WO2019242688A1 - 3-羟基氨基苯甲酸与索拉非尼联合用药治疗肿瘤 - Google Patents

3-羟基氨基苯甲酸与索拉非尼联合用药治疗肿瘤 Download PDF

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WO2019242688A1
WO2019242688A1 PCT/CN2019/092081 CN2019092081W WO2019242688A1 WO 2019242688 A1 WO2019242688 A1 WO 2019242688A1 CN 2019092081 W CN2019092081 W CN 2019092081W WO 2019242688 A1 WO2019242688 A1 WO 2019242688A1
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active ingredient
pharmaceutically acceptable
kinase inhibitor
sorafenib
acid
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PCT/CN2019/092081
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English (en)
French (fr)
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糜军
甘桂芳
石兆鹏
张洁莹
袁园
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上海交通大学医学院
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to the field of medicine, and in particular, the present invention relates to a combination of 3-hydroxyaminobenzoic acid and sorafenib for treating tumors.
  • Cancer is a very complex and deadly disease, and it is a huge health crisis that developed and developing countries are currently experiencing. By 2020, there will be more than 15 million new cancer patients worldwide, which will have a serious impact on the social, economic and medical care of any country.
  • the purpose of the present invention is to provide a combined medicine, which can improve the antitumor effect and reduce side effects.
  • composition comprising:
  • the kinase inhibitor is a tyrosine kinase inhibitor.
  • the kinase inhibitor includes a raf enzyme inhibitor.
  • the kinase inhibitor comprises a multi-target kinase inhibitor type anticancer drug.
  • the content of the first active ingredient ranges from 0.01% to 99.99% based on the total weight of the active ingredients of the composition; preferably 0.1% to 99.9%; more preferably 1% to 99%; Preferably 10% to 99%; more preferably 20% to 99%; more preferably 30-99%, more preferably 40-99%.
  • the content of the second active ingredient ranges from 0.01% to 99.99%, based on the total weight of the active ingredients of the composition; preferably 0.1% to 99.9%; more preferably 1% to 99%; more Preferably 1% to 90%; more preferably 1% to 80%; more preferably 1 to 70%, more preferably 1 to 60%.
  • a weight ratio of the 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof to an anticancer drug of a kinase inhibitor class is 1-50: 0.5-15, preferably 1-30: 0.5 -10, more preferably 1-20: 0.5-5, most preferably 5-15: 0.5-5.
  • the molar ratio of the 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof to an anticancer drug of a kinase inhibitor is 1-150: 1, preferably 1-100: 1. More preferably 1-70: 1, most preferably 5-50: 1.
  • the kinase inhibitor anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof.
  • the kinase inhibitor class anticancer drug is sorafenib tosylate.
  • a pharmaceutical composition comprising the composition according to the first aspect of the present invention; and a pharmaceutically acceptable carrier.
  • a kit is provided, and the kit includes:
  • the kinase inhibitor anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof.
  • a weight ratio of the 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof to an anticancer drug of a kinase inhibitor class is 1-50: 0.5-15, preferably 1-30: 0.5 -10, more preferably 1-20: 0.5-5, most preferably 5-15: 0.5-5.
  • the molar ratio of the 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof to an anticancer drug of a kinase inhibitor is 1-150: 1, preferably 1-100: 1. More preferably 1-70: 1, most preferably 5-50: 1.
  • the instructions for use indicate that the first preparation and the second preparation are used in combination to prevent and / or treat cancer.
  • the first preparation and the second preparation are administered simultaneously, separately or sequentially in the prevention and / or treatment of cancer.
  • first preparation and the second preparation are independent of each other.
  • the first preparation and the second preparation are combined.
  • an active ingredient combination includes the following components:
  • a first active ingredient said first activity being 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof;
  • At least one active ingredient is independent.
  • the kinase inhibitor anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof.
  • a weight ratio of the 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof to an anticancer drug of a kinase inhibitor class is 1-50: 0.5-15, preferably 1-30: 0.5 -10, more preferably 1-20: 0.5-5, most preferably 5-15: 0.5-5.
  • the molar ratio of the 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof to an anticancer drug of a kinase inhibitor is 1-150: 1, preferably 1-100: 1. More preferably 1-70: 1, most preferably 5-50: 1.
  • a composition according to the first aspect of the present invention or a pharmaceutical composition according to the second aspect of the present invention, or a kit according to the third aspect of the present invention, or
  • the use of the active ingredient combination according to the fourth aspect of the present invention is for preparing a medicament for preventing and / or treating cancer.
  • the cancer is selected from the group consisting of liver cancer, kidney cancer, and leukemia.
  • the cancer is liver cancer.
  • a non-therapeutic method for inhibiting the growth of cancer cells in vitro includes the steps of: combining cancer cells with the composition according to the first aspect of the present invention, or the second aspect of the present invention.
  • the pharmaceutical composition, or the active ingredient combination according to the fourth aspect of the present invention is contacted to inhibit the growth of cancer cells.
  • a method for preventing and / or treating cancer comprising the steps of: administering to a subject in need thereof the composition according to the first aspect of the present invention, or the second aspect according to the present invention A pharmaceutical composition according to an aspect, or a kit according to the third aspect of the present invention, or an active ingredient combination according to the fourth aspect of the present invention.
