WO2020106050A1 - Composition pharmaceutique comprenant à la fois de la streptonigrine et un agent anticancéreux pour empêcher ou traiter le cancer - Google Patents

Composition pharmaceutique comprenant à la fois de la streptonigrine et un agent anticancéreux pour empêcher ou traiter le cancer

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Publication number
WO2020106050A1
WO2020106050A1 PCT/KR2019/015907 KR2019015907W WO2020106050A1 WO 2020106050 A1 WO2020106050 A1 WO 2020106050A1 KR 2019015907 W KR2019015907 W KR 2019015907W WO 2020106050 A1 WO2020106050 A1 WO 2020106050A1
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Prior art keywords
cancer
cisplatin
streptonigreen
paclitaxel
agent
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PCT/KR2019/015907
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English (en)
Korean (ko)
Inventor
김수열
허균
임명철
강석범
Original Assignee
(주)엠디바이오랩
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Publication of WO2020106050A1 publication Critical patent/WO2020106050A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is streptoni green; And any one or more additional anti-cancer agents selected from the group consisting of cisplatin, gemcitabine and paclitaxel; It relates to a pharmaceutical composition or an anti-cancer adjuvant for use in the prevention or treatment of cancer comprising all.
  • the present invention is streptoni green; And any one or more additional anti-cancer agents selected from the group consisting of cisplatin, gemcitabine and paclitaxel; It relates to a cancer prevention or treatment method comprising the step of administering a pharmaceutical composition comprising all of the.
  • 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 severe 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 severe pain and eventually death.
  • the number of cancer patients in Korea has increased continuously, 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 combine and treat the anti-cancer agent has been proposed.
  • Transglutaminase (Transglutaminase 2, TGase2) is an enzyme that promotes the binding between ⁇ -carboxamide groups of glutamine residues bound to specific peptides and various amines, and primarily promotes the prevention, repair, and repair of damage.
  • TGase2 Transglutaminase 2, TGase2
  • TGase2 is an enzyme that promotes the binding between ⁇ -carboxamide groups of glutamine residues bound to specific peptides and various amines, and primarily promotes the prevention, repair, and repair of damage.
  • diseases such as neurodegenerative diseases, atherosclerosis, inflammatory diseases, and autoimmune diseases.
  • TGase2 polymerizes and destabilizes p53 and thus disappears. Accordingly, it has been reported that the inhibition of TGase2 may have an anti-cancer effect on overexpressed kidney cancer.
  • 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 composition having a significantly increased anti-cancer effect by using streptonigrin and other anti-cancer agents, and as a result, streptonigrin and gemcitabine, cisplatin or paclitaxel were used in combination with cancer cells, particularly ovarian cancer cells. Upon treatment, it was confirmed that it exhibited excellent anticancer effects and the present invention was completed.
  • the object of the present invention is streptoni green; And any one or more additional anti-cancer agents selected from the group consisting of cisplatin, gemcitabine and paclitaxel; It is to provide a pharmaceutical composition, anti-cancer adjuvant to cancer prevention or treatment method for use in the prevention or treatment of cancer comprising all.
  • the present invention is a streptoni green; And any one or more additional anti-cancer agents selected from the group consisting of cisplatin, gemcitabine and paclitaxel; It provides a pharmaceutical composition or an anti-cancer adjuvant for use in the prevention or treatment of cancer comprising all.
  • the streptonigreen and the additional anticancer agent may be included in a concentration ratio of 1:10 to 1:10 6 .
  • the streptonigreen and the additional anticancer agent may be included in a ratio of 1: 1 to 1: 100000.
  • the cancer may be ovarian cancer.
  • the present invention is streptoni green; And any one or more additional anti-cancer agents selected from the group consisting of cisplatin, gemcitabine and paclitaxel; It provides a method for preventing or treating cancer comprising the step of administering to a patient a pharmaceutical composition comprising all.
  • the streptonigreen and the additional anticancer agent may be included in a concentration ratio of 1:10 to 1:10 6 .
  • the streptonigreen and the additional anticancer agent may be included in a ratio of 1: 1 to 1: 100000.
