WO2017146528A1 - Nouveau peptide pour atténuer des effets secondaires de médicament anticancéreux et composition pharmaceutique le comprenant comme principe actif - Google Patents

Nouveau peptide pour atténuer des effets secondaires de médicament anticancéreux et composition pharmaceutique le comprenant comme principe actif Download PDF

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WO2017146528A1
WO2017146528A1 PCT/KR2017/002080 KR2017002080W WO2017146528A1 WO 2017146528 A1 WO2017146528 A1 WO 2017146528A1 KR 2017002080 W KR2017002080 W KR 2017002080W WO 2017146528 A1 WO2017146528 A1 WO 2017146528A1
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seq
anticancer
damage
polypeptide
peptide
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PCT/KR2017/002080
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English (en)
Korean (ko)
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배재성
진희경
박민희
김남오
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경북대학교 산학협력단
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Publication of WO2017146528A1 publication Critical patent/WO2017146528A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression

Definitions

  • the present invention relates to a novel peptide for mitigating side effects by an anticancer agent and a pharmaceutical composition comprising the same as an active ingredient, and more particularly, to bone marrow induced by an anticancer agent Including the peptide of SEQ ID NO: 1 as an essential component having an effect of alleviating side effects such as damage, nerve damage or kidney damage, 1 to 5 amino acids added to the N-terminal or C-terminal of the peptide
  • the present invention relates to a linked polypeptide, a pharmaceutical composition for alleviating side effects by an anticancer agent comprising the same as an active ingredient, and a use and method thereof.
  • cancer causes death.
  • cancer treatment which accounts for most of the causes of death, includes surgery, radiation therapy, biotherapy and chemotherapy.
  • anticancer drugs used as chemotherapy intervene in the metabolic pathways of cancer cells and directly interact with DNA to block DNA replication, transcription, and translation processes, interfere with the synthesis of nucleic acid precursors, and inhibit cell division. Cytotoxicity against. Therefore, anticancer drugs cause fatal damage to normal cells when administered, resulting in bone marrow hematopoietic immunosuppression, hair loss, gastrointestinal disorders, liver, kidney toxicity, and so on.
  • Toxicity due to chemotherapy may be due to bone marrow destruction. Hypocytopenia of plate, red blood cells, hair loss due to hair follicle cell destruction, dysmenorrhea and male infertility due to side effects to ovaries and testicles, stomatitis, nausea and vomiting due to side effects from mucosal cell destruction of digestive organs Disorders, diarrhea symptoms, renal toxicity caused by tubular necrosis, peripheral neuritis and weakness caused by nervous system disorders, vascular disorders such as vascular pain and rash, and skin and nail discoloration.
  • Cisplatin which is used as an anticancer agent, is an effective chemotherapy agent for malignant tumors including testes, head and neck, ovaries, cervix, non-small cell tumors and various types of cancer.
  • Renal toxicity induced by cisplatin causes inflammatory reactions, direct microtubule toxicity, vascular disease, and oxidative stress (Ramesh and Reeves, 2002). Inflammatory reactions provide an important mechanism of renal toxicity induced by cisplatin (Davi s et al., 2001). Recent studies have reported that inflammation-inducing factors such as tumor necrosis factor-a (TNF-a), interleukin-6, and interleukin-1 ⁇ are associated with renal toxicity caused by cisplatin (Faubel et al., Ramesh and Reeves, 2002, 2004). The most common side effects of chemotherapy include nausea and vomiting. Nausea and vomiting vary depending on the anticancer drugs.
  • TNF-a tumor necrosis factor-a
  • interleukin-6 interleukin-6
  • interleukin-1 ⁇ interleukin-1 ⁇
  • Nausea and vomiting due to cisplatin administration which is frequently used for kidney and lung cancer, are very severe. In anorexia, vomiting is easily induced. Toxic to liver.
  • Various anti-emetic drugs are selected and combined according to clinical symptoms and used before and after chemotherapy, and vomiting can be successfully controlled by various paths and various time-of-day administration, but the quality of life is deteriorated.
  • Ondansetron used to suppress acute and delayed vomiting, causes allergic reactions, irregular heart rhythms, muscle spasms, secondary side effects that can't move, and metoclopramide is nerve hypersensitivity, breathing.
  • Diazepam (Di azepam) is part of bronchial pain, rash, hallucinations, etc. Action appears.
  • chemotherapy supplements are used for the purpose of alleviating the side effects of chemotherapy, increasing the efficacy of chemotherapy, increasing the survival rate of cancer patients and improving the quality of life, but chemotherapy supplements also cause secondary side effects.
  • Interferon and interleukin are excellent protein preparations with excellent antitumor and immunopotentiating effects.