  • the subject is a human and a non-human mammal.
  • the object is a person.
  • Figure 1 is a schematic diagram of the mechanism by which 3-HAA enhances sorafenib in the treatment of liver cancer
  • Figure 2 shows the inhibitory effect of sorafenib alone on liver cancer cells in Example 1.
  • the dose gradient experiment of sorafenib treatment time was 4 days (Figure 2A), and the time gradient experiment of sorafenib treatment.
  • the dose was 20 ⁇ M ( Figure 2B), and cell viability was measured by CCK8.
  • FIG. 3 shows the inhibitory effect of 3-HAA alone on liver cancer cells in Example 2.
  • the dose gradient experiment 3-HAA treatment time was 4 days (3A picture), and the time gradient experiment 3-HAA treatment dose was 100 ⁇ M.
  • Figure 3B Cell survival was measured by CCK8.
  • FIG. 4 is a synergistic inhibitory effect of 3-HAA and sorafenib on liver cancer cells in Example 3.
  • the treatment time of sorafenib and 3-HAA was 4 days, and the cell survival rate was detected by CCK8.
  • FIG. 5 is the synergistic induction of apoptosis of liver cancer cells by 3-HAA and sorafenib in Example 3.
  • the treatment time of sorafenib and 3-HAA is 1 day.
  • Fig. 6 shows the synergistic inhibition of SMMC-7721 xenograft by 3-HAA and sorafenib in Example 4, wherein Fig. 6A shows the growth of xenograft volume; Fig. 6B shows the weight of xenograft in each group, *: P ⁇ 0.05, ** : P ⁇ 0.01.
  • FIG. 7 is the synergistic inhibition of PDX xenografts by 3-HAA and sorafenib in Example 5.
  • FIG. 7A is the volume growth of PDX model 1 xenografts;
  • FIG. 7B is the volume growth of PDX model 2 xenografts.
  • the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions, but also semi-closed, and open definitions. In other words, the term includes “consisting of”, “consisting essentially of”.
  • ingredients of the term "pharmaceutically acceptable carrier” refer to those that are suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergies), that is, have a reasonable benefit / risk ratio substance.
  • the term "therapeutically effective amount” refers to an amount that is functional or active in humans and / or animals and is acceptable to humans and / or animals. Those of ordinary skill in the art should understand that the “therapeutically effective amount” may vary depending on the form of the pharmaceutical composition, the route of administration, the excipients of the drugs used, the severity of the disease, and the combination with other drugs. A little different.
  • the "prevention” and “treatment” in the present invention include delaying and stopping the progression of the disease, or eliminating the disease, and do not need to be 100% inhibited, eliminated and reversed.
  • the composition of the formula or the pharmaceutical composition of the present invention prevents, reduces, inhibits and / or reverses the cancer compared to the level observed in the absence of the composition or the pharmaceutical composition of the present invention. For example, at least about 10%, at least about 30%, at least about 50%, or at least about 80%.
  • the first active ingredient is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof.
  • 3-hydroxyaminobenzoic acid (3-HAA) or a pharmaceutically acceptable salt thereof is an inhibitor of the AKT and ERK pathway.
  • the AKT pathway inhibitor is an inhibitor that inhibits the AKT pathway by promoting DUSP6 expression and inhibiting PDK1 activity.
  • 3-Hydroxyaminobenzoic acid is a metabolite of tryptophan with a molecular weight of 153.1 and a molecular formula of C7H7NO3.
  • the structure is as follows:
  • 3-hydroxyaminobenzoic acid refers to 3-hydroxyaminobenzoic acid of formula, or a pharmaceutically acceptable salt thereof. It should be understood that the term also includes mixtures of the aforementioned components.
  • the second active ingredient according to the present invention is a kinase inhibitor type anticancer drug.
  • the kinase inhibitor is a tyrosine kinase inhibitor.
  • the kinase inhibitor includes a raf enzyme inhibitor.
  • the kinase inhibitor comprises a multi-target kinase inhibitor type anticancer drug.
  • the kinase inhibitor class anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof. More preferably, the kinase inhibitor class anticancer drug is sorafenib tosylate.
  • sorafenib refers to formula sorafenib, or a pharmaceutically acceptable salt thereof. It should be understood that the term also includes mixtures of the aforementioned components.
  • Broad-spectrum tyrosine kinase sorafenib is a first-line chemotherapeutic drug for the treatment of liver cancer, but its curative effect is unsatisfactory.
  • the low clinical response and acquired resistance are the key factors that lead to its failure.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention and an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • One preferred type of salt is a salt of a compound of the invention with an acid.
  • Suitable acids for forming salts include, but are not limited to, inorganic acids such as toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • a preferred type of salt is a salt formed by a compound of the present invention with a base.
  • Suitable bases for forming the salt include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, ammonia, and Organic bases such as ethylamine and diethylamine.
  • composition Composition, kit, active ingredient combination and pharmaceutical composition
  • the invention provides a composition comprising:
  • the content of the first active ingredient ranges from 0.01% to 99.99%, based on the total weight of the active ingredients of the composition; preferably from 0.1% to 99.9%; more preferably from 1% to 99% Preferably 10% to 99%; more preferably 20% to 99%; more preferably 30-99%, more preferably 40-99%.
