Streptonigrin, bevacizumab (bevacizumab; avastin, avastin) or streptonigrin and bevacizumab combination in a mouse injected with a brain tumor cell line (83NS), respectively It shows the survival rate of mice when administered. It was confirmed that the survival rate of the mouse was significantly increased when streptonigreen and bevacizumab were used in combination compared to the single treatment group, respectively.
- 83NS brain tumor cell line
- Figure 3 is a solvent (vehicle), Streptonigrin, bevacizumab (bevacizumab; avastin, avastin) or streptonigrin and bevacizumab combination (Combination) in mice transplanted with brain tumor cell line (U87) into the brain ) Is the result of H&E staining of the brain tumor after administration, and results of MRI of the brain tumor on the 15th or 24th day after administration. Compared to the single treatment group, it was confirmed that the size of brain tumors was significantly reduced when streptonigreen and bevacizumab were used in combination.
- TMZ Temozolomide
- a 3.0 ⁇ 10 3 (cell/well) 83NS cell line was solvent (Vehicle), streptonigreen (100 nM), TMZ (50 ⁇ M), radiation treatment (Radiation 5 Gy, RT), streptonigreen (100 nM) + TMZ (50 ⁇ M) or streptonigreen (100 nM) + radiation treatment (5 Gy), respectively, and after 0, 1, and 2 days, samples were collected and ATP Luminescence assay was used for cell growth. The inhibitory activity of the indicator ATP was evaluated.
- mice 5.0 ⁇ 10 4 brain tumor cell lines (U87) cultured with 10% FBS and 1% penicillin/streptomycin in DMEM were injected into the left parenchymal tissue of the brain into a 5 week old Balb/c-nude mouse model.
- the injection coordinates were 0.2 mm deep, 2.2 mm from the left side of the midline and 3.5 mm behind the bregma.
- GraphPad PRISM software (Vehicle), 0.5 mg/kg of streptonigreen and/or 10 mg/kg of Avastin (or bevacizumab) was administered orally and the changes in survival or tumor size of mice over time were graphPad PRISM software ( Version 7).
- Tumor size was confirmed by M&R imaging by obtaining brain tumors of mice 15 or 24 days after H&E staining or drug administration.
- H&E staining obtained brains of brain tumor mice 49 days after drug administration, and fixed at 4° C. for 24 hours using 4% paraformaldehyde to make paraffin blocks and cut them to a thickness of 4 ⁇ m. And stained with hematoxylin (DaKo) and 0.25% eosin (Merck). Staining was performed after sufficiently hydrating the paraffin block using xylene and ethanol.
- the tissues stained through the above method were mounted using xylene, and the mounted tissues were observed and photographed using an Epifluorescence and Brightfield microscope (Axioimager M1, Carl Zeiss, MA, USA).
- mice As a result, as shown in [Fig. 2], the survival rate of mice was significantly increased when treated with Streptonigreen and Avastin (bevacizumab, bevacizumab) in combination with each treatment group.
- the median survival of the solvent, streptonigreen and/or avastin administration groups was 28, 33, 38 and 49 days, respectively.
- HIF-1a, TGM2, C/EBP ⁇ , or pSTAT3 which are cancer cell-related indicators, are significantly reduced when streptonigreen and avastin are used in combination, respectively, compared to the single treatment group. I could confirm that.
- both streptonigrin and temozolomide or bevacizumab according to the present invention are included, the growth or growth of the cancer cell line is inhibited, thereby generating a significant anti-cancer effect, so as to prevent or treat cancer, to a pharmaceutical composition or as an anticancer adjuvant effective.
- the anti-cancer effect of streptonigreen can be significantly increased when used in combination with radiation therapy, and thus has great industrial applicability.
Abstract
The present invention relates to a method or pharmaceutical composition for prevention or treatment of brain tumor by using streptonigrin and an anticancer agent. Specifically, the composition comprising streptonigrin and temozolomide, or streptonigrin and bevacizumab (Avastin) according to the present invention shows an excellent inhibitory effect on brain tumor cell lines, compared to the use of the individual compounds alone and can be effectively used in a method or as a pharmaceutical composition for prevention or treatment of brain tumors. Particularly, streptonigrin and temozolomide or bevacizumab may be administered simultaneously or sequentially. The use of streptonigrin in combination of radiotherapy can result in a significant increase in inhibitory effect against brain tumor cell lines.
Description
본 출원은 2019년 01월 29일 출원된 대한민국 특허출원 제10-2019-0011477호 를 우선권으로 주장하고, 상기 명세서 전체는 출원의 참고문헌이다. This application claims priority to Korean Patent Application No. 10-2019-0011477 filed on January 29, 2019, and the entire specification is a reference to the application.
본 발명은 스트렙토니그린 및 항암제를 포함하는 뇌종양 예방, 개선 또는 치료용 조성물 내지 항암보조제에 대한 것이다. The present invention relates to a composition or anticancer adjuvant for preventing, improving or treating brain tumors comprising streptonigreen and anticancer agents.
정상세포는 필요에 따라 규칙적이고 탄력적인 증식과 억제를 할 수 있는 반면에 암세포는 무제한의 증식을 하며, 이는 미분화 세포로 구성된 세포덩어리로서 종양이라고도 한다. 이러한 암세포는 주위의 조직으로 침투하고 신체의 다른 기관으로 전이가 되어 심각한 고통을 수반하고 결국 죽음을 초래한다. 의학의 발전에도 불구하고, 국내 암환자 발생자수는 지속적으로 증가하여 최근 10년간 약 44%가 증가하였으며, 국제적으로도 항암제 시장 역시 증가하여 연간 약 1000억 달러의 규모를 가지는 것으로 보고된 바 있다.Normal cells can perform regular and elastic proliferation and suppression as needed, whereas cancer cells proliferate indefinitely, which is also called a tumor as a cell mass composed of undifferentiated cells. These cancer cells penetrate into surrounding tissues and metastasize to other organs of the body, causing serious pain and eventually death. Despite the development of medicine, the number of cancer patients in Korea has continuously increased, increasing by about 44% in the last 10 years, and the market for anticancer drugs has also increased internationally, and has been reported to have a size of about 100 billion dollars per year.
항암제는 1세대 항암제인 화학항암제, 2세대 항암제인 표적항암제가 있으며, 이들의 부작용을 극복하고자 3세대 항암제로서 면역항암제가 개발되어 계속적으로 연구가 진행되고 있다. 그러나 현재 암 치료에서 가장 큰 문제가 되는 점은 암의 재발에 있는데 그 이유는 암의 돌연변이가 다양하여 특정 암을 표적으로 하는 것이 어려울 뿐더러, 재발된 암의 치료 과정에서 사용한 항암제에 내성이 발생하는 경우가 비일비재하기 때문이이다. 결국, 원발암을 치료한 이후에도 전이 및 재발한 암에 의해 환자가 사망하는 경우가 대부분이다. 이에 따라, 항암제의 효과를 증진시키기 위해, 항암제를 혼합하여 병용치료하고자 하는 전략이 제시되고 있다.Anticancer drugs are chemotherapy drugs, which are first-generation anti-cancer drugs, and targeted anti-cancer drugs, which are second-generation anti-cancer drugs. To overcome these side effects, immuno-cancer drugs have been developed as third-generation anti-cancer drugs and research is ongoing. However, the biggest problem in the treatment of cancer is the recurrence of cancer, which is why it is difficult to target a specific cancer due to various mutations in cancer, and resistance to anticancer drugs used in the treatment of recurrent cancer occurs. This is because the case is non-existent. As a result, most patients die from metastases and recurring cancers even after treatment of primary cancer. Accordingly, in order to enhance the effectiveness of the anti-cancer agent, a strategy to mix and treat the anti-cancer agent has been proposed.