  • Mesna TM which is used to prevent urine toxicity, has side effects such as nausea, vomiting, decreased appetite, gastrointestinal pain, diarrhea, fever, and dizziness. Aminfost ine TM Because of its antihypertensive action, continuous administration is not possible 24 hours before administration.
  • conventional techniques for mitigating the side effects of chemotherapy include:
  • Korean Laid-Open Patent Publication No. 2002-0015906 discloses a pharmaceutical composition comprising an extract of Gr if ola frondasa, which can suppress the side effects of an anticancer agent. It is disclosed to suppress renal toxicity, digestive toxicity, hematopoietic toxicity and the like caused by the administration of cisplatin, an anticancer agent.
  • Korean Patent Laid-Open Publication No. 2002-0015906 discloses a pharmaceutical composition comprising an extract of Gr if ola frondasa, which can suppress the side effects of an anticancer agent. It is disclosed to suppress renal toxicity, digestive toxicity, hematopoietic toxicity and the like caused by the administration of cisplatin, an anticancer agent.
  • 2004-0000757 discloses a herbal composition having an effect of inhibiting side effects of anticancer treatment, wherein the herbal composition has a dry weight ratio of 7-20 parts by weight of sucrose and 5-15 parts by weight, Angelica 5-15 parts, and Cheongung 5-15 It is composed of 5 parts by weight, 5 to 15 parts by weight, 3 to 10 parts by weight of cornus oil, 1.5 to 5 parts by weight of bark skin, 1.5 to 5 parts by weight of wolfberry, 0.5 to 2.0 parts by weight of safflower and 1 to 3 parts by weight of licorice.
  • 2002-0040532 discloses an antioxidant drink having a side effect inhibitory effect according to an anticancer therapy prepared by using a low molecular weight red ginseng saponin and a glutate (GMT) having an active oxygen inhibitory effect, and a method of preparing the same Doing.
  • the antioxidant drink exhibits excellent free radical scavenging ability and can suppress various side effects caused by free radicals.
  • Conventional anticancer drug side effects inhibitors are mostly active in the case of natural substances. In many cases, the powder is not clearly identified, and in the case of chemicals, the side effect of the desired anticancer agent is reduced, but it is pointed out as a problem that causes another toxicity. For example, to prevent cardiotoxicity of anthracycline-based drugs including doxorubicin
  • Dexrazoxane a derivative of ED hy 1 ened i am i ne t et r aacet ic acid, has been used, but transient thrombocytopenia, nausea, vomiting, liver failure and mutagenicity have been reported (Levine BS). et al. Cancer Treat Rep. 1980, vol. 64 (12), pp. 1211-1215; Von Hoff DD. etal. Cancer Treat Rep. 1981, vol. 65 (3-4), pp. 249-252; Whittaker , P. et al. Environ Mol Mutagen. 2001, vol. 38 (4), p.347-356; Levine, BS et al. Cancer Treat Rev. 1991, vol. 18 (4), pp.241-252) . Therefore, there is a need for the development of new substances to alleviate various side effects caused by anticancer drugs.
  • the present inventors have made intensive efforts to develop a drug that can alleviate the side effects of the anticancer agent, and as a result, the peptide having the amino acid sequence of SEQ ID NO: 2 or 3 is caused by bone marrow damage, nerve damage or The present invention was completed by confirming that there is an effect of alleviating side effects such as kidney damage. Accordingly, it is an object of the present invention to provide a polypeptide comprising the peptide of SEQ ID NO: 1 as an essential component, wherein 1 to 5 amino acids are additionally linked to the N-terminus or C-terminus of the peptide.
  • It is also an object of the present invention is to provide a polypeptide consisting of the peptide of SEQ ID NO: 1 as an essential component, wherein 1 to 5 amino acids are additionally linked to the N-terminal or C-terminal of the peptide.
  • Another object of the present invention is a disease selected from the group consisting of bone marrow damage, nerve damage and kidney damage by an anticancer agent comprising the polypeptide as an active ingredient or It is to provide a pharmaceutical composition for the prevention or treatment of the condition.
  • Another object of the present invention is to provide a use for the preparation of a therapeutic agent for a disease or condition selected from the group consisting of bone marrow damage, nerve damage and kidney damage by the anticancer agent of the polypeptide.
  • Another object of the present invention to provide a method for treating a disease or condition selected from the group consisting of bone marrow damage, nerve damage and kidney damage by an anticancer agent, characterized in that the polypeptide is administered to an individual in need thereof in an effective amount.
  • an anticancer adjuvant comprising the poly3 ⁇ 4tide as an active ingredient.
  • the present invention includes a peptide of SEQ ID NO: 1 as an essential component, and provides a polypeptide in which 1 to 5 amino acids are additionally linked to the N-terminus or C-terminus of the peptide.
  • the present invention comprises a peptide consisting of the essential component of the peptide of SEQ ID NO: 1, provides a polypeptide in which 1 to 5 amino acids are additionally linked to the N-terminal or C-terminal of the peptide .