  • the content of the second active ingredient ranges from 0.01% to 99.99%, based on the total weight of the active ingredients of the composition; preferably 0.1% to 99.9%; more preferably 1% to 99%; more Preferably 1% to 90%; more preferably 1% to 80%; more preferably 1 to 70%, more preferably 1 to 60%.
  • the weight ratio of the 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof to an anticancer drug of a kinase inhibitor class is 1-50: 0.5-15, preferably 1 -30: 0.5-10, more preferably 1-20: 0.5-5, and most preferably 5-15: 0.5-5.
  • the molar ratio of the 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof to an anticancer drug of a kinase inhibitor is 1-150: 1, preferably 1-100: 1. More preferably 1-70: 1, most preferably 5-50: 1.
  • composition may further include a pharmaceutically acceptable carrier to prepare a pharmaceutical composition (drug).
  • the composition further includes a pharmaceutically acceptable carrier to make a pharmaceutical composition
  • the pharmaceutical composition includes:
  • the pharmaceutical composition containing the first active ingredient and the second active ingredient according to the present invention may be various dosage forms suitable for oral administration, and may also be various external administration preparations or other parenteral administration preparations.
  • the preparations for external administration according to the present invention can be further supplemented with auxiliary materials such as surfactants, transdermal absorption enhancers, preservatives, solvents, antioxidants, humectants, pH adjusters, colorants, and perfumes, Prepared (including but not limited to): tinctures, tinctures, oils, ointments, plasters, pastes, ironing agents, plasters, patches, film coatings, films, gels, rags, Acupoint patches, sprays, aerosols, implants, emulsions, etc.
  • preferred dosage forms include various dosage forms for oral administration, implants, and injections.
  • the carrier is not particularly limited, and is a material commonly used in the art, and its kind, method of use, and source are well known to those skilled in the art.
  • Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc.), gelatin, talc, and solid lubricants. (Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), buffering agents, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavoring agents, stabilizers, antioxidants, preservatives , Bacteriostatic agent, pyrogen-free water, etc.
  • cellulose and its derivatives such as methyl cellulose, ethyl cellulose, hydroxy
  • the content range of the first active ingredient and the second active ingredient, and the quality of the first active ingredient and the second active ingredient are as described in the above composition. Description.
  • the present invention also provides an active ingredient composition.
  • the active ingredient combination includes the following components:
  • the content range of the first active ingredient and the second active ingredient, and the quality of the first active ingredient and the second active ingredient are as described in the above composition Description.
  • the invention also provides a pill box, which comprises:
  • the instruction manual states that the first preparation and the second preparation are used in combination to prevent and / or treat cancer.
  • the first preparation and the second preparation in the kit of the present invention may be used in combination, the first preparation and the second preparation may be administered simultaneously, separately or sequentially.
  • composition, active ingredient combination, pharmaceutical composition, pillbox, food and health products of the present invention can be prepared by conventional methods and equipment.
  • the present invention provides the use of a composition, an active ingredient composition, and a pharmaceutical composition described herein in the manufacture of a medicament for the prevention and / or treatment of cancer.
  • the first active ingredient and the second active ingredient in the composition, the active ingredient composition, the pharmaceutical composition and the kit according to the present invention can have a synergistic effect on the prevention and treatment of liver cancer, kidney cancer, and leukemia, and enhance the treatment of cancer. Effect, reduce the dosage of a single drug, reduce drug toxicity.
  • Figure 1 a schematic diagram of the combined use of 3-HAA and sorafenib to enhance the effect of treating liver cancer is shown in Figure 1.
  • compositions, active ingredient combination, pharmaceutical composition and kit of the present invention Before, simultaneously or after using the composition, active ingredient combination, pharmaceutical composition and kit of the present invention, other active substances for treating cancer (e.g., toposide, 5-fluorouracil, anticancer active substances such as, Imatinib sulfonate), perform surgery for cancer or administer radiation therapy for cancer, or use it in combination with gene therapy, or in combination with biomodulators.
  • active substances for treating cancer e.g., toposide, 5-fluorouracil, anticancer active substances such as, Imatinib sulfonate
  • the administration method of the present invention includes sequentially administering the first active ingredient and the second active ingredient in sequence, or simultaneously applying the first active ingredient and the second active ingredient.
  • the pharmaceutical preparation should match the mode of administration.
  • a safe and effective amount of the drug is administered to a desired subject (such as a human or non-human mammal).
  • the dosage used is usually at least about 0.1 mg, and in most cases no more than about 2000 mg.
  • the dose is from 1 mg to 500 mg; the safe and effective amount of the second active ingredient is usually at least about 0.01 mg, and in most cases no more than 1500 mg.
  • the dosage range is from 0.1 mg to 1500 mg. (In which, the safe and effective amount of the first active ingredient usually does not exceed about 2000 mg / kg body weight.
  • the dose is about 100 micrograms / kg body weight to about 1000 mg / kg body weight; the safe and effective amount of the second active ingredient Usually does not exceed about 2000 mg / kg body weight. Preferably, the dose is about 10 micrograms / kg body weight to about 1000 mg / kg body weight.
  • the specific dose should also consider the route of administration, patient health and other factors, these All are within the skill of a skilled physician. When the first active ingredient and the second active ingredient are applied successively, there is no particular requirement for the interval of application.