트랜스글루타미나제(Transglutaminase 2, TGase2)는 특이 펩티드에 결합된 글루타민 잔기의 γ-카르복사미드기와 다양한 아민들 사이의 결합을 촉진하는 효소로, 일차적으로는 손상의 예방과 방어 및 복구를 촉진하는데 있어서 주요한 역할을 하는 것으로 알려졌으나, 최근 연구에 의하면 비정상적으로 과도한 발현이 나타나면 신경퇴행성 질환, 죽상동맥경화증, 염증성 질환, 및 자가면역 질환과 같은 질병의 발생에 원인을 제공할 수 있는 것으로 보고된 바 있다. 특히, TGase2의 발현이 p53을 중합화하고 불안정하게 하여 소멸시킨다는 것이 보고되었으며, 이에 따라 TGase2의 억제를 통해 TGase2가 과발현된 신장암에 대한 항암 효과를 나타낼 수 있음이 보고된 바 있다. Transglutaminase (Transglutaminase 2, TGase2) is an enzyme that promotes the binding between the γ-carboxamide group and various amines of a glutamine residue bound to a specific peptide, primarily promoting damage prevention, defense and repair Although it is known to play a major role in recent studies, recent studies have reported that abnormally excessive expression may contribute to the development of diseases such as neurodegenerative diseases, atherosclerosis, inflammatory diseases, and autoimmune diseases. There is a bar. In particular, it has been reported that the expression of TGase2 polymerizes and destabilizes p53 and thus disappears, and accordingly, it has been reported that TGase2 may have an anti-cancer effect on re-expressed kidney cancer through inhibition of TGase2.
대한민국 공개특허 제 10-2016-0009146호 에서는 스트렙토니그린을 포함하는 트랜스글루타미나제2 활성 증가에 의해 초래되는 질병을 치료 또는 예방하기 위한 약제학적 조성물을 제공하면서, 상기 질병에 췌장암, 자궁암 내지 유방암이 포함된다고 개시하고 있다. Republic of Korea Patent Publication No. 10-2016-0009146 provides a pharmaceutical composition for treating or preventing a disease caused by an increase in transglutaminase 2 activity including streptonigreen, pancreatic cancer, uterine cancer to the disease It is disclosed that breast cancer is included.
그러나, 스트렙토니그린과 다른 항암제를 병용하여 암세포의 생장 억제 등 그 항암효과에 시너지 효과를 발생시키고자 하는 연구 내지 기재는 개시된바 없다.However, studies or descriptions have not been disclosed to generate a synergistic effect on the anti-cancer effect, such as suppressing the growth of cancer cells by using streptonigreen and other anti-cancer agents in combination.
이에, 본 발명자들은 스트렙토니그린과 다른 항암제들을 병용하여 유의적으로 상승한 항암효과를 제공하고자 노력한 결과, 스트렙토니그린과 테모졸로마이드 또는 베바시주맙(bevacizumab; 아바스틴, avastin)을 각각 병용하거나, 스트렙토니그린과 방사선 요법을 병행하여 뇌종양 세포에 처리하는 경우 우수한 항암효과를 나타내는 것을 확인하고 본 발명을 완성하였다. Thus, the present inventors tried to provide a significantly increased anti-cancer effect by using streptonigreen and other anti-cancer drugs, and as a result, streptonigreen and temozolomide or bevacizumab (bevacizumab; avastin, avastin) were used in combination, respectively. It was confirmed that it exhibited an excellent anti-cancer effect when treated with brain tumor cells in combination with nigreen and radiation therapy, and the present invention was completed.
따라서, 본 발명의 목적은 스트렙토니그린(Streptonigrin) 및 항암제를 뇌종양 환자에게 투여하는 단계를 포함하는 뇌종양 예방 또는 치료방법을 제공하는 것이다. Accordingly, an object of the present invention is to provide a method for preventing or treating brain tumor, comprising the step of administering Streptonigrin and an anticancer agent to a brain tumor patient.
본 발명의 또 다른 목적은, 방사선 요법과 병용되는 것을 특징으로 하는, 스트렙토니그린(Streptonigrin)을 뇌종양 환자에게 투여하는 단계를 포함하는 뇌종양 예방 또는 치료방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating brain tumor, comprising administering Streptonigrin to a brain tumor patient, characterized in that it is used in combination with radiation therapy.
본 발명의 또 다른 목적은, 스트렙토니그린 및 항암제를 포함하는 뇌종양 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating brain tumor, including streptonigreen and anticancer agent.
상기 목적을 달성하기 위해, 본 발명은 스트렙토니그린(Streptonigrin) 및 항암제를 뇌종양 환자에게 투여하는 단계를 포함하는 뇌종양 예방 또는 치료방법을 제공한다. In order to achieve the above object, the present invention provides a method for preventing or treating brain tumor comprising the step of administering Streptonigrin and an anticancer agent to a patient with a brain tumor.
본 발명의 바람직한 일실시예에 따르면, 상기 항암제는 테모졸로마이드(temozolomide) 또는 베바시주맙(bevacizumab)인 것일 수 있다. According to one preferred embodiment of the present invention, the anti-cancer agent may be temozolomide or bevacizumab.
본 발명의 바람직한 일실시예에 따르면, 상기 스트렙토니그린 및 항암제는 1 : 1 내지 1 : 100000 의 몰농도비로 포함되는 것일 수 있다. According to a preferred embodiment of the present invention, the streptonigreen and anticancer agent may be included in a molar concentration ratio of 1:1 to 1:100000.
본 발명의 바람직한 일실시예에 따르면, 상기 스트렙토니그린 및 항암제는 동시에, 또는 순차적으로 투여되는 것일 수 있다. According to a preferred embodiment of the present invention, the streptonigreen and anti-cancer agent may be administered simultaneously or sequentially.
본 발명의 바람직한 일실시예에 따르면, 상기 조성물은 방사선 요법과 병용되는 것일 수 있다. According to one preferred embodiment of the present invention, the composition may be used in combination with radiation therapy.
본 발명은 또한, 방사선 요법과 병용되는 것을 특징으로 하는, 스트렙토니그린(Streptonigrin)을 뇌종양 환자에게 투여하는 단계를 포함하는 뇌종양 예방 또는 치료방법을 제공한다. The present invention also provides a method for preventing or treating brain tumor, comprising administering Streptonigrin to a brain tumor patient, characterized in that it is used in combination with radiation therapy.
본 발명은 또한, 스트렙토니그린(Streptonigrin) 및 항암제를 포함하는 뇌종양 예방 또는 치료에 사용하기 위한 약학적 조성물을 제공한다. The present invention also provides pharmaceutical compositions for use in the prevention or treatment of brain tumors, including Streptonigrin and anticancer agents.
본 발명의 바람직한 일실시예에 따르면, 상기 항암제는 테모졸로마이드(temozolomide) 또는 베바시주맙(bevacizumab)인 것일 수 있다. According to one preferred embodiment of the present invention, the anti-cancer agent may be temozolomide or bevacizumab.
본 발명의 바람직한 일실시예에 따르면, 상기 스트렙토니그린 및 항암제는 1 : 1 내지 1 : 100000 의 몰농도비로 포함되는 것일 수 있다. According to a preferred embodiment of the present invention, the streptonigreen and anticancer agent may be included in a molar concentration ratio of 1:1 to 1:100000.
본 발명의 바람직한 일실시예에 따르면, 상기 항암보조제는 방사선 요법과 병용되는 것일 수 있다. According to a preferred embodiment of the present invention, the anti-cancer adjuvant may be used in combination with radiation therapy.