  • the present invention essentially consists of the peptide of SEQ ID NO: 1 as an essential component in order to achieve the object of the present invention, a polypeptide wherein 1 to 5 amino acids are additionally linked to the N-terminal or C-terminal of the peptide To provide.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease or condition selected from the group consisting of bone marrow damage, nerve damage and kidney damage by an anticancer agent comprising the polypeptide as an active ingredient. to provide.
  • the present invention provides a use for the preparation of a therapeutic agent for a disease or condition selected from the group consisting of bone marrow damage, nerve damage and kidney damage by the anticancer agent of the polypeptide.
  • the present invention is a disease selected from the group consisting of bone marrow damage, nerve damage and kidney damage by an anticancer agent, characterized in that the polypeptide is administered to an individual in need thereof.
  • the present invention provides an anticancer adjuvant comprising the polypeptide as an active ingredient.
  • the present invention includes a peptide of SEQ ID NO: 1 as an essential component, and provides a polypeptide in which 1 to 5 amino acids are additionally linked to the N-terminus or C-terminus of the peptide.
  • the present invention comprises a polypeptide consisting of the essential component of the 3 ⁇ 4 tide of SEQ ID NO: 1, and provides a polypeptide in which 1 to 5 amino acids are additionally connected to the N-terminus or C-terminus of the peptide.
  • the present invention consists essentially of the peptide of SEQ ID NO: 1 as an essential component, and provides a polypeptide in which 1 to 5 amino acids are additionally linked to the N-terminus or C-terminus of the peptide.
  • polypeptide is characterized in that SEQ ID NO: 2, may comprise a polypeptide of SEQ ID NO: 3.
  • the peptide of the present invention and SEQ ID NO: 2 is a peptide consisting of an amino acid sequence in which Tyr-Pro-Ser-Lys-Pro is linked to the peptide N-terminus of SEQ ID NO: 1, and the sequence
  • the peptide of No. 3 is a peptide consisting of an amino acid sequence in which Asp-Met-Ala-Arg-Tyr is linked to the C-terminus of Peptide of SEQ ID NO: 1.
  • the peptide of the present invention includes a specific sequence, and is a concept including a peptide with 1 to 50 amino acids additionally at the N- and / or C-terminal. It has not been reported previously that the peptide can improve the anti-cancer drug side effects, it will be disclosed for the first time in the present invention
  • the peptide of SEQ ID NO: 2 and 3 is a short fragment of neuropeptide Y (Neuropeptide Y, NPY, NCBI accesion No. P69101.1, SEQ ID NO: 6) consisting of 36 amino acids, one embodiment of the present invention According to the example, the peptide deganuro 3 ⁇ 4tide Y of SEQ ID NO: 2 and 3 showed better anti-cancer drug side effects.
  • the peptide represented by the amino acid sequence of SEQ ID NO: 1 consists of a total of 10 amino acids
  • the peptide represented by the amino acid sequence of SEQ ID NO: 2 or 3 consists of a total of 15 amino acids, having a relatively short sequence It is very good in that it has fewer side effects, excellent drug efficacy, and relatively low production cost.
  • the polypeptide essentially comprising the peptide of SEQ ID NO: 1 of the present invention has a shorter amino acid sequence than neuropeptide Y, thereby minimizing immunogenicity, toxic side effects, etc. in human use, and is relatively easy to add. It can be easily mass-produced and cost-effective.
  • the small molecular weight has the advantage of being able to cross tissue barriers more quickly.
  • the peptide of the present invention essentially includes the amino acid sequence of SEQ ID NO: 1, and is understood as a concept including a functional equivalent of a peptide having the amino acid sequence of SEQ ID NO: 2 or 3.
  • functional equivalent is meant a peptide that exhibits substantially homogeneous physiological activity with the peptide of SEQ ID NO: 2 or 3 above.
  • “Homogeneous bioactivity” refers to having an isomerization capability and having at least 60% amino acid sequence homology of at least 60%, preferably 703 ⁇ 4>, more preferably at least 90%.
  • “Functional Dong” also includes amino acid sequence variants in which some or all of the naturally occurring protein amino acids are substituted, or some of the amino acids are deleted or added. Substitutions of amino acids are preferably conservative substitutions. Examples of conservative substitutions of amino acids present in nature are Is the same; Aliphatic amino acids (Gly, Ala, Pro), hydrophobic amino acids (lie, Leu, Val), aromatic amino acids (Phejyr, Trp), acidic amino acids (Asp, G hi), basic amino acids (His, Lys, Arg, Gin, Asn ) And sulfur-containing amino acids (Cys, Met).
  • the peptide of the present invention can be prepared by a method known to those skilled in the art.