  • the first active ingredient and the second active ingredient in the composition, the active ingredient combination, the pharmaceutical composition, and the kit of the present invention are administered simultaneously or sequentially by the same or different routes, including, but not limited to, oral administration , Injection administration, intratumoral administration, implantation administration, intracavity administration, anal administration, transdermal administration, internal and external application;
  • Preferred injections include: intravenous, intramuscular, subcutaneous, and intracavitary injection.
  • the present invention also provides a non-therapeutic method for inhibiting the growth of cancer cells in vitro.
  • the method includes the steps of: contacting cancer cells with the composition of the present invention or the combination of the active ingredients to inhibit the growth of cancer cells. .
  • the present invention also provides a method for preventing and / or treating cancer.
  • the method includes the step of administering to a desired subject a composition, an active ingredient combination, a pharmaceutical composition, or a drug according to the present invention. box.
  • the administration method of the present invention includes sequentially applying the first active ingredient and the second active ingredient, or simultaneously applying the first active ingredient and the second active ingredient.
  • the subject is a human and a non-human mammal.
  • the non-human mammal includes (but is not limited to): pets (such as dogs, cats), domestic animals (such as cattle, sheep, horses, pigs), various zoo animals (panda, elephant, tiger )Wait.
  • the first active ingredient and the second active ingredient can produce a synergistic effect, enhance the effect of treating cancer, reduce the dosage of a single drug, and reduce the toxicity of the drug.
  • the IC50 of the four hepatocellular carcinoma cells were: PLC8024 8.4 ⁇ M; SMMC-7721: 15.3 ⁇ M; HepG2: 2.6 ⁇ M; Hep3B: 3.2 ⁇ M.
  • PLC8024 and SMMC-7721 responded to sorafenib significantly lower than HepG2 and Hep3B.
  • the CCK8 experiment was used to calculate the 50% inhibition concentration (IC50) of 3-HAA (3-hydroxyaminobenzoic acid) on 4 liver cancer cells (PLC8024, SMMC-7721, HepG2 and Hep3B).
  • the IC50 of the four hepatoma cells were: PLC8024: 147.7 ⁇ M; SMMC-7721: 165.4 ⁇ M; HepG2: 73.2 ⁇ M; Hep3B: 101.5 ⁇ M.
  • PLC8024 and SMMC-7721 had significantly lower response to 3-HAA treatment than HepG2 and Hep3B.
  • 3-HAA works in concert with sorafenib to inhibit liver cancer cells
  • 3-HAA can significantly enhance the therapeutic sensitivity of sorafenib.
  • the IC50 of SMMC7721 and PLC8024 decreased from 14.5 ⁇ M and 8.1 ⁇ M to 4.9 ⁇ M and 2.4 ⁇ M, respectively.
  • the cell survival rates of the two strains were 88.4 ⁇ 1.6% and 76.3 ⁇ 4.7%, respectively.
  • the cell survival rates of the two strains decreased to 43.8 ⁇ 2.1% and 23.5 ⁇ 2.3%, respectively .
  • the apoptotic detection in Figure 5 further confirms that the two have a synergistic effect.
  • a nude mouse xenograft model of SMMC-7721 cells was constructed.
  • Four groups of transplanted nude mice were used as the control group (administered with DMSO), the 3-HAA administration group (100 mg / kg.day), the sorafenib administration group (10 mg / kg.day), and 3-HAA and sora
  • the fenib combined administration group (the doses of 3-HAA and sorafenib were 100 mg / kg.day and 10 mg / kg.day, respectively).
  • the administration method was intraperitoneal injection and daily administration. 8 consecutive days.
  • sorafenib and 3-HAA can exert a synergistic inhibitory effect on the growth of transplanted tumors of SMMC-7721 cells.
  • Intraperitoneal injection of 10 mg / Kg.day of sorafenib did not significantly inhibit the tumor growth curve of sorafenib low-response liver cancer cells.
  • 100 mg / Kg.day of 3-HAA tumor growth was significantly inhibited ( Figure 6A).
  • the tumor weight also had similar results.
  • the combined use of sorafenib and 3-HAA had an average tumor weight of 0.15 ⁇ 0.05g, which was only 27% of the control group (0.41 ⁇ 0.08g) ( Figure 6B).