상술한 바와 같이, 종래 기술에서는 스트렙토니그린의 트랜스글루타미나제(TGase2) 억제 효과를 이용하여 항암효과를 나타낼 수 있음을 확인하고 있었을 뿐 이와 병용하는 경우 유의적으로 항암효과가 증가하는 항암제와의 시너지 효과에 대한 연구 내지 기재는 개시된 바 없다. As described above, in the prior art, it has been confirmed that the anti-cancer effect can be exhibited by using the transglutaminase (TGase2) inhibitory effect of streptonigreen, and when used in combination with the anticancer agent, the anticancer effect is significantly increased. No studies or descriptions of synergistic effects have been disclosed.
본 발명에 따른 스트렙토니그린과 테모졸로마이드 또는 베바시주맙(bevacizumab; 아바스틴, avastin)을 모두 포함하는 경우 암 세포주의 성장 내지 생장을 억제하여 유의적인 항암효과를 발생시키므로, 암 예방 또는 치료방법 내지 조성물로서 효과적이다. 또한 상기 스트렙토니그린은 방사선 요법과 병용되는 경우 그 항암효과가 유의적으로 증가할 수 있다. When both streptonigreen and temozolomide or bevacizumab (bevacizumab; avastin) according to the present invention are included, the growth or growth of the cancer cell line is inhibited to generate a significant anti-cancer effect, thereby preventing or treating cancer. It is effective as a composition. In addition, the anti-cancer effect of the streptonigreen can be significantly increased when used in combination with radiation therapy.
따라서, 본 발명은 스트렙토니그린(Streptonigrin) 및 항암제를 뇌종양 환자에게 투여하는 단계를 포함하는 뇌종양 예방 또는 치료방법을 제공할 수 있다. Accordingly, the present invention can provide a method for preventing or treating brain tumor, comprising the step of administering Streptonigrin and an anticancer agent to a brain tumor patient.
상기 스트렙토니그린은 스트렙토마이세스 플로쿨루스(Streptomyces floculus)에 의해 생산되는 트랜스글루타미나제(Transglutaminase 2) 억제제로서, 염색체 절단을 일으키는 항생물질을 말한다. The streptonigreen is a transglutaminase 2 inhibitor produced by Streptomyces floculus, and refers to an antibiotic that causes chromosome cleavage.
본 발명의 상기 항암제는 테모졸로마이드(temozolomide) 또는 베바시주맙(bevacizumab)인 것이 바람직하다. 상기 테모졸로마이드는 경구 투여용 화학요법 약물로서, DNA 중 특히 구아닌(Guanine) 잔기에서 일어나는 알킬화 내지 메틸화를 조절하여 항암효과를 일으킨다. 상기 베바시주맙(bevacizumab; 아바스틴, avastin)은 대장암 등 여러 암 내지 특정 안과 질환을 치료용으로 사용되는 약물로서, 종양의 성장을 늦출수는 있지만 다형성 교모세포종(giloblastoma multiform) 환자의 생존률에는 영향을 미치지 않은 것으로 알려져 있다. It is preferable that the anti-cancer agent of the present invention is temozolomide or bevacizumab. The temozolomide is a chemotherapeutic drug for oral administration. In particular, it controls the alkylation to methylation occurring at a guanine residue in DNA, thereby causing an anticancer effect. The bevacizumab (bevacizumab; avastin) is a drug used to treat various cancers or specific ophthalmic diseases such as colorectal cancer, which may slow the growth of tumors but affect the survival rate of patients with glioblastoma multiform. It is said to have not gone crazy.
본 발명의 상기 스트렙토니그린 및 항암제는 1 : 1 내지 1 : 100000 의 몰농도비로 투여되는 것이 바람직하나, 더욱 바람직하게는 1 : 10 내지 1 : 10000 의 몰농도비로 투여되는 것이 바람직하고, 가장 바람직하게는 1 : 50 내지 1 : 1000 의 몰농도비로 투여되는 것이 바람직하다. The streptonigreen and anticancer agent of the present invention is preferably administered in a molar concentration ratio of 1:1 to 100000, more preferably in a molar concentration ratio of 1:10 to 1:10000, most preferably Preferably it is administered in a molar concentration ratio of 1:50 to 1:1000.
뇌종양(brain tumor)은 비정상적인 세포가 뇌 내부에서 형성될 때 발생하는 것으로서 뇌의 다양한 부위에서 발생할 수 있으며 양성(benign) 또는 악성(malignant)일 수 있고 일차(원발, primary) 또는 이차(secondary)일 수 있다. 흔히 발생하는 원발성 종양은 신경 교종(gliomas), 수막종(meningiomas), 뇌하수체 선종(pituitary adenomas) 또는 신경외피 종양(nerve sheath tumors) 등이 있다. 주로 성인에게서 발생하는 원발성 종양(primary tumor)은 수막종(meningiomas) 또는 다형성 교모세포종(glioblastoma multiform; GBM) 등의 아교세포종(astrocytomas)이며, 소아에게서 발생하는 원발성 종양은 악성 수모세포종(malignant medulloblastoma)이다. 본 발명의 조성물은 모든 유형의 뇌종양에 대하여 예방 내지 치료 효과를 가질 수 있으나, 바람직하게는 다형성 교모세포종 뇌종양에서 유의적으로 효과를 가질 수 있다.Brain tumors, which occur when abnormal cells form inside the brain, can occur in various parts of the brain and can be benign or malignant, primary (primary) or secondary (secondary) Can. Common primary tumors include gliomas, meningiomas, pituitary adenomas, or nerve sheath tumors. Primary tumors mainly occurring in adults are astrocytomas such as meningiomas or glioblastoma multiform (GBM), and primary tumors occurring in children are malignant medulloblastomas. . The composition of the present invention may have a prophylactic or therapeutic effect on all types of brain tumors, but may preferably have a significant effect on glioblastoma multiforme brain tumors.
본 발명의 상기 스트렙토니그린(Streptonigrin) 및 항암제는 동시에, 또는 순차적으로 투여되는 것일 수 있다. The Streptonigrin and anticancer agent of the present invention may be administered simultaneously or sequentially.
본 발명의 상기 치료방법은 화학적 요법, 방사선 요법, 외과적 요법 또는 면역세포치료법 등 통상적인 항암치료방법과 병용될 수 있으나, 방사선 요법과 병용되는 것이 바람직하다. 상기 병용은 방사선 요법 수행시 개별 제형으로서 사용되거나 방사선 요법시 필요한 방사선 요법제 내지 면역치료제 등 다른 치료제와 혼합된 단일 약학 제형으로서 공동투여, 또는 및 순서대로 연속 투여되는 것을 포함한다. 상기 방사선 요법은 X선 심부치료, 라듐요법, 코발트 60의 대량조사, 초고압방사선요법 및 방사성 동위원소 내용요법 등 공지된 방사선 요법을 의미할 수 있다. 상기 방사선 요법은 1Gy 내지 100Gy의 저준위방사선으로 조사하는 것이 바람직하며, 더욱 바람직하게는 2Gy 내지 50Gy의 저준위방사선인 것이 바람직하고, 가장 바람직하게는 3Gy 내지 10Gy의 저준위방사선인 것이 바람직하나 이에 한정되지 않는다. 상기 범위에서 방사선 항암치료의 부작용을 최소화하면서 방사선에 의한 항암치료 효과와 본 발명에 의한 치료방법의 시너지 효과를 극대화할 수 있다.The treatment method of the present invention can be used in combination with conventional anti-cancer treatment methods such as chemotherapy, radiation therapy, surgical therapy or immune cell therapy, but is preferably used in combination with radiation therapy. The combination includes co-administration, or continuous administration in order, as a single pharmaceutical formulation used as a separate formulation when performing radiation therapy or mixed with other therapeutic agents such as radiotherapy or immunotherapy required for radiation therapy. The radiation therapy may mean known radiation therapy such as X-ray deep treatment, radium therapy, mass irradiation of cobalt 60, ultra-high-pressure radiation therapy, and radioisotope content therapy. The radiation therapy is preferably irradiated with 1Gy to 100Gy low-level radiation, more preferably 2Gy to 50Gy low-level radiation, most preferably 3Gy to 10Gy low-level radiation, but not limited thereto. . In the above range, while minimizing the side effects of radiation chemotherapy, it is possible to maximize the anticancer treatment effect by radiation and the synergistic effect of the treatment method according to the present invention.