  • Such peptides can often be produced in prokaryotic or eukaryotic cells by expressing the polynucleotides encoding the peptide sequences of the invention as part of a larger polypeptide. Alternatively, such peptides can be synthesized by chemical methods.
  • the present invention is a pharmaceutical for the prevention or treatment of diseases or conditions selected from the group consisting of bone marrow damage, nerve damage and kidney damage by an anticancer agent comprising a polypeptide comprising the peptide of SEQ ID NO: 1 as an essential component as an active ingredient Provide composition.
  • an anticancer agent comprising a polypeptide comprising the peptide of SEQ ID NO: 1 as an essential component as an active ingredient
  • the term 'anticancer agent' refers to a chemotherapeutic agent used to treat malignant tumors, and most anticancer agents intervene in various metabolic pathways of cancer cells and mainly suppress the synthesis of nucleic acids to show anticancer activity. Means a drug.
  • Anticancer drugs use the difference in sensitivity to drugs between normal cells and cancer cells, which are relatively less toxic to normal cells and act more selectively on cancer cells, but because normal cells are damaged to some extent, side effects become worse. do. This is because the anticancer agent acts anywhere on fast dividing cells, so it does not only act on rapidly dividing cancer cells, but also bone marrow, gastrointestinal tract, and hair follicle cells, which are also fast dividing cells, are affected by the anticancer agent. Therefore, the common side effect of these drugs is temporary blood cell loss, nausea. Vagina, vomiting, diarrhea, loss of appetite, and hair loss will appear.
  • the anticancer agents currently used in cancer treatment are classified into six categories: alkylating agents, metabolic antagonists, antibiotics, mitosis inhibitors, hormonal agents and others according to biochemical mechanisms of action.
  • side effects of the anticancer agent include bone marrow damage, cytopenia due to bone marrow destruction, hair loss, menstrual irregularities, male infertility, stomatitis, vomiting, food swallowing disorders, digestive disorders, diarrhea, kidney damage, nerve damage, vascular disorders, skin or nails Discoloration, dyspnea, hearing loss, tinnitus, peripheral neuritis, convulsions, hypersensitivity reactions, cardiovascular reactions, neuromotor toxicity, neuroesthesia, myalgia, joint pain, nausea, fever, anemia, loss of appetite, weakness, nausea, constipation, fatigue , Infections, hematuria, proteinuria, allergies, abdominal cramps, cell necrosis, or tissue necrosis, without limitation.
  • the composition of the present invention may exhibit a mitigating effect on a disease or condition selected from the group consisting of bone marrow damage, neuropathy and kidney damage, which are side effects due to anticancer agents.
  • the bone marrow injury may be accompanied by symptoms such as leukopenia, platelets, erythrocytopenia due to bone marrow destruction.
  • the nerve injury includes peripheral neuritis, neuromotor toxicity, neurosensory toxicity, neuropathy, or neuropathic pain, and the like, without limitation.
  • the anticancer agents include cisplatin, doxorubicin, etoposide, pacl itaxel, doxetaxel, fluoropyrimidine, oxaliplatin, and oxaliplatin.
  • the anticancer agent may be cisplatin.
  • the anticancer agent may include ACTH producing tumor, acute lymphocytic or lymphoblastic leukemia, acute or chronic lymphocytic leukemia, acute nonlymphocytic leukemia, bladder cancer, brain tumor, breast cancer, cervical cancer, chronic myeloid leukemia, intestinal cancer, T-zone Lymphoma, Endometriosis, Esophageal cancer, Biliary bladder cancer, Ewing's sarcoma, Head and neck carcinoma, Tongue, Hopkins lymphoma, Kaposi's sarcoma, Kidney cancer, Liver cancer, Lung cancer, Mesothelioma, Multiple myeloma, Neuroblastoma, Non-Hopkin Lymphoma, osteosarcoma, ovarian cancer, neuroblastoma, mammary cancer, cervical cancer, prostate cancer, pancreatic cancer, colon cancer, penis cancer, retinoblastoma, skin cancer, stomach cancer, thyroid cancer, uterine cancer.
  • ACTH producing tumor acute lymphocytic or
  • the composition of the present invention can alleviate bone marrow damage, nerve damage or kidney damage caused by cisplatin administration.
  • Cisplatin is a chemotherapeutic agent for treating kidney cancer, and the drug is known to exhibit anticancer activity by inhibiting cell division. Tumor cells are characterized by uncontrolled cell proliferation and continually occurring. Treatment with cispulatin, which inhibits cell division of tumor cells, can prevent tumor cell proliferation in some cancers and may have anticancer effects. All. In some cases, it is known to reduce tumor cell proliferation as well as reduce the size of already existing tumor cells.