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Abstract

本发明涉及一种3-羟基氨基苯甲酸与索拉非尼联合用药治疗肿瘤。具体地，本发明提供一种组合物，所述组合物包括(a)治疗有效量的第一活性成分，所述第一活性成分3-羟基氨基苯甲酸或其药学上可接受的盐；和(b)治疗有效量的第二活性成分，所述第二活性成分为激酶抑制剂类抗癌药物。本发明所述的第一活性成分和第二活性成分能够产生协同作用，增强治疗癌症的效果，降低单个药物的用药剂量，降低药物的毒性。

Description

3-羟基氨基苯甲酸与索拉非尼联合用药治疗肿瘤 技术领域
本发明涉及药物领域，具体地，本发明涉及一种3-羟基氨基苯甲酸与索拉非尼联合用药治疗肿瘤。
背景技术
癌症是一种非常复杂和致命的疾病，是发达国家和发展中国家目前正在经历的一个巨大的健康危机。到2020年，世界范围内将有1500万多个新增癌症患者，这对任何国家的社会、经济和医疗都将带来严重的影响。
癌症治疗的临床结果普遍令人失望，在很大程度上归因于这种毁灭性疾病的异质性和复杂性。传统的手术和放疗仅用于局部疾病的治疗，而激素治疗、化疗、免疫治疗和靶向治疗用于单独治疗或与别的治疗方法联用。多年来，包括化疗在内的单一和组合疗法已经发展成为有效治疗方法。当然，联合治疗的临床效果并不像预期的那样好，通常都有更高的毒性，还受限于药物成分无法以自由分子形式达到所需时空分布，也就是说，在适当的时机将药物成分运送到正确的位置。除非使用有效的药物载体，否则药物成分之间的物理化学和药代动力学性质的固有差异会阻止这种情况的发生。目前，肿瘤化疗耐药性或多药耐药性的出现已经成为肿瘤化疗研究者面临的主要挑战。为了解决这一固有的问题和让协同药物到达同一靶细胞以克服外排转运体介导的多药耐药性，越来越多的科研工作者投入这项研究中。
因此，本领域需要开发新的药物，提高抗肿瘤效果，降低副作用。
发明内容
本发明的目的在于提供一种联合用药，提高抗肿瘤效果，降低副作用。
本发明的第一方面，提供一种组合物，所述组合物包括：
(a)治疗有效量的第一活性成分，所述第一活性成分3-羟基氨基苯甲酸或其药学上可接受的盐；和
(b)治疗有效量的第二活性成分，所述第二活性成分为激酶抑制剂类抗癌药物。
在另一优选例中，所述的激酶抑制剂为酪氨酸激酶抑制剂。
在另一优选例中，所述的激酶抑制剂包括raf酶抑制剂。
在另一优选例中，所述的激酶抑制剂包括多靶点激酶抑制剂类抗癌药物。
在另一优选例中，第一活性成分的含量范围为0.01％至99.99％，以组合物活性成分的总重量计；较佳地0.1％至99.9％；更佳地1％至99％；较佳地10％至99％；更佳地20％至99％；更佳地30-99％，更佳地40-99％。
在另一优选例中，第二活性成分的含量范围为0.01％至99.99％，以组合物活性成分的总重量计；较佳地0.1％至99.9％；更佳地1％至99％；更佳地1％至90％；更佳地1％至80％；更佳地1-70％，更佳地1-60％。
在另一优选例中，所述3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类抗癌药物的重量比为1-50：0.5-15，较佳地1-30：0.5-10，更佳地1-20：0.5-5，最佳地5-15：0.5-5。
在另一优选例中，所述的3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类抗癌药物的摩尔比为1-150：1，较佳地1-100：1，更佳地1-70：1，最佳地5-50：1。
在另一优选例中，所述的激酶抑制剂类抗癌药物为索拉非尼或其药学上可接受的盐。
在另一优选例中，所述的激酶抑制剂类抗癌药物为甲苯磺酸索拉非尼。
本发明第二方面，提供一种药物组合物，所述的药物组合物包括如本发明第一方面所述的组合物；和药学上可接受的载体。
本发明第三方面，提供一种药盒，所述药盒包括：
(A)含有3-羟基氨基苯甲酸或其药学可接受的盐的第一制剂；
(B)含有激酶抑制剂类抗癌药物的第二制剂；和
(C)使用说明书。
在另一优选例中，所述的激酶抑制剂类抗癌药物为索拉非尼或其药学上可接受的盐。
在另一优选例中，所述3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类抗癌药物的重量比为1-50：0.5-15，较佳地1-30：0.5-10，更佳地1-20：0.5-5，最佳地5-15：0.5-5。
在另一优选例中，所述的3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类 抗癌药物的摩尔比为1-150：1，较佳地1-100：1，更佳地1-70：1，最佳地5-50：1。
在另一优选例中，所述的使用说明书中注明将所述第一制剂、第二制剂进行联用，从而预防和/或治疗癌症。
在另一优选例中，所述的第一制剂、第二制剂在预防和/或治疗癌症中同时给药、分别给药或顺序给药。
在另一优选例中，所述的第一制剂和第二制剂是各自独立的。
在另一优选例中，所述的第一制剂和第二制剂是合并的。
本发明第四方面，提供一种活性成分组合，所述的活性成分组合包括以下组分：
(1)第一活性成分，所述第一活性为3-羟基氨基苯甲酸或其药学上可接受的盐；和
(2)第二活性成分，所述第二活性成分为激酶抑制剂类抗癌药物。