또한, 본 발명은 방사선 요법과 병용되는 것을 특징으로 하는, 스트렙토니그린(Streptonigrin)을 뇌종양 환자에게 투여하는 단계를 포함하는 뇌종양 예방 또는 치료방법을 제공할 수 있다. In addition, the present invention can provide a method for preventing or treating brain tumor, comprising the step of administering Streptonigrin to a brain tumor patient, characterized in that it is used in combination with radiation therapy.
상기 방사선 요법, 병용 및 스트렙토니그린은 상기 예방 또는 치료방법에서 사용되는 개념과 동일하므로 설명은 그 기재로 대신한다. The radiation therapy, combination, and streptonigreen are the same as the concepts used in the prevention or treatment method, so the description is replaced by the description.
또한, 본 발명은 스트렙토니그린(Streptonigrin) 및 항암제를 포함하는 뇌종양 예방 또는 치료에 사용하기 위한 약학적 조성물을 제공할 수 있다. In addition, the present invention can provide a pharmaceutical composition for use in the prevention or treatment of brain tumors, including Streptonigrin and anticancer agents.
상기 스트렙토니그린 및 항암제는 상기 예방 또는 치료방법에서 사용되는 개념과 동일하므로 설명은 그 기재로 대신한다. The streptonigreen and anti-cancer agent is the same as the concept used in the prevention or treatment method, so the description is replaced by the description.
본 발명의 상기 항암제는 테모졸로마이드(temozolomide) 또는 베바시주맙(bevacizumab)인 것이 바람직하다. 상기 테모졸로마이드는 경구 투여용 화학요법 약물로서, DNA 중 특히 구아닌(Guanine) 잔기에서 일어나는 알킬화 내지 메틸화를 조절하여 항암효과를 일으킨다. 상기 베바시주맙은 대장암 등 여러 암 내지 특정 안과 질환을 치료용으로 사용되는 약물로서, 종양의 성장을 늦출수는 있지만 다형성 교모세포종(giloblastoma multiform) 환자의 생존률에는 영향을 미치지 않은 것으로 알려져 있다. It is preferable that the anti-cancer agent of the present invention is temozolomide or bevacizumab. The temozolomide is a chemotherapeutic drug for oral administration. In particular, it controls the alkylation to methylation occurring at a guanine residue in DNA, thereby causing an anticancer effect. The bevacizumab is a drug used for the treatment of various cancers or specific ophthalmic diseases such as colorectal cancer, and is known to slow the growth of tumors but does not affect the survival rate of patients with glioblastoma multiform.
본 발명의 상기 스트렙토니그린 및 항암제는 1 : 1 내지 1 : 100000 의 몰농도비로 포함되는 것이 바람직하나, 더욱 바람직하게는 1 : 10 내지 1 : 10000 의 몰농도비로 포함되는 것이 바람직하고, 가장 바람직하게는 1 : 50 내지 1 : 1000 의 몰농도비로 포함되는 것이 바람직하다. The streptonigreen and anti-cancer agent of the present invention is preferably included in a molar concentration ratio of 1:1 to 100000, more preferably in a molar concentration ratio of 1:1 to 10000, and most preferably It is preferably included in a molar concentration ratio of 1:50 to 1:1000.
본 발명의 상기 약학적 조성물은 화학적 요법, 방사선 요법, 외과적 요법 또는 면역세포치료법 등 통상적인 항암치료방법과 병용될 수 있으나, 방사선 요법과 병용되는 것이 바람직하다. 상기 병용은 방사선 요법 수행시 개별 제형으로서 사용되거나 방사선 요법시 필요한 방사선 요법제 내지 면역치료제 등 다른 치료제와 혼합된 단일 약학 제형으로서 공동투여, 또는 및 순서대로 연속 투여되는 것을 포함한다. 상기 방사선 요법은 X선 심부치료, 라듐요법, 코발트 60의 대량조사, 초고압방사선요법 및 방사성 동위원소 내용요법 등 공지된 방사선 요법을 의미할 수 있다. 상기 방사선 요법은 1Gy 내지 100Gy의 저준위방사선으로 조사하는 것이 바람직하며, 더욱 바람직하게는 2Gy 내지 50Gy의 저준위방사선인 것이 바람직하고, 가장 바람직하게는 3Gy 내지 10Gy의 저준위방사선인 것이 바람직하나 이에 한정되지 않는다. 상기 범위에서 방사선 항암치료의 부작용을 최소화하면서 방사선에 의한 항암치료 효과와 본 발명에 의한 약학적 조성물의 시너지 효과를 극대화할 수 있다.The pharmaceutical composition of the present invention can be used in combination with conventional anti-cancer treatment methods such as chemotherapy, radiation therapy, surgical therapy or immune cell therapy, but is preferably used in combination with radiation therapy. The combination includes co-administration, or continuous administration in order, as a single pharmaceutical formulation used as a separate formulation when performing radiation therapy or mixed with other therapeutic agents such as radiotherapy or immunotherapy required for radiation therapy. The radiation therapy may mean known radiation therapy such as X-ray deep treatment, radium therapy, mass irradiation of cobalt 60, ultra-high-pressure radiation therapy, and radioisotope content therapy. The radiation therapy is preferably irradiated with 1Gy to 100Gy low-level radiation, more preferably 2Gy to 50Gy low-level radiation, most preferably 3Gy to 10Gy low-level radiation, but not limited thereto. . In the above range, while minimizing the side effects of radiation chemotherapy, it is possible to maximize the anticancer treatment effect by radiation and the synergistic effect of the pharmaceutical composition according to the present invention.
본 발명의 약학적 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 상기 조성물을 제형화할 경우에는 하나 이상의 완충제(예를 들어, 식염수 또는 PBS), 항산화제, 정균제, 킬레이트화제(예를 들어, EDTA 또는 글루타치온), 충진제, 증량제, 결합제, 아쥬반트(예를 들어, 알루미늄 하이드록사이드), 현탁제, 농후제 습윤제, 붕해제 또는 계면활성제, 희석제 또는 부형제를 사용하여 조제될 수 있다. The pharmaceutical composition of the present invention may be various oral or parenteral formulations. When formulating the composition, one or more buffers (e.g. saline or PBS), antioxidants, bacteriostatic agents, chelating agents (e.g. EDTA or glutathione), fillers, extenders, binders, adjuvants (e.g., Aluminum hydroxide), suspending agents, thickener wetting agents, disintegrating agents or surfactants, diluents or excipients.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분(옥수수 전분, 밀 전분, 쌀 전분, 감자 전분 등 포함), 칼슘카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 덱스트로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨 말티톨, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필메틸-셀룰로즈 또는 젤라틴 등을 섞어 조제된다. 예컨대, 활성성분을 고체 부형제와 배합한 다음 이를 분쇄하고 적합한 보조제를 첨가한 후 과립 혼합물로 가공함으로써 정제 또는 당의정제를 수득할 수 있다. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in one or more compounds, such as starch (corn starch, wheat starch, rice starch, potato Starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl -It is prepared by mixing cellulose or gelatin. For example, tablets or dragees can be obtained by blending the active ingredient with a solid excipient and then grinding it and adding a suitable adjuvant to the granule mixture.