  • kidney toxicity (Cerosimo RJ, Ann. Pharm., 27: pp 438-441, 1993; Cavalli F. et al., Cancer Treat. Rep. , 62: pp 2125-2126, 1978; Pol lera CF et al. , J. Cl in. Oncol. , Pp. 318-319, 1987)
  • the term 'renal toxicity' is one of the side effects after administration of an anticancer agent, which includes a decrease in renal function, an increase in urea concentration in the blood, and an increase in the concentration of inflammatory factors in the kidney. Means status.
  • the degree of renal tubular damage caused by administration of cisplatin is alleviated by the administration of a peptide having the amino acid sequence of SEQ ID NO: 1.
  • the peptide having the amino acid sequence of SEQ ID NO: 2 or 3 was found to be effective in alleviating bone marrow damage or nerve damage caused by the administration of cisplatin.
  • the present inventors prepared a short fragment (SEQ ID NO: 4 and SEQ ID NO: 5) comprising a part of the amino acid sequence of neuropeptide Y in addition to the peptide of SEQ ID NO: 2 or 3 to evaluate the effect.
  • composition of the present invention may further include a pharmaceutically acceptable additive, and the pharmaceutically acceptable additive may include starch, gelatinized starch, microcrystalline salose, lactose, povidone, colloidal silicon dioxide and calcium hydrogen phosphate.
  • the pharmaceutically acceptable additive may include starch, gelatinized starch, microcrystalline salose, lactose, povidone, colloidal silicon dioxide and calcium hydrogen phosphate.
  • Lactose, Manni, Peeled, Araba rubber Pregelatinized starch, Corn starch, Powdered cellulose, Hydroxypropyl cellulose, Opadry, Sodium starch glycolate, Carnauba lead, Aluminum silicate, Stearic acid, Magnesium stearate, aluminum stearate, cala stearate, white sugar, dextrose, cattle Lerby and talc and the like can be used.
  • the pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.01 to 90 parts by weight based on the composition, but is not limited thereto.
  • the composition of the present invention can be administered in a variety of oral and parenteral formulations during actual clinical administration, when formulated, diluents such as layering agents, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. that are commonly used Or excipients.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like. Such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose, and the like having a peptide having the amino acid sequence of SEQ ID NO: 1.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups. Water, liquid paraffin, and other excipients, such as wetting agents, sweeteners, fragrances, and preservatives, may be used. have.
  • Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories.
  • non-aqueous solvents and suspensions propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethylate may be used.
  • injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.
  • compositions of the present invention may be used in any physiologically acceptable carrier, excipient or stabilizer (Remington: The Science and Pract ice of Pharmacy, 19th Edion, Al fonso, R., ed, Mack Publishing Co. (Easton, PA: 1995)).
  • Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphoric acid, citric acid and other organic acids; Ascor Antioxidants, including formic acid; Low molecular weight (less than about 10 residues) polypeptides; Proteins such as serum albumin, gelatin or immunoglobulins; Hydrophilic polymers such as polyvinylpyridone; Amino acids such as glycine, glutamine, asparagine, arginine or lysine; Monosaccharides, disaccharides, and other carbohydrates including glucose mannose or dextrinol; Chelating agents such as EDTA; Sugar alcohols such as manny or sorbbi; Salt-forming counterions such as sodium; And / or nonionic surfactants such as tweenone, pluronics or polyethylene glycol (PEG).
  • buffers such as phosphoric acid, citric acid and other organic acids
  • Ascor Antioxidants including formic
  • the dosage of the pharmaceutical composition of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally 0.01-100 mg / kg / day, preferably 0.1-20 mg / kg / day, more preferably 1-5 mg / kg / day, but is not limited thereto. It may also be divided at regular intervals according to the judgment of the doctor or pharmacist.
  • the present invention provides an anticancer adjuvant comprising a polypeptide comprising the peptide of SEQ ID NO: 1 as an essential component.
  • the anticancer adjuvant means improving the side effects exerted when the anticancer agent is administered, or enhancing the anticancer effect of the existing anticancer agent.
  • the adjuvant of the present invention may be administered simultaneously with the anticancer drug (simutaneous), separate (separate) or sequential (sequent i al).
  • the order of administration of the anticancer adjuvant according to the present invention that is, at which point in time at the same time, individually or sequentially, in the anticancer and anticancer adjuvant may be determined by a doctor or an expert. This order of administration can vary depending on many factors.
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer, comprising the anticancer adjuvant and an anticancer agent as an active ingredient.
  • the anticancer agent is cisplat in (cisplat in), doxorubicin (doxorubicin), etoposide, pacl itaxel, doxetaxel, fluoropyr imidine, oxaliplatin, campthotecan, belotecan, grape Podophyl lotoxin, vinblastine sulfate, cyclophosphamide, actinomycin, vincristine sulfate, methotrexate, bevacizumab bevacuzum ab, thalidomide, thai idomide, eriotinib, gefitinib, caraptothecin, tamoxifen, anasterozole, gleevec, 5- Fluorouracil (5-FU), Fluoxuridine, Leuprolide,
  • the anticancer adjuvant and the anticancer agent may be formulated in the form of a single composit ion or in the form of a separate composition.