在另一优选例中，所述的活性成分组合中，至少有一种活性成分是独立的。
在另一优选例中，所述的激酶抑制剂类抗癌药物为索拉非尼或其药学上可接受的盐。
在另一优选例中，所述3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类抗癌药物的重量比为1-50：0.5-15，较佳地1-30：0.5-10，更佳地1-20：0.5-5，最佳地5-15：0.5-5。
在另一优选例中，所述的3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类抗癌药物的摩尔比为1-150：1，较佳地1-100：1，更佳地1-70：1，最佳地5-50：1。
本发明第五方面，提供一种如本发明第一方面所述的组合物，或如本发明第二方面所述的药物组合物，或如本发明第三方面所述的药盒，或如本发明第四方面所述的活性成分组合的用途，用于制备预防和/或治疗癌症的药物。
在另一优选例中，所述的癌症选自下组：肝癌、肾癌、白血病。
在另一优选例中，所述的癌症为肝癌。
本发明第六方面，提供一种体外非治疗性的抑制癌细胞生长的方法，所述的方法包括步骤：将癌细胞与如本发明第一方面所述的组合物，或本发明第二方面所述的药物组合物，或如本发明第四方面所述的活性成分组合接触，来抑制癌细胞的生长。
本发明第七方面，提供一种预防和/或治疗癌症的方法，所述的方法包括步骤：给所需的受试者如本发明第一方面所述的组合物，或如本发明第二方面所述的药物组合物，或如本发明第三方面所述的药盒，或如本发明第四方面所述的活性成分组合。
在另一优选例中，所述对象为人和非人哺乳动物。
较佳地，所述的对象为人。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为3-HAA增强索拉非尼治疗肝癌的机制示意图
图2为实施例1中单用索拉非尼对肝癌细胞的抑制作用，其中IC50测定中，剂量梯度实验索拉非尼处理时间为4天(2A图)，时间梯度实验索拉非尼处理剂量为20μM(2B图)，通过CCK8检测细胞存活率。
图3为实施例2中单用3-HAA对肝癌细胞的抑制作用，其中IC50测定中，剂量梯度实验3-HAA处理时间为4天(3A图)，时间梯度实验3-HAA处理剂量为100μM(3B图)，通过CCK8检测细胞存活率。
图4为实施例3中3-HAA与索拉非尼协同抑制肝癌细胞，其中IC50测定中，索拉非尼及3-HAA处理时间为4天，通过CCK8检测细胞存活率。
图5为实施例3中3-HAA与索拉非尼协同诱导肝癌细胞凋亡，其中凋亡检测中，索拉非尼及3-HAA处理时间为1天。
图6为实施例4中3-HAA与索拉非尼协同抑制SMMC-7721移植瘤，其中图6A为移植瘤体积生长情况；图6B为各组移植瘤重量，*:P<0.05，**:P<0.01。
图7为实施例5中3-HAA与索拉非尼协同抑制PDX移植瘤，其中，7A图为PDX模型1移植瘤体积生长情况；7B图为PDX模型2移植瘤体积生长情况。
具体实施方式
本发明人经过广泛而深入地研究，意外地发现了3-羟基氨基苯甲酸或其药学上 可接受的盐和激酶抑制剂类抗癌药物可协同作用于预防和/或治疗癌症。协同治疗效果明显优于二者的单独使用，同时降低单个药物的用药剂量，降低药物的毒性。在此基础上，完成了本发明。
术语
除非另有定义,否则本文中所用的所有技术和科学术语的含义与本发明所属领域普通技术人员普遍理解的含义相同。
如本文所用，术语“包含”、“包括”、“含有”可互换使用，不仅包括封闭式定义，还包括半封闭、和开放式的定义。换言之，所述术语包括了“由……构成”、“基本上由……构成”。
如本文所用，术语“药学上可接受的载体”的成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)的，即有合理的效益/风险比的物质。
如本文所用，术语“治疗有效量”，是指对人和/或动物产生功能或活性的且可被人和/或动物所接受的量。本领域的普通技术人员应该理解，所述的“治疗有效量”可随着药物组合物的形式、给药途径、所用药物的辅料、疾病的严重程度以及与其他药物联合用药等情况的不同而有所不同。
本发明所述的“预防”和“治疗”包括延缓和终止疾病的进展，或消疾病，并不需要100％抑制、消灭和逆转。在一些实施方案中，与不存在本发明所述组合物或药物组合物时观察到的水平相比，本发明所述式组合物或哎药物组合物将癌症预防，减轻、抑制和/或逆转了例如至少约10％、至少约30％、至少约50％、或至少约80％。
第一活性成分
本发明中，第一活性成分为3-羟基氨基苯甲酸或其药学上可接受的盐。3-羟基氨基苯甲酸(3-HAA)或其药学上可接受的盐为AKT和ERK通路抑制剂。，所述AKT通路抑制剂为一种通过促进DUSP6表达以及抑制PDK1活性来抑制AKT通路的抑制剂。
3-羟基氨基苯甲酸是色氨酸的代谢中间产物，分子量为153.1，分子式为C7H7NO3，结构如下：
Figure PCTCN2019092081-appb-000001
如本文所用，“3-羟基氨基苯甲酸”，是指式3-羟基氨基苯甲酸、或其药学上可接受的盐。应理解，该术语还包括上述组分的混合物。
第二活性成分
本发明所述的第二活性成分为激酶抑制剂类抗癌药物。
在另一优选例中，所述的激酶抑制剂为酪氨酸激酶抑制剂。
在另一优选例中，所述的激酶抑制剂包括raf酶抑制剂。
在另一优选例中，所述的激酶抑制剂包括多靶点激酶抑制剂类抗癌药物。