또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 또는 보존제 등이 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있으며, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In addition, lubricants such as magnesium stearate, talc and the like are used in addition to simple excipients. Liquid preparations for oral administration include suspending agents, intravenous solutions, emulsions or syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as wetting agents, sweeteners, flavoring agents or preservatives, are included. Can. In addition, if necessary, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and may further include an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, and a preservative. .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제 또는 좌제 등이 포함된다. 비수성용제 및 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized preparations or suppositories. As the non-aqueous solvent and suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
본 발명의 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여시 피부외용; 복강내, 직장, 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사하는 주사제; 또는 비강 흡입제의 형태로 당업계에 공지된 방법에 따라 제형화할 수 있다.The composition of the present invention may be administered orally or parenterally, and for parenteral administration, external application to the skin; Injections that are injected intraperitoneally, rectal, intravenous, intramuscular, subcutaneous, intrauterine dura mater or cerebrovascular; Alternatively, nasal inhalants may be formulated according to methods known in the art.
상기 주사제의 경우에는 반드시 멸균되어야 하며 박테리아 및 진균과 같은 미생물의 오염으로부터 보호되어야 한다. 주사제의 경우 적합한 담체의 예로는 이에 한정되지는 않으나, 물, 에탄올, 폴리올(예를 들어, 글리세롤, 프로필렌 글리콜 및 액체 폴리에틸렌 글리콜 등), 이들의 혼합물 및/또는 식물유를 포함하는 용매 또는 분산매질일 수 있다. 보다 바람직하게는, 적합한 담체로는 행크스 용액, 링거 용액, 트리에탄올 아민이 함유된 PBS (phosphate buffered saline) 또는 주사용 멸균수, 10% 에탄올, 40% 프로필렌 글리콜 및 5% 덱스트로즈와 같은 등장 용액 등을 사용할 수 있다. 상기 주사제를 미생물 오염으로부터 보호하기 위해서는 파라벤, 클로로부탄올, 페놀, 소르빈산, 티메로살 등과 같은 다양한 항균제 및 항진균제를 추가로 포함할 수 있다. 또한, 상기 주사제는 대부분의 경우 당 또는 나트륨 클로라이드와 같은 등장화제를 추가로 포함할 수 있다.The injections must be sterile and protected from contamination of microorganisms such as bacteria and fungi. Examples of suitable carriers for injections include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycols, etc.), mixtures thereof and/or solvents or vegetable media comprising vegetable oils Can. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with ethanol amine or sterile water for injection, isotonic solutions such as 10% ethanol, 40% propylene glycol and 5% dextrose. Etc. can be used. In order to protect the injection from microbial contamination, it may further include various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, the injection may additionally include an isotonic agent such as sugar or sodium chloride in most cases.
흡입 투여제의 경우, 본 발명에 따라 사용되는 화합물은 적합한 추진제, 예를 들면, 디클로로플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소 또는 다른 적합한 기체를 사용하여, 가압 팩 또는 연무기로부터 에어로졸 스프레이 형태로 편리하게 전달 할 수 있다. 가압 에어로졸의 경우, 투약 단위는 계량된 양을 전달하는 밸브를 제공하여 결정할 수 있다. 예를 들면, 흡입기 또는 취입기에 사용되는 젤라틴 캡슐 및 카트리지는 화합물, 및 락토즈 또는 전분과 같은 적합한 분말 기제의 분말 혼합물을 함유하도록 제형화할 수 있다. In the case of inhalation dosages, the compounds used according to the invention may be pressurized packs or, using suitable propellants, such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray from a nebulizer. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges used in inhalers or insufflators can be formulated to contain a powder mixture of a compound and a suitable powder base such as lactose or starch.
본 발명의 약학적 조성물은 약제학적으로 유효한 양으로 투여한다. 약제학적으로 유효한 양은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 즉, 본 발명의 조성물의 총 유효량은 단일 투여량(single dose)으로 환자에게 투여될 수 있으며, 다중 투여량(multiple dose)으로 장기간 투여되는 분할 치료 방법(fractionated treatment protocol)에 의해 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. A pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the patient's disease type, severity, drug activity, drug sensitivity, and administration time , The route of administration and rate of excretion, duration of treatment, factors including co-drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. That is, the total effective amount of the composition of the present invention can be administered to a patient in a single dose, and can be administered by a fractionated treatment protocol that is administered for a long time in multiple doses. . Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 약학적 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하다. 일일 투여량으로는, 비경구 투여 시 본 발명의 스트렙토니그린, 테모졸로마이드 또는 베바시주맙(bevacizumab; 아바스틴, avastin)을 기준으로 하루에 체중 1 kg당 바람직하게 0.01 내지 50 mg, 더 바람직하게는 0.1 내지 30 mg의 양으로 투여되도록, 그리고 경구 투여 시는 본 발명의 스트렙토니그린, 테모졸로마이드 또는 베바시주맙을 기준으로 하루에 체중 1 kg당 바람직하게 0.01 내지 100 mg, 더 바람직하게는 0.01 내지 10 mg의 양으로 투여되도록 1 내지 수회에 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and disease severity. The daily dosage is preferably from 0.01 to 50 mg per kg of body weight per day, more preferably, based on the streptonigrin, temozolomide or bevacizumab (bevacizumab; avastin) of the present invention when administered parenterally. Is administered in an amount of 0.1 to 30 mg, and when administered orally, preferably 0.01 to 100 mg per kg of body weight per day, more preferably, based on the streptonigrin, temozolomide, or bevacizumab of the present invention. It can be divided into 1 to several times to be administered in an amount of 0.01 to 10 mg. However, since the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.
본 발명은 또한 스트렙토니그린(Streptonigrin) 및 항암제를 포함하는 항암보조제를 제공할 수 있다. The present invention can also provide an anti-cancer adjuvant comprising Streptonigrin and an anti-cancer agent.
상기 항암보조제는 항암제의 항암효과를 증대시키거나 항암제의 부작용을 억제 또는 개선시키기 위한 모든 형태를 의미한다. 본 발명의 항암보조제는 다양한 종류의 항암제 또는 항암보조제와 병용투여될 수 있으며, 병용투여시 통상적인 항암제의 투여량보다 낮은 수준으로 항암제를 투여하더라도 동등한 수준의 항암치료효과를 나타낼 수 있으므로 보다 안전한 항암치료를 수행할 수 있다. The anticancer adjuvant refers to all forms for enhancing the anticancer effect of the anticancer agent or suppressing or improving side effects of the anticancer agent. The anti-cancer adjuvant of the present invention may be administered in combination with various types of anti-cancer agents or anti-cancer adjuvants. Treatment can be performed.
상기 항암보조제의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 본 발명의 항암보조제는 목적하는 바에 따라 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 경구 투여, 폐 내 투여, 직장 내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 상기 항암보조제는 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다. The route of administration of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue. The anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, orally, pulmonarily, or rectally, as desired, but is not limited thereto. In addition, the anti-cancer adjuvant may be administered by any device capable of transporting the active substance to the target cell.
상기 항암보조제는 투여를 위해서 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 항암보조제로 바람직하게 제제화할 수 있다. 본 발명의 항암치료 보조제에 포함될 수 있는 담체, 부형제 또는 희석제로는, 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 포함하나 이에 제한되는 것은 아니다. The anticancer adjuvant may be preferably formulated as an anticancer adjuvant by including one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration. Carriers, excipients or diluents that may be included in the anticancer treatment adjuvants of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
상기 항암보조제는 경구 또는 비경구 투여를 위한 제제일 수 있으며, 제제에 대한 설명은 상기 약학적 조성물의 제제에 대한 기재로 대신한다. The anticancer adjuvant may be a formulation for oral or parenteral administration, and the description of the formulation is replaced by a description of the formulation of the pharmaceutical composition.