  • the carrier, administration route, and the like, which may be additionally included in the pharmaceutical composition, are as described above.
  • the present invention includes the peptide of SEQ ID NO: 1 as an essential component It provides a use for the manufacture of a therapeutic agent for a disease or condition selected from the group consisting of bone marrow damage, nerve damage and kidney damage by an anticancer agent of the polypeptide.
  • the invention marrow hand by cancer which comprises administering to the "effective dose to an object that requires them to a composition comprising a polypeptide or a polypeptide comprising as an essential ingredient a peptide of the SEQ ID NO: 1, as an active ingredient
  • Provided is a method of treating a disease or condition selected from the group consisting of upper nerve injury and kidney injury.
  • the polypeptide is a peptide N-terminal of the amino acid further connected to the peptide N-terminal of the Tyr-Pn) -Ser-Lys-Pro to administer a polypeptide or a composition comprising the same as an active ingredient Can be.
  • the polypeptide may be SEQ ID NO: 2 or 3, the composition may be an anticancer adjuvant.
  • the anticancer adjuvant may be administered in combination with an anticancer agent, and the anticancer adjuvant may be administered simultaneously with the anticancer drug (sinmtaneous), separately (sparate), or sequentially.
  • the anticancer adjuvant and the anticancer agent are as described above.
  • the 'effective amount' of the present invention when administered to an individual, refers to an amount that shows an effect of improving, treating, preventing, detecting, or diagnosing bone marrow damage, nerve damage, and kidney damage by an anticancer agent.
  • a mammal especially an animal including a human, and may be a cell, tissue, organ or the like derived from the animal.
  • the subject may be a patient in need of the effect.
  • the 'treatment' of the present invention is a symptom of bone marrow damage, nerve damage and kidney damage caused by an anticancer agent or bone marrow damage, nerve damage and kidney damage related disease caused by an anticancer agent or bone marrow damage, nerve damage and kidney damage related disease caused by an anticancer agent
  • To improve the condition of the disease which may include treating, substantially preventing, or ameliorating the condition, including bone marrow damage caused by an anticancer agent, nerve damage and kidney damage, or bone marrow injury caused by an anticancer agent. Or alleviating, healing or preventing one or most of the symptoms resulting from neurological and kidney injury related diseases.
  • the term 'compr ising' of the present invention means 'containing' or 'features' It is used in the same way as, and does not exclude additional component elements or method steps, etc. which are not mentioned in the composition or method.
  • essential ly ly consi sting of includes a component element or step described in the scope of the composition or method, as well as a component element or step that does not substantially affect its basic properties, and the like. Means that.
  • composition comprising a polypeptide containing the peptide of SEQ ID NO: 1 as an essential component of the present invention as an active ingredient has the effect of alleviating side effects caused by the administration of an anticancer agent, in particular bone marrow damage, nerve damage and kidney damage It can be used as an anticancer adjuvant that can alleviate the side effects of anticancer drugs and enhance the anticancer effects.
  • an anticancer agent in particular bone marrow damage, nerve damage and kidney damage It can be used as an anticancer adjuvant that can alleviate the side effects of anticancer drugs and enhance the anticancer effects.
  • FIG. 1 is a diagram showing that the neuropathy induced by cisplatin is alleviated by SEQ ID NOs: 2 and 3.
  • FIG. 2 is a diagram showing that myeloid apoptosis induced by cisplatin is alleviated by the peptides of SEQ ID NOs: 2 and 3.
  • FIG. 2 is a diagram showing that myeloid apoptosis induced by cisplatin is alleviated by the peptides of SEQ ID NOs: 2 and 3.
  • FIG. 3 is a diagram showing that the reduction of myeloid hematopoietic stem cells induced by cisplatin is inhibited by the peptides of SEQ ID NOS: 2 and 3.
  • FIG. 4 is a diagram showing that the reduction of nerve fibers in the bone marrow by cispulatin is inhibited by the peptides of SEQ ID NOS: 2 and 3.
  • FIG. 6 is a diagram showing that renal toxicity by cisplatin is alleviated by peptides of SEQ ID NOS: 2 and 3.
  • FIG. 6 is a diagram showing that renal toxicity by cisplatin is alleviated by peptides of SEQ ID NOS: 2 and 3.
  • mice Male or female C57BL / 6 from 6 to 8 weeks of age was purchased from the Jackson laboratory. Animals were divided into experimental groups using the block randomizat ion method. To remove the polarization, the inspectors were blinded to data collection and analysis. Mice were reared under 12 hour night-day cycles and under free access to water and feed pellets. All mouse studies were approved by Kyungpook National University Animal Ethics Committee.