优选地，所述激酶抑制剂类抗癌药物为索拉非尼或其药学上可接受的盐。更优选地，所述激酶抑制剂类抗癌药物为甲苯磺酸索拉非尼。
如本文所用，“索拉非尼”，是指式索拉非尼、或其药学上可接受的盐。应理解，该术语还包括上述组分的混合物。
广谱酪氨酸激酶索拉非尼，是肝癌治疗的一线化疗药，但其疗效却差强人意，临床低应答及获得性耐药是导致其治疗失败的关键因素。
在本发明中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：甲苯磺酸、盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的盐，适合形成盐的碱包括但并不限于：氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱，氨水、三乙胺、二乙胺等有机碱。
组合物、药盒、活性成分组合和药物组合物
本发明提供一种组合物，所述组合物包括：
(a)治疗有效量的第一活性成分，所述第一活性成分3-羟基氨基苯甲酸或其药学 上可接受的盐；和
(b)治疗有效量的第二活性成分，所述第二活性成分为激酶抑制剂类抗癌药物。
在另一优选例中，第一活性成分的含量范围为0.01％至99.99％，以组合物活性成分的总重量计；较佳地0.1％至99.9％所述；更佳地1％至99％；较佳地10％至99％；更佳地20％至99％；更佳地30-99％，更佳地40-99％。
在另一优选例中，第二活性成分的含量范围为0.01％至99.99％，以组合物活性成分的总重量计；较佳地0.1％至99.9％；更佳地1％至99％；更佳地1％至90％；更佳地1％至80％；更佳地1-70％，更佳地1-60％。
在另一优选例中，其特征在于，所述3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类抗癌药物的重量比为1-50：0.5-15，较佳地1-30：0.5-10，更佳地1-20：0.5-5，最佳地5-15：0.5-5。
在另一优选例中，所述的3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类抗癌药物的摩尔比为1-150：1，较佳地1-100：1，更佳地1-70：1，最佳地5-50：1。
必要时，所述的组合物还可以包括药学上可接受的载体，制成药物组合物(药品)。
代表性地，所述的组合物还包括药学上可接受的载体，制成药物组合物，所述的药物组合物包括：
(a)治疗有效量的第一活性成分，所述第一活性成3-羟基氨基苯甲酸或其药学上可接受的盐；
(b)治疗有效量的第二活性成分，所述第二活性成分为激酶抑制剂类抗癌药物；和
(c)药学上可接受的载体。
本发明所述的含有第一活性成分和第二活性成分药物组合物，可以是适宜口服给药的各种剂型外，还可以是各种外用给药制剂或其它胃肠道外给药制剂。例如，本发明所述的外用给药制剂，还可以通过添加表面活性剂、透皮吸收促进剂、防腐剂、溶剂、抗氧剂、保湿剂、pH调节剂、着色剂、香料等辅料，进一步制备成(包括但不限于)：搽剂、酊剂、油剂、软膏剂、硬膏剂、糊剂、熨剂、贴膏、贴片、涂膜剂、膜剂、凝胶剂、巴布剂、穴位贴敷剂、喷雾剂、气雾剂、植入剂、乳剂等。对于癌症，优选的剂型包括：口服给药的各种剂型、植入剂、注射剂。
应理解，在本发明中，所述的载体没有特别的限制，为本领域常用材料，其种类、使用方法、来源为本领域技术人员所熟知。
药学可接受的载体部分例子有纤维素及其衍生物(如甲基纤维素、乙基纤维素、羟丙甲基纤维素、羧甲基纤维素钠等)、明胶、滑石粉、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油、等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、缓冲剂、螯合剂、增稠剂、pH调节剂、透皮促进剂、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、抑菌剂、无热原水等。
在另一优选例中，在所述的药物组合物中，所述的第一活性成分和第二活性成分含量范围，以及第一活性成分和第二活性成分的质量比如上文所述组合物中描述。
本发明还提供一种活性成分组合物，所述的活性成分组合包括以下组分：
(a)治疗有效量的第一活性成分，所述第一活性成分3-羟基氨基苯甲酸或其药学上可接受的盐；
(b)治疗有效量的第二活性成分，所述第二活性成分为激酶抑制剂类抗癌药物。
在另一优选例中，在所述的药物成分组合中，所述的第一活性成分和第二活性成分含量范围，以及第一活性成分和第二活性成分的质量比如上文所述组合物中描述。
本发明还提供一种药盒，所述药盒包括：
(A)含有3-羟基氨基苯甲酸或其药学上可接受的盐的第一制剂；
(B)含有激酶抑制剂类抗癌药物的第二制剂；和
(C)使用说明书。
所述的使用说明书中注明将所述第一制剂和第二制剂进行联用，从而预防和/或治疗癌症。
在联用本发明的药盒中的第一制剂和第二制剂时，第一制剂和第二制剂可以同时给药、分别给药或顺序给药。
本发明的组合物、活性成分组合、药物组合物、药盒、食品和保健品均可采用常规方法和设备进行制备。
用途和给药方式
本发明提供了一种本文所述组合物、活性成分组合物、药物组合物在制备用于预 防和/或治疗癌症的药物中的用途。