따라서 본 발명의 스트렙토니그린과 테모졸로마이드 또는 스트렙토니그린과 베바시주맙(bevacizumab; 아바스틴, avastin)을 각각 포함하는 경우 단독으로 사용하는 경우에 비하여 뇌종양 세포주에 대한 저해효과가 우수하므로 뇌종양 예방 또는 치료방법 내지 약학적 조성물로서 효과적으로 사용될 수 있다. 특히 상기 스트렙토니그린과 테모졸로마이드 또는 베바시주맙(bevacizumab; 아바스틴, avastin)은, 동시에 또는 순차적으로 투여할 수 있으며, 상기 스트렙토니그린은 방사선 요법과 병행하는 경우 뇌종양 세포주에 대한 저해효과가 유의적으로 증가할 수 있다.Therefore, when the streptonigrin and temozolomide of the present invention or the strepttonigrin and bevacizumab (avacstin, avastin) are included, the inhibitory effect on the brain tumor cell line is superior compared to the case of being used alone, thus preventing or preventing brain tumors. It can be effectively used as a treatment method or a pharmaceutical composition. Particularly, the streptonigrin and temozolomide or bevacizumab (avastin) can be administered simultaneously or sequentially, and the streptonigrin has a significant inhibitory effect on the brain tumor cell line when combined with radiation therapy. May increase.
도 1은 뇌종양 세포주(83NS)에 용매(vehicle), 스트렙토니그린(Streptonigrin), 테모졸로마이드(TMZ), 방사선 요법(Radiation 5Gy), 스트렙토니그린과 테모졸로마이드 병용(Streptonigrin+TMZ) 또는 스트렙토니그린과 방사선 요법(Streptonigrin+RT) 병용을 각각 처리하는 경우 뇌종양 세포주의 성장의 변화를 나타낸다. 각각 단독처리군에 비하여 스트렙토니그린과 테모졸로마이드를 병용하여 처리하는 경우 뇌종양 세포주에 대한 성장억제 효과가 유의적으로 증가하였으며, 스트렙토니그린과 방사선 요법을 병용하는 경우에도 비슷한 수준의 뇌종양 세포주 성장억제 효과가 나타나는 것을 확인할 수 있었다. 1 is a brain tumor cell line (83NS) in a solvent (vehicle), streptonigrin (Streptonigrin), temozolomide (TMZ), radiation therapy (Radiation 5Gy), streptonigrin and temozolomide in combination (Streptonigrin+TMZ) or strepto When the combination of nigrin and radiation therapy (Streptonigrin+RT) is treated, the growth of brain tumor cell lines is shown. Compared to the single treatment group, the growth inhibitory effect on the brain tumor cell line was significantly increased when streptonigrin and temozolomide were used in combination, and similar levels of the brain tumor cell growth were also observed when the combination of streptonigrin and radiation therapy was used. It was confirmed that the inhibitory effect appeared.
도 2는 뇌종양 세포주(83NS)를 주입한 마우스에 용매(vehicle), 스트렙토니그린(Streptonigrin), 베바시주맙(bevacizumab; 아바스틴, avastin) 또는 스트렙토니그린 및 베바시주맙 병용(Combination)을 각각 경구투여하는 경우 마우스의 생존률을 나타낸다. 각각 단독처리군에 비하여 스트렙토니그린과 베바시주맙을 병용하여 처리하는 경우 마우스의 생존률이 유의적으로 증가하는 것을 확인할 수 있었다. Figure 2 orally, the solvent (vehicle), Streptonigrin, bevacizumab (bevacizumab; avastin, avastin) or streptonigrin and bevacizumab combination in a mouse injected with a brain tumor cell line (83NS), respectively It shows the survival rate of mice when administered. It was confirmed that the survival rate of the mouse was significantly increased when streptonigreen and bevacizumab were used in combination compared to the single treatment group, respectively.
도 3은 뇌에 뇌종양 세포주(U87)을 뇌에 이식한 마우스에 용매(vehicle), 스트렙토니그린(Streptonigrin), 베바시주맙(bevacizumab; 아바스틴, avastin) 또는 스트렙토니그린 및 베바시주맙 병용(Combination)을 각각 투여한 후 뇌종양을 H&E 염색한 결과 및 투여한 후 15일 또는 24일째에 뇌종양을 MRI로 촬영한 결과를 나타낸다. 각각 단독처리군에 비하여 스트렙토니그린과 베바시주맙을 병용하여 처리하는 경우 뇌종양의 크기가 유의적으로 감소한 것을 확인할 수 있었다. Figure 3 is a solvent (vehicle), Streptonigrin, bevacizumab (bevacizumab; avastin, avastin) or streptonigrin and bevacizumab combination (Combination) in mice transplanted with brain tumor cell line (U87) into the brain ) Is the result of H&E staining of the brain tumor after administration, and results of MRI of the brain tumor on the 15th or 24th day after administration. Compared to the single treatment group, it was confirmed that the size of brain tumors was significantly reduced when streptonigreen and bevacizumab were used in combination.
도 4는 뇌에 뇌종양 세포주(U87)을 뇌에 이식한 마우스에 용매(vehicle), 스트렙토니그린(Streptonigrin), 베바시주맙(bevacizumab; 아바스틴, avastin) 또는 스트렙토니그린 및 베바시주맙 병용(Combination)을 각각 투여한 후 암 세포와 관련된 TGM2, C/EBPβ, pSTAT3 또는 HIF-1a를 확인한 결과를 나타낸다. 각각 단독처리군에 비하여 스트렙토니그린과 베바시주맙을 병용하여 처리하는 경우 각 인자의 수준이 유의적으로 감소하는 것을 확인할 수 있었다(스케일바=50㎛).Figure 4 is a brain tumor cell line (U87) transplanted into the brain mouse (vehicle), Streptonigrin (Streptonigrin), bevacizumab (Avastin, avastin) or streptonigreen and bevacizumab combination (Combination) ), respectively, and TGM2, C/EBPβ, pSTAT3 or HIF-1a associated with cancer cells. It was confirmed that the level of each factor was significantly decreased when streptonigreen and bevacizumab were used in combination compared to the single treatment group (scale bar=50 μm).
[실시예 1][Example 1]
뇌종양(교모세포종) 세포주의 세포생장의 저해활성 평가(in vitro)Evaluation of inhibitory activity of cell growth of brain tumor (glioblastoma) cell line (in vitro)
본 발명의 스트렙토니그린(Streptonigrin; 383) 및/또는 테모졸로마이드(Temozolomide; TMZ) 내지 스트렙토니그린 및 방사선 요법치료(RT)의 병행이 뇌종양 세포주(83NS)의 생장을 효과적으로 억제할 수 있는지 여부를 확인하고자 하였다. Whether the combination of Streptonigrin (383) and/or Temozolomide (TMZ) to Streptonigrin and radiotherapy (RT) of the present invention can effectively inhibit the growth of brain tumor cell lines (83NS) I wanted to check.
구체적으로, 3.0×103(세포/웰)의 83NS 세포주를 용매(Vehicle), 스트렙토니그린(100nM), TMZ(50μM), 방사선 처리(Radiation 5Gy, RT), 스트렙토니그린(100nM) + TMZ(50μM) 또는 스트렙토니그린(100nM) + 방사선 처리(5Gy) 로 각각 처리하고, 0일, 1일, 2일이 경과한 후 샘플을 수집하여 ATP 발광 분석법(ATP Luminescence assay)을 통해 세포생장의 지표인 ATP의 억제 활성을 평가하였다. Specifically, a 3.0×10 3 (cell/well) 83NS cell line was solvent (Vehicle), streptonigreen (100 nM), TMZ (50 μM), radiation treatment (Radiation 5 Gy, RT), streptonigreen (100 nM) + TMZ (50 μM) or streptonigreen (100 nM) + radiation treatment (5 Gy), respectively, and after 0, 1, and 2 days, samples were collected and ATP Luminescence assay was used for cell growth. The inhibitory activity of the indicator ATP was evaluated.