  • Cisplatin (Enzo; 10 mg / kg per week) was used to induce sensory nervous system (SNS) damage. Mice were euthanized after intraperitoneal infusion (i.p) of cisplatin for 7 weeks. In order to confirm whether the peptides of SEQ ID NOs: 2 to 6 (50 y g / kg) could alleviate the anticancer side effects from cisplatin, the combination was administered daily for 7 weeks, which is the cisplatin treatment period.
  • hot-plate tests were conducted.
  • the hotplates were maintained at 50 ° C. and each mouse was placed at the end of the heated surface and the time to first nocicept ion, ie jump or foot lick, was measured. The cutoff time was 60 seconds. Between measurements, the heated surface was wiped with detergent and ethanol and the temperature was maintained at 50 ° C.
  • Bone marrow tissue of the mouse was cut to a thickness of 5 ⁇ using mi crotom and stained. TUNEL assays were performed using In Situ Cel l Detect ion Kit, Fluorescein (Roche Diagnost ic) according to manufacturer's instructions. Bone Marrow Nervous System Destruction To determine the degree, the tissue of the mouse was stained with Tyrosine hydroxylase (rabbit, 1: 250, Milipore). In addition, CD31 (mouse, 1:50, BD Bioscience) staining was performed on the bone marrow tissue of the mouse to confirm the degree of destruction of the bone marrow endothelial cells.
  • Fluoview SV1000 imaging software (Olympus FV1000, And a laser scanning confocal microscope equipped with Japan) or an Olympus BX51 microscope. Met amor ph sof tware (Molecular Devices) was used to quantify the percentage of area of stained area to area of total tissue.
  • Bone marrow was isolated from the tibia and femur of each mouse.
  • Red blood cells (RBCs, Red blood cells) were hemolyzed at 4 ° C for 5 minutes using 0.15 M NH 4 C1 (STEMCELLTechnologies), washed with PBS (Gibco) and counted using a hemocytometer.
  • Lin using magnetic d ⁇ letion using biotinylated lineage-specific antibodies (CD5, CD45R, CDllb, Gr-1, and Ter-119) to detect HSCs, MSCs, or osteoblasts + Cells were removed and subsequently reduced using MACs beads combined with monoclonal anti-biotin (Miltenyi Biotec).
  • Chemotherapy causes acute bone marrow damage and impairs hematopoietic stem cell (HSC) function or bone marrow regeneration in the bone marrow.
  • anticancer drugs such as ci spl at in reduce sympathetic neuropathy by reducing the expression of Th fibers in the bone marrow.
  • the present inventors evaluated whether the peptide having the amino acid sequence of SEQ ID NOS: 2 to 5 can prevent or treat neuropathy or bone marrow dysfunction induced by anticancer drug treatment.
  • the effect of the entire sequence of neuropeptide Y (NPY) of SEQ ID NO: 6 as a positive control group was also evaluated.
  • mice were intraperitoneally injected with cisplatin once a week for a total of seven weeks and peptides having an amino acid sequence of SEQ ID NO: 2 to SEQ ID NO: 6 were injected intraperitoneally each day for seven weeks for seven weeks during injection of cisplatin. 1A and 2A).
  • the inventors conducted a hot-plate test and increased neuropathy in mice injected with cisplatin was used to detect peptides of SEQ ID NO: 2 and SEQ ID NO: 3. Significant decrease was observed in the mice injected (FIG. IB, p ⁇ 0.05).
  • Bone marrow apoptosis is one of the pathogenesis of bone marrow damage caused by cispulatin treatment.
  • Treatment with anticancer agents causes acute bone marrow damage and a decrease in the number of hematopoietic stem cells in the bone marrow.
  • LSK eel I s a hematopoietic stem progenitor cell labeled with Lineage- Sca-1 + c-ki t +, reduced by cisplatin It was alleviated by the peptides of numbers 2 and 3 (Fig. 3A, p ⁇ 0.05).
  • mice injected with peptides of SEQ ID NOS: 2 and 3 compared to mice injected with Th (Tyrosine hydroxylase) reaction, which represents nerve fibers in bone marrow, were injected with cisplatin 4A and 4B, p ⁇ 0.05).
  • Th Tethyrosine hydroxylase
  • Endothelial cell marker CD31 staining was performed to confirm whether endothelial cell damage in bone marrow could be alleviated by peptides of SEQ ID NOs: 2 and 3 during bone marrow injury by cisplatin. As a result, it was confirmed that the peptides of SEQ ID NOs: 2 and 3 inhibit not only the nerve fibers in the bone marrow but also the reduction of endothelial cells in the bone marrow (FIGS. 5A and 5B, p ⁇ 0.05). These results indicate that the peptides of SEQ ID NOS: 2 and 3 have a moderating effect on the reduction of endothelial cells in cispulatin-induced bone marrow.