  • the cancer may be ovarian cancer.
  • the anti-cancer effect can be exhibited by using the transglutaminase (TGase2) inhibitory effect of streptonigreen, and when used in combination with the anti-cancer agent, the anticancer effect is significantly increased. No studies or descriptions of synergistic effects have been disclosed.
  • TGase2 transglutaminase
  • composition comprising both streptonigreen and other anticancer agents according to the present invention inhibits the growth or growth of cancer, it generates a significant anticancer effect, and thus can be effectively used in cancer prevention or treatment compositions, anticancer adjuvants or cancer prevention or treatment Can be.
  • the present invention is streptonigreen; And any one or more additional anti-cancer agents selected from the group consisting of cisplatin, gemcitabine and paclitaxel; It can provide a pharmaceutical composition for use in the prevention or treatment of cancer comprising all.
  • the Streptonigreen is a Tgase2 inhibitor produced by Streptomyces floculus, and refers to an antibiotic that causes chromosomal cleavage.
  • the cisplatin cisplatin
  • the gemcitabine is an anticancer agent used for various cancers such as breast cancer, ovarian cancer, or pancreatic cancer, and has an effect of inhibiting DNA production related to cell death.
  • the paclitaxel is an anticancer agent belonging to the taxane drug group, and has an effect of interfering with the normal function of microtubules during cell division.
  • the additional anti-cancer agent means an anti-cancer agent that may be included in the pharmaceutical composition of the present invention in addition to streptonigrin, and refers to cisplatin, gemcitabine, or paclitaxel. Cisplatin, gemcitabine, or paclitaxel, which are additional anticancer agents, may all be included, but are preferably included alone.
  • the streptonigreen and the additional anti-cancer agent are preferably included in a concentration ratio of 1:10 to 1:10 6 , but are not limited thereto.
  • streptonigreen and cisplatin are preferably included in a concentration ratio of 1: 100 to 1: 100000, more preferably in a concentration ratio of 1: 1000 to 1: 10000.
  • Streptonigreen and gemcitabine are preferably included in a concentration ratio of 1: 100 to 1: 10000, more preferably in a concentration ratio of 1: 100 to 1: 1000.
  • the streptonigreen and the additional anti-cancer agent are preferably included in a ratio of 1: 1 to 1: 100000, more preferably 1:10 to 1: 10000. It is preferred.
  • the ratio may be a dose ratio, more preferably a mg / kg ratio.
  • the cancer of the present invention is ovarian cancer.
  • the pharmaceutical composition for use in the prevention or treatment of cancer 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 granular mixture.
  • starch corn starch, wheat starch, rice starch, potato Starch, etc.
  • calcium carbonate sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, ery
  • 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, etc. are included.
  • cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and may further include an anti-coagulant, lubricant, wetting agent, fragrance, emulsifier, and 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; Transdermal administration; Alternatively, nasal inhalants may be formulated according to methods known in the art.
  • suitable carriers include, but are not limited to, solvents or dispersion media including water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils.
  • suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanol amine or sterile water for injection, isotonic solutions such as 10% ethanol, 40% propylene glycol and 5% dextrose. Etc. can be used.
  • various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, etc. may be further included.
  • the injection may additionally contain isotonic agents such as sugars or sodium chloride in most cases.
  • transdermal administration means that the pharmaceutical composition is topically administered to the skin, so that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin.
  • the compounds used according to the invention may be used in the form of pressurized packs, using suitable propellants, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. 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 for use in the prevention or treatment of cancer 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, sensitivity to the drug, 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 a conventional therapeutic agent, 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.
  • a daily dose when administered parenterally, it is preferably administered in an amount of 0.01 to 50 mg per kg of body weight per day, more preferably 0.1 to 30 mg per kg of body weight per day, based on streptonigreen and an anticancer agent used in combination, and orally