그 결과, [도 1]에 나타난 바와 같이 각각 단독처리군에 비하여 스트렙토니그린과 TMZ를 병용하여 처리하는 경우 뇌종양 세포주에 대한 생장억제 효과가 유의적으로 증가하였으며, 스트렙토니그린과 방사선 요법을 병용하는 경우에도 비슷한 수준의 뇌종양 세포주 생장억제 효과가 나타나는 것을 확인할 수 있었다.As a result, as shown in FIG. 1, when treated with streptonigreen and TMZ in combination, respectively, as compared to the single treatment group, the growth inhibition effect on the brain tumor cell line was significantly increased, and streptonigreen and radiation therapy were used in combination. It was also confirmed that a similar level of brain tumor cell line growth inhibitory effect was exhibited.
[실시예 2][Example 2]
뇌종양(교모세포종) 동물모델에 대한 항암활성 평가(in vivo)Evaluation of anticancer activity against brain tumor (glioblastoma) animal model (in vivo)
본 발명의 스트렙토니그린(Streptonigrin; 383) 및/또는 베바시주맙(Bevacizumab; 아바스틴, Avastin)이 뇌종양(U87) 동물모델에 대한 항암활성을 갖는지 여부를 확인하고자 하였다. 모든 동물 실험은 대한민국 국립암센터의 기관 동물 관리 및 사용위원회가 승인한 프로토콜에 따라 수행하였다. It was intended to confirm whether the Streptonigrin (383) and/or Bevacizumab (Avastin) of the present invention has anti-cancer activity against a brain tumor (U87) animal model. All animal experiments were performed according to the protocol approved by the Institutional Animal Care and Use Committee of the National Cancer Center of Korea.
구체적으로, DMEM에서 FBS 10 % 및 페니실린/스트렙토마이신 1 %로 배양한 뇌종양 세포주(U87) 5.0×104개를 5주령 Balb/c-nude 마우스 모델에 뇌의 좌측 실질조직에 주입하였다. 주입 좌표는 0.2mm 깊이에서, 중간선의 왼쪽에서 2.2mm, 브레그마 뒤 3.5mm 였다. 용매(Vehicle), 스트렙토니그린 0.5 mg/kg 및/또는 아바스틴(Avastin; 베바시주맙, bevacizumab) 10 mg/kg을 경구로 투여하고 시간 경과에 따른 마우스의 생존률 또는 종양 크기 변화를 GraphPad PRISM 소프트웨어(버전 7)를 사용하여 분석하였다. Specifically, 5.0×10 4 brain tumor cell lines (U87) cultured with 10% FBS and 1% penicillin/streptomycin in DMEM were injected into the left parenchymal tissue of the brain into a 5 week old Balb/c-nude mouse model. The injection coordinates were 0.2 mm deep, 2.2 mm from the left side of the midline and 3.5 mm behind the bregma. GraphPad PRISM software (Vehicle), 0.5 mg/kg of streptonigreen and/or 10 mg/kg of Avastin (or bevacizumab) was administered orally and the changes in survival or tumor size of mice over time were graphPad PRISM software ( Version 7).
종양의 크기는 H&E 염색(Staining) 또는 약물 투여 후 15일 또는 24일 경과한 마우스의 뇌종양을 수득하여 MRI 촬영을 통하여 확인하였다. H&E 염색은 약물 투여 후 49일 경과한 뇌종양 마우스의 뇌를 수득하고, 4%의 파라포름알데하이드를 이용하여 4 ℃에서 24 시간 동안 고정하여 파라핀 블록을 만든 후 4 ㎛ 두께로 잘랐으며, 이를 슬라이드 글라스에 붙여 헤마톡실린(DaKo) 및 0.25 % 에오신(Merck)으로 염색하였다. 염색은 자일렌 및 에탄올을 이용하여 상기 파라핀 블록을 충분히 수화시킨 후 수행하였다. 상기 방식을 통해 염색이 완료된 조직은 자일렌을 이용하여 마운팅시켰고, 마운팅된 조직은 Epifluorescence and Brightfield 현미경(Axioimager M1, Carl Zeiss, MA, USA)을 이용하여 관찰한 후 촬영하였다. Tumor size was confirmed by M&R imaging by obtaining brain tumors of mice 15 or 24 days after H&E staining or drug administration. H&E staining obtained brains of brain tumor mice 49 days after drug administration, and fixed at 4° C. for 24 hours using 4% paraformaldehyde to make paraffin blocks and cut them to a thickness of 4 μm. And stained with hematoxylin (DaKo) and 0.25% eosin (Merck). Staining was performed after sufficiently hydrating the paraffin block using xylene and ethanol. The tissues stained through the above method were mounted using xylene, and the mounted tissues were observed and photographed using an Epifluorescence and Brightfield microscope (Axioimager M1, Carl Zeiss, MA, USA).
추가적으로, 암 줄기 세포 마커 및 TGM2 관련 유전자 TGM2(Cell Signaling), C/EBPβ(Santa Cruz), pSTAT3(Cell Signaling) 또는 HIF-1a(Bethyl)의 면역 조직 화학적 염색의 경우, 구연산 완충액으로 항원 검색 공정 후(pH 6.0) 및 3 % 과산화수소로 내인성 퍼옥시다제를 차단하고, 조직 절편을 IHC 세계 항체 희석 완충액을 사용하여 4 ℃의 가습 챔버에서 1차 항체로 24시간 동안 인큐베이션하였다. 3,3-diaminobenzidine(DAB, Vector Laboratories)을 발색체로 사용하여 샘플을 확인하였다.Additionally, for immunohistochemical staining of cancer stem cell markers and TGM2-related genes TGM2 (Cell Signaling), C/EBPβ (Santa Cruz), pSTAT3 (Cell Signaling) or HIF-1a (Bethyl), the antigen retrieval process with citric acid buffer The endogenous peroxidase was blocked with post (pH 6.0) and 3% hydrogen peroxide, and tissue sections were incubated with primary antibody in a humidified chamber at 4° C. for 24 hours using an IHC world antibody dilution buffer. Samples were identified using 3,3-diaminobenzidine (DAB, Vector Laboratories) as a chromosome.
그 결과, [도 2]에 나타난 바와 같이 각각 단독처리군에 비하여 스트렙토니그린과 아바스틴(Avastin; 베바시주맙, bevacizumab)을 병용하여 처리하는 경우 마우스의 생존률이 유의적으로 높아졌다. 용매, 스트렙토니그린 및/또는 아바스틴 투여군의 평균 생존은 각각 28, 33, 38 및 49 일이었다. As a result, as shown in [Fig. 2], the survival rate of mice was significantly increased when treated with Streptonigreen and Avastin (bevacizumab, bevacizumab) in combination with each treatment group. The median survival of the solvent, streptonigreen and/or avastin administration groups was 28, 33, 38 and 49 days, respectively.
또한, [도 3] 에서 나타난 바와 같이 각각 단독처리군에 비하여 스트렙토니그린과 아바스틴을 병용하여 처리하는 경우 뇌종양 세포주에 대한 종양억제효과가 유의적으로 증가하였으며, 특히 시간의 경과에 따라 종양의 크기가 지속적으로 감소하는 것을 확인할 수 있었다.In addition, as shown in [Fig. 3], when treated with Streptonigreen and Avastin in combination, respectively, compared to the single treatment group, the tumor suppression effect on the brain tumor cell line was significantly increased, especially the size of the tumor over time. It was confirmed that is continuously decreasing.