  • Kidney toxicity is another side effect of anticancer drugs. Histological analysis using H & E staining was performed to determine whether this nephrotoxicity was alleviated by the peptides of SEQ ID NOs: 2 and 3. As a result, it was confirmed that apoptosis was increased in tubule cells in the neocortex by cispulatin treatment, which was reduced by the peptides of SEQ ID NOS: 2 and 3 (Figs. 6A and 6B, p ⁇ 0.05). These results indicate that the peptides of SEQ ID NOS: 2 and 3 have a protective effect against cisplatin-induced kidney failure.
  • the renal toxicity alleviating effect of SEQ ID NO: 3 showed the same or better effect than the entire sequence of NPY, while SEQ ID NO: 4 and 5 was confirmed that the effect is not great (Fig. 6).
  • the results essentially include the peptide of SEQ ID NO.
  • Anticancer agents comprising the polypeptides of SEQ ID NO: 2 and SEQ ID NO: 3, which may be able to alleviate bone marrow damage, neurotoxicity and nephrotoxicity, which are side effects caused by cisplatin, Compared better.
  • the peptides of SEQ ID NOs: 2 and 3 have an amino acid sequence shorter than the entire NPY sequence, immunogenicity, toxic side effects can be minimized, and they can be synthesized relatively easily, which facilitates mass production and reduces costs. It can bring the effect of, and has the advantage of being able to cross the tissue barrier more quickly due to the small molecular weight.
  • a peptide having the amino acid sequence of SEQ ID NO: 2 or 3, 5'-chloro-3, 2'-dihydroxychalcone or 5'-chloro-2,3'-dihydroxychalcone; 250 g of hydrochloride It was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid. 103 ⁇ 4 gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of stearic acid magnesium to tablets.
  • Composition comprising a polypeptide containing the peptide of SEQ ID NO: 1 as an essential component as an active ingredient has an effect of alleviating side effects caused by the administration of an anticancer agent, in particular bone marrow damage, nerve damage and kidney damage, It can be usefully used as an anticancer adjuvant that can alleviate side effects and enhance anticancer effects.

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Abstract

La présente invention concerne un nouveau peptide pour atténuer un effet secondaire de médicament anticancéreux et une composition pharmaceutique le comprenant comme principe actif. Plus spécifiquement, l'invention concerne un polypeptide qui peut atténuer un effet secondaire induit par un médicament anticancéreux comme une lésion de la moelle osseuse, une lésion neuronale ou une lésion rénale, ledit polypeptide comprenant un peptide selon la SEQ ID Nº : 1 comme composant essentiel et ayant en outre un à cinq acides aminés connectés à l'extrémité N-terminale ou C-terminale du peptide. L'invention concerne aussi une composition pharmaceutique comprenant le polypeptide en tant qu'ingrédient actif, destinée à atténuer l'effet secondaire d'un médicament anticancéreux, ainsi qu'une utilisation et un procédé associés. La composition comprenant, comme principe actif, le polypeptide comportant le peptide de SEQ ID Nº : 1 en tant que composant essentiel peut, selon la présente invention, être utile en tant qu'adjuvant anticancéreux capable d'atténuer un effet secondaire d'un médicament anticancéreux et d'augmenter l'efficacité d'un médicament anticancéreux par atténuation d'effets secondaires induits par l'administration du médicament anticancéreux, en particulier des lésions de la moelle osseuse, des lésions neuronales et des lésions rénales.
PCT/KR2017/002080 2016-02-26 2017-02-24 Nouveau peptide pour atténuer des effets secondaires de médicament anticancéreux et composition pharmaceutique le comprenant comme principe actif WO2017146528A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014166497A2 (fr) * 2013-04-10 2014-10-16 University Of Copenhagen Peptides dérivés du neuropeptide y
KR101492053B1 (ko) * 2014-07-14 2015-02-11 경북대학교 산학협력단 뉴로펩티드 y를 포함하는 항암제 부작용 억제용 조성물

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014166497A2 (fr) * 2013-04-10 2014-10-16 University Of Copenhagen Peptides dérivés du neuropeptide y
KR101492053B1 (ko) * 2014-07-14 2015-02-11 경북대학교 산학협력단 뉴로펩티드 y를 포함하는 항암제 부작용 억제용 조성물

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE NCBI [O] 11 November 2015 (2015-11-11), XP055411553, Database accession no. P68006.1 *
INTONDI ET AL.: "Intrathecal Neuropeptide Y Reduces Behavioral and Molecular Markers of Innammatory or Neuropathic Pain", PAIN, vol. 137, no. 2, 2008, pages 352 - 365, XP022765575 *
QUASTHOFF ET AL.: "Chemotherapy-induced Peripheral Neuropathy", JOURNAL OF NEUROLOGY, vol. 249, 2002, pages 9 - 17, XP001104073 *

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