  • it can be divided into 1 to several times to be administered in an amount of preferably 0.01 to 100 mg, more preferably 0.01 to 10 mg per 1 kg of body weight per day, based on the streptonigrin of the present invention and an anticancer agent used in combination. have.
  • the dosage since the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, and age, the above dosage does not limit the scope of the present invention in any way.
  • composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormonal therapy, chemotherapy and biological response modifiers.
  • the pharmaceutical composition of the present invention can also be provided as a formulation of an external preparation containing streptonigreen and an anticancer agent used in combination therewith as an active ingredient.
  • an external preparation for skin, fat substances, organic solvents, solubilizers, thickeners and gelling agents, emollients, antioxidants, suspending agents, stabilizers, blowing agents (foaming agent), fragrance, surfactant, water, ionic emulsifier, nonionic emulsifier, filler, metal ion blocker, chelating agent, preservative, vitamin, blocker, wetting agent, essential oil, dye, pigment, hydrophilic active agent, It may contain adjuvants commonly used in the field of skin science, such as lipophilic actives or any other ingredients commonly used in external skin preparations such as lipid vesicles. In addition, the ingredients may be introduced in an amount commonly used in the field of skin science.
  • the pharmaceutical composition for use in the prevention or treatment of cancer of the present invention is provided as an external preparation for skin
  • the present invention is not limited thereto, and may be a formulation such as ointment, patch, gel, cream or spray.
  • the present invention is streptoni green; And any one or more additional anti-cancer agents selected from the group consisting of cisplatin, gemcitabine and paclitaxel; It may provide an anti-cancer adjuvant rule containing all.
  • streptonigreen, cisplatin, gemcitabine, or paclitaxel are the same as those used in the composition for preventing or treating cancer, the description is replaced by the above description.
  • the anti-cancer adjuvant of the present invention means all forms for enhancing the anti-cancer effect of the anti-cancer agent or suppressing or improving side effects of the anti-cancer 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 anti-cancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, orally, pulmonarily, intrarectally, 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 of the present invention can be preferably formulated as an anticancer adjuvant by including at least one pharmaceutically acceptable carrier in addition to the active ingredient for administration.
  • Carriers, excipients, or diluents that may be included in the anticancer treatment adjuvant 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 anti-cancer adjuvant of the present invention may be an agent for oral or parenteral administration, and the description of the agent is replaced by the description of the agent of the pharmaceutical composition.
  • the present invention is streptoni green; And any one or more additional anti-cancer agents selected from the group consisting of cisplatin, gemcitabine and paclitaxel; It may provide a method for preventing or treating cancer, comprising the step of administering a pharmaceutical composition comprising all to a patient.
  • the streptonigreen, cisplatin, gemcitabine, paclitaxel, and pharmaceutical compositions are the same as those used in the pharmaceutical compositions for use in the prevention or treatment of cancer, so the description is replaced by the above description.
  • the administration is a concept including both administration of streptonigreen and cisplatin, gemcitabine or paclitaxel simultaneously or sequentially.
  • the cancer is ovarian cancer.
  • the composition comprising both the streptonigreen of the present invention and other anti-cancer agents is effective as a composition for preventing or treating cancer because it has an excellent effect of inhibiting the growth of cancer cells, especially the effect of inhibiting the growth of ovarian cancer cells. .
  • Figure 1 shows the results of monitoring the progress of the tumor through bioluminescence imaging in the case of treatment with streptonigreen alone in an ovarian cancer xenograft model.
  • Figure 2 shows the results of monitoring the progress of the tumor through bioluminescence imaging when cisplatin or paclitaxel are respectively treated in an ovarian cancer xenograft model.