또한, [도 4]에서 나타난 바와 같이 각각 단독처리군에 비하여 스트렙토니그린과 아바스틴을 병용하여 처리하는 경우 암 세포 관련 지표인 HIF-1a, TGM2, C/EBPβ 또는 pSTAT3의 수준이 유의적으로 감소하는 것을 확인할 수 있었다.In addition, as shown in [Fig. 4], the levels of HIF-1a, TGM2, C/EBPβ, or pSTAT3, which are cancer cell-related indicators, are significantly reduced when streptonigreen and avastin are used in combination, respectively, compared to the single treatment group. I could confirm that.
본 발명에 따른 스트렙토니그린과 테모졸로마이드 또는 베바시주맙을 모두 포함하는 경우 암 세포주의 성장 내지 생장을 억제하여 유의적인 항암효과를 발생시키므로, 암 예방 또는 치료방법 내지 약학적 조성물 내지 항암보조제로서 효과적이다. 또한 상기 스트렙토니그린은 방사선 요법과 병용되는 경우 그 항암효과가 유의적으로 증가할 수 있어 산업상 이용가능성이 크다. When both streptonigrin and temozolomide or bevacizumab according to the present invention are included, the growth or growth of the cancer cell line is inhibited, thereby generating a significant anti-cancer effect, so as to prevent or treat cancer, to a pharmaceutical composition or as an anticancer adjuvant effective. In addition, the anti-cancer effect of streptonigreen can be significantly increased when used in combination with radiation therapy, and thus has great industrial applicability.
Claims (10)
- 스트렙토니그린(Streptonigrin) 및 항암제를 뇌종양 환자에게 투여하는 단계를 포함하는 뇌종양 예방 또는 치료방법. A method for preventing or treating brain tumor, comprising administering Streptonigrin and an anticancer agent to a brain tumor patient.
- 제1항에 있어서, 상기 항암제는 테모졸로마이드(temozolomide) 또는 베바시주맙(bevacizumab)인 것을 특징으로 하는 뇌종양 예방 또는 치료방법. The method of claim 1, wherein the anti-cancer agent is temozolomide or bevacizumab.
- 제1항에 있어서, 상기 스트렙토니그린 및 항암제는 1 : 1 내지 1 : 100000 의 몰농도비로 투여되는 것을 특징으로 하는 뇌종양 예방 또는 치료방법.The method for preventing or treating brain tumor according to claim 1, wherein the streptonigreen and anticancer agent are administered in a molar ratio of 1:1 to 100000.
- 제1항에 있어서, 상기 스트렙토니그린(Streptonigrin) 및 항암제는 동시에, 또는 순차적으로 투여되는 것을 특징으로 하는 뇌종양 예방 또는 치료방법. The method for preventing or treating brain tumor according to claim 1, wherein the Streptonigrin and the anticancer agent are administered simultaneously or sequentially.
- 제1항에 있어서, 상기 방법은 방사선 요법과 병용되는 것을 특징으로 하는 뇌종양 예방 또는 치료방법. The method according to claim 1, wherein the method is used in combination with radiation therapy.
- 방사선 요법과 병용되는 것을 특징으로 하는, 스트렙토니그린(Streptonigrin)을 뇌종양 환자에게 투여하는 단계를 포함하는 뇌종양 예방 또는 치료방법.A method of preventing or treating brain tumor, comprising administering Streptonigrin to a brain tumor patient, characterized in that it is used in combination with radiation therapy.
- 스트렙토니그린(Streptonigrin) 및 항암제를 포함하는 뇌종양 예방 또는 치료에 사용하기 위한 약학적 조성물. A pharmaceutical composition for use in the prevention or treatment of brain tumors comprising Streptonigrin and anticancer agents.
- 제7항에 있어서, 상기 항암제는 테모졸로마이드(temozolomide) 또는 베바시주맙(bevacizumab)인 것을 특징으로 하는 뇌종양 예방 또는 치료에 사용하기 위한 약학적 조성물. The pharmaceutical composition for use in the prevention or treatment of brain tumor according to claim 7, wherein the anti-cancer agent is temozolomide or bevacizumab.
- 제7항에 있어서, 상기 스트렙토니그린 및 항암제는 1 : 1 내지 1 : 100000 의 몰농도비로 포함되는 것을 특징으로 하는 뇌종양 예방 또는 치료에 사용하기 위한 약학적 조성물. The pharmaceutical composition for use in the prevention or treatment of brain tumors according to claim 7, wherein the streptonigreen and anticancer agent are contained in a molar ratio of 1:1 to 100000.
- 제7항에 있어서, 상기 약학적 조성물은 방사선 요법과 병용되는 것을 특징으로 하는 뇌종양 예방 또는 치료에 사용하기 위한 약학적 조성물.The pharmaceutical composition for use in the prevention or treatment of brain tumor according to claim 7, wherein the pharmaceutical composition is used in combination with radiation therapy.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2019-0011477 | 2019-01-29 | ||
| KR20190011477 | 2019-01-29 |
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| WO2020159203A1 true WO2020159203A1 (en) | 2020-08-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/KR2020/001307 WO2020159203A1 (en) | 2019-01-29 | 2020-01-29 | Composition comprising streptonigrin and anticancer agent for preventing or treating brain tumor |
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| Country | Link |
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| KR (1) | KR20200094110A (en) |
| WO (1) | WO2020159203A1 (en) |
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| KR20220129447A (en) | 2021-03-16 | 2022-09-23 | (주)엠디바이오랩 | Novel compounds as Transglutaminase 2 inhibitors and composition for preventing or treating cancer containing the compounds |
| KR20230092793A (en) | 2021-12-17 | 2023-06-26 | 숙명여자대학교산학협력단 | Combination therapy with griseofulvin for encephaloma |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012010551A1 (en) * | 2010-07-19 | 2012-01-26 | F. Hoffmann-La Roche Ag | Method to identify a patient with an increased likelihood of responding to an anti-cancer therapy |
| EP2583685A1 (en) * | 2004-06-10 | 2013-04-24 | Regeneron Pharmaceuticals, Inc. | Method of administering and using VEGF inhibitors for the treatment of human cancer |
| KR20160009146A (en) * | 2014-07-15 | 2016-01-26 | 국립암센터 | Pharmaceutical compositions for treating or preventing transglutaminase 2-related disease comprising streptonigrin, and uses thereof |
-
2020
- 2020-01-29 KR KR1020200010210A patent/KR20200094110A/en not_active Application Discontinuation
- 2020-01-29 WO PCT/KR2020/001307 patent/WO2020159203A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2583685A1 (en) * | 2004-06-10 | 2013-04-24 | Regeneron Pharmaceuticals, Inc. | Method of administering and using VEGF inhibitors for the treatment of human cancer |
| WO2012010551A1 (en) * | 2010-07-19 | 2012-01-26 | F. Hoffmann-La Roche Ag | Method to identify a patient with an increased likelihood of responding to an anti-cancer therapy |
| KR20160009146A (en) * | 2014-07-15 | 2016-01-26 | 국립암센터 | Pharmaceutical compositions for treating or preventing transglutaminase 2-related disease comprising streptonigrin, and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| SEON-HYEONG LEE, WON-KYU LEE, NAYEON KIM, JOON KANG, KYUNG-HEE KIM, SEUL-GI KIM, JAE-SEON LEE, SOOHYUN LEE, JONGKOOK LEE, JUNGNAM : "Renal cell carcinoma is abrogated by p53 stabilization through transglutaminase 2 inhibition", CANCER, vol. 10, no. 11, 19 November 2018 (2018-11-19), pages 455 - 18, XP055728166 * |
| WANG, H.: "Isolation of streptonigrin and its novel derivative from micromonospora as inducing agents of p53-dependent cell apoptosis", JOURNAL OF NATURAL PRODUCTS, vol. 65, no. 5, May 2002 (2002-05-01), pages 721 - 724, XP055728171, DOI: 10.1021/np0104572 * |
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| KR20200094110A (en) | 2020-08-06 |
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