  • Figure 3 shows the results of monitoring the progress of the tumor through bioluminescence imaging in the case of treatment with streptonigreen, cisplatin and / or paclitaxel in an ovarian cancer xenograft model. It was confirmed that the progression of the tumor was suppressed when streptonigrin and cisplatin, or streptonigrin and paclitaxel were used in combination, respectively, compared to the case of treating streptonigrin, cisplatin or paclitaxel alone.
  • Figure 4 shows the results of quantifying the bioluminescence of the progression of tumors when streptonigreen and / or paclitaxel is treated in an ovarian cancer xenograft model. It was confirmed that the bioluminescence degree for the tumor was decreased and the survival rate of mice was increased when streptonigrin and paclitaxel were treated in combination, respectively, compared to the case of treatment with streptonigrin or paclitaxel alone.
  • Figure 5 shows the results of quantifying the bioluminescence for the progression of tumors in the treatment of streptonigrin and / or cisplatin in an ovarian cancer xenograft model. It was confirmed that the bioluminescence degree for the tumor was decreased and the survival rate of mice was increased when streptonigrin and cisplatin were treated in combination, respectively, compared to the case where streptonigrin or cisplatin was treated alone.
  • FIG. 6 shows changes in cell growth when ovarian cancer cells are treated with only solvent (DMSO 1%, PBS 99%), streptonigreen, cisplatin or gemcitabine alone, or when streptonigreen and cisplatin or gemcitabine are used in combination, respectively. Indicates. It was confirmed that the growth rate of ovarian cancer cells was significantly reduced when streptonigrin and cisplatin or gemcitabine were treated in combination with a solvent or a single treatment group.
  • solvent 1%, PBS 99%
  • a preclinical xenograft tumor model was prepared to confirm the effect of streptonigreen and / or cisplatin or paclitaxel on ovarian cancer tumors.
  • tumors were induced in Balb / c-nu mice (Central Lab Animal, Seoul, Korea) of 6 to 8 weeks of age.
  • OVCAR-8 / luc cells (1.0 ⁇ 10 7 ) were injected intraperitoneally using a 1 ml syringe.
  • PBS was orally administered to all mice, and streptonigreen (20 nM) was orally administered 0.01 mg / kg 5 times a week, paclitaxel (10 nM, 1 mg / kg and 10 mg / kg) or cisplatin (1 mg / kg).
  • paclitaxel 10 nM, 1 mg / kg and 10 mg / kg
  • cisplatin (1 mg / kg).
  • Tumor progress was monitored once weekly using In Vivo Imaging System (IVS) bioluminescence imaging.
  • IVS In Vivo Imaging System
  • A2780-luciferase and SK-OV-3-luciferase cells were received in the laboratory of ph.D Heo Kyun. Ovarian cancer cells were cultured in a complete RPMI 1640 medium (Hyclone, UT, USA) containing 10% fetal bovine serum (Hyclone, UT, USA) in an environment of 5% CO 2, 100% humidity and 37 ° C.
  • cells 100 ⁇ l were seeded in 96-well microtiter plates with plating densities of 5000 to 40000 cells / well depending on the doubling time of individual cell lines. After cell inoculation, the cells were cultured for 24 hours prior to the addition of the experimental drug. After 100 ⁇ l of each drug was added to each well, the plate was incubated for 48 hours in a 37 ° C. CO 2 incubator. Cells were treated with cold 50% TCA (trichloroacetic acid, 50 ⁇ l / well), and then incubated at 4 ° C. for 60 minutes to fix the cells. The supernatant was discarded, washed 5 times with tap water and naturally dried at room temperature for 12 to 24 hours.
  • TCA trichloroacetic acid
  • GI50 0.4% (w / v) solution of sulforhodamine B (100 ⁇ l) in 1% acetic acid was added to each well, and the plate was left at room temperature for 10 minutes. After staining, washing was performed 5 times with 1% acetic acid to remove non-binding dyes and allowed to air dry. The bound dye was then solubilized with 10 mM Trizma base and absorbance was recorded using an automated plate reader at 515 nm. The effect of the drug was expressed as GI50 (50% growth inhibition), TGI (total growth inhibition) or LC50 (lethal concentration).
  • the concentration of each drug is 20 nM for streptonigreen, 100 ⁇ M for cisplatin, 10 ⁇ M for gemcitabine, or 1 ⁇ M for doxorubicin.
  • composition further comprising streptonigreen and cisplatin, gemcitabine or paclitaxel provided in the present invention has a synergistic effect and is excellent in inhibiting cancer, especially ovarian cancer, so that it is a pharmaceutical composition for use in preventing or treating cancer , Since it can be effectively used in anticancer adjuvants or cancer prevention or treatment methods using the same, it has great industrial applicability.

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Abstract

La présente invention concerne une composition pharmaceutique ou un agent anticancéreux adjuvant pour la prévention ou le traitement du cancer comprenant à la fois la streptonigrine et un ou plusieurs agents anticancéreux choisis dans le groupe constitué de cisplatine, de gemcitabine et de paclitaxel. De plus, la présente invention concerne un procédé de prévention ou de traitement du cancer comprenant l'étape pour administrer, à un patient, la composition pharmaceutique comprenant à la fois de la streptonigrine et un ou plusieurs agents anticancéreux choisis dans le groupe constitué de cisplatine, de gemcitabine et de paclitaxel. Par conséquent, la composition selon la présente invention comprenant à la fois la streptonigrine et d'autres agents anticancéreux est hautement efficace dans l'inhibition de la croissance des cellules cancéreuses, en particulier la croissance de cellules cancéreuses ovariennes, et peut ainsi être efficacement utilisée dans une composition ou un procédé utilisant la composition pour prévenir ou traiter le cancer.
PCT/KR2019/015907 2018-11-20 2019-11-20 Composition pharmaceutique comprenant à la fois de la streptonigrine et un agent anticancéreux pour empêcher ou traiter le cancer WO2020106050A1 (fr)

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KR10-2018-0143938 2018-11-20
KR20180143938 2018-11-20

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WO2020106050A1 true WO2020106050A1 (fr) 2020-05-28

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PCT/KR2019/015906 WO2020106049A1 (fr) 2018-11-20 2019-11-20 Composition pharmaceutique comprenant à la fois de la streptonigrine et un agent anti-cancéreux permettant la prévention ou le traitement d'un cancer
PCT/KR2019/015907 WO2020106050A1 (fr) 2018-11-20 2019-11-20 Composition pharmaceutique comprenant à la fois de la streptonigrine et un agent anticancéreux pour empêcher ou traiter le cancer
PCT/KR2019/015908 WO2020106051A2 (fr) 2018-11-20 2019-11-20 Composition pharmaceutique à utiliser dans la prévention ou le traitement du cancer, comprenant à la fois de la streptonigrine et un agent anticancéreux

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482802B1 (en) * 1998-05-11 2002-11-19 Endowment For Research In Human Biology, Inc. Use of neomycin for treating angiogenesis-related diseases
US20060276527A1 (en) * 2003-01-17 2006-12-07 Thresold Pharmaceuticals, Inc. Combination therapies for the treatment of cancer
US20080119440A1 (en) * 2006-08-31 2008-05-22 Keizo Koya Combination with Bis(thiohydrazide amides) for treating cancer
EP2583685A1 (fr) * 2004-06-10 2013-04-24 Regeneron Pharmaceuticals, Inc. Procédé d'administration et d'utilisation d'inhibiteurs de VEGF pour le traitement d'un cancer humain
CN108703958A (zh) * 2018-08-11 2018-10-26 西华大学 一种协同链黑菌素制备抗肿瘤纳米组合药物的方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2570887C (fr) * 2004-06-18 2014-09-16 Genentech, Inc. Traitement tumoral
KR101643459B1 (ko) * 2014-07-15 2016-07-28 국립암센터 스트렙토니그린을 포함하는 트랜스글루타미나제２ 관련 질환 치료 또는 예방용 약제학적 조성물 및 이의 용도
KR102147721B1 (ko) * 2017-10-24 2020-08-25 (주)엠디바이오랩 스트렙토니그린 및 라파마이신을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482802B1 (en) * 1998-05-11 2002-11-19 Endowment For Research In Human Biology, Inc. Use of neomycin for treating angiogenesis-related diseases
US20060276527A1 (en) * 2003-01-17 2006-12-07 Thresold Pharmaceuticals, Inc. Combination therapies for the treatment of cancer
EP2583685A1 (fr) * 2004-06-10 2013-04-24 Regeneron Pharmaceuticals, Inc. Procédé d'administration et d'utilisation d'inhibiteurs de VEGF pour le traitement d'un cancer humain
US20080119440A1 (en) * 2006-08-31 2008-05-22 Keizo Koya Combination with Bis(thiohydrazide amides) for treating cancer
CN108703958A (zh) * 2018-08-11 2018-10-26 西华大学 一种协同链黑菌素制备抗肿瘤纳米组合药物的方法

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KR102387563B1 (ko) 2022-04-18
KR102387564B1 (ko) 2022-04-18
WO2020106049A1 (fr) 2020-05-28
KR20200059176A (ko) 2020-05-28
KR102387565B1 (ko) 2022-04-18
WO2020106051A3 (fr) 2020-07-09
KR20200059178A (ko) 2020-05-28
WO2020106051A2 (fr) 2020-05-28

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