本发明所述的组合物、活性成分组合物、药物组合物以及药盒中的第一活性成分和第二活性成分可对肝癌、肾癌、白血病的预防和治疗产生协同作用，增强治疗癌症的效果，降低单个药物的用药剂量，降低药物的毒性。典型地，3-HAA和索拉非尼联合应用协同增强治疗肝癌效果的示意图如图1所示。
在使用本发明的组合物、活性成分组合、药物组合物以及药盒之前、同时或之后，可配合使用其他治疗癌症的活性物质(例如托泊甙、5-氟尿嘧啶、等抗癌活性物质、甲磺酸伊马替尼)、实施针对癌症的外科手术或给予针对癌症的放射性治疗，或与基因治疗联合使用，或与生物调节剂联合使用。
在联合用药过程中，药物的相互作用根据药物共同使用时的效应分为加合作用、协同作用、拮抗作用，协同作用是指联合用药的药物共同使用时的效应要比单独使用大很多倍，加和作用是指联合用药的药物共同使用时的效应要与单独使用相当，拮抗作用是指联合用药的药物共同使用时的效应要比单独使用小。在本发明中，首次发现第一活性成分和第二活性成分联合使用具有协同作用。
在抑制癌细胞生长或预防和治疗癌症时，本发明的给药方式包括先后依次施用第一活性成分和第二活性成分，或同时施用第一活性成分和第二活性成分。
药物制剂应与给药方式相匹配，使用药物组合物或制剂时，是将安全有效量的药物施用于所需对象(如人或非人哺乳动物)，其中，第一活性成分的安全有效日使用剂量通常至少约0.1mg，而且在大多数情况下不超过约2000mg。较佳地，该剂量是1mg-500mg；第二活性成分的安全有效量通常至少约0.01mg，而且在大多数情况下不超过1500mg。较佳地，该剂量范围是0.1mg至1500mg。(其中，第一活性成分的安全有效量通常不超过约2000毫克/千克体重。较佳地，该剂量是约100微克/千克体重至约1000毫克/千克体重；第二活性成分的安全有效量通常不超过约2000毫克/千克体重。较佳地，该剂量是约10微克/千克体重至约1000毫克/千克体重。)当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是在熟练医师技能范围之内的。当先后依次施用第一活性成分和第二活性成分时，施用的间隔时间无特别要求。本发明的组合物、活性成分组合、药物组合物以及药盒中的第一活性成分和第二活性成分分别以相同或不同的途径同时或相继给药，其中包括但并不限于：口服给药、注射给药、瘤内给药、植入给药、腔内给药、肛门给药、透皮给药、内外敷；
优选的注射给药包括：静脉注射、肌肉注射、皮下注射、腔内注射。
体外非治疗性的抑制癌细胞生长的方法
本发明还提供一种体外非治疗性的抑制癌细胞生长的方法，所述的方法包括步骤：将癌细胞与本发明所述的组合物或所述活性成分组合接触，来抑制癌细胞的生长。
预防和/或癌症的方法
本发明还提供了一种预防和/或治疗癌症癌症的方法，所述的方法包括步骤：给所需的受试者施用如本发明所述的组合物、活性成分组合、药物组合物或药盒。
在抑制癌细胞生长或预防和治疗癌症时，本发明的施用方式包括先后依次施用第一活性成分和第二活性成分，或同时施用第一活性成分和第二活性成分。
在另一优选例中，所述对象为人和非人哺乳动物。代表性地，所述的非人哺乳动物包括(但并不限于)：宠物(如狗、猫)、家畜(如牛、羊、马、猪)、各种动物园动物(熊猫、大象、虎)等。
本发明的优点主要包括：
1、本发明所述组合中，第一活性成分和第二活性成分能够产生协同作用，增强治疗癌症的效果，降低单个药物的用药剂量，降低药物的毒性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1
单用索拉非尼对肝癌细胞的抑制作用
实验方法
4株肝癌细胞(PLC8024、SMMC-7721、HepG2和Hep3B)加入剂量梯度(剂量分别为：0、1.25、2.5、5、10、20和40μM)及时间梯度(时间分别为：0、1、2、3和4天)的索拉非尼处理，通过CCK8实验计算索拉非尼对4株肝癌细胞的半数抑制浓度(50％Inhibition concentration,IC50)。
实验结果
如图2所述，4株肝癌细胞的IC50分别为：PLC8024 8.4μM；SMMC-7721:15.3μM；HepG2:2.6μM；Hep3B：3.2μM。其中PLC8024及SMMC-7721对索拉非尼治疗应答明显低于HepG2和Hep3B。
实施例2
单用3-HAA对肝癌细胞的抑制作用
通过CCK8实验计算3-HAA(3-羟基氨基苯甲酸)对4株肝癌细胞(PLC8024、SMMC-7721、HepG2和Hep3B)的半数抑制浓度(50％Inhibition concentration,IC50)。
实验结果
如图3所示，4株肝癌细胞的IC50分别为：PLC8024:147.7μM；SMMC-7721:165.4μM；HepG2:73.2μM；Hep3B:101.5μM。其中PLC8024及SMMC-7721对3-HAA治疗应答明显低于HepG2和Hep3B。
实施例3
3-HAA与索拉非尼协同抑制肝癌细胞
考察3-HAA能否作为索拉非尼的辅助用药，增强索拉非尼的治疗敏感性。
实验方法
通过CCK8实验，检测单用索拉非尼或3-HAA和索拉非尼联合使用时，低应答的SMMC-7721及PLC8024细胞的存活率。
实验结果
从图4中可以看出，3-HAA可以明显增强索拉非尼的治疗敏感性。联用3-HAA(50μM)，SMMC7721及PLC8024的IC50分别从14.5μM和8.1μM下降至4.9μM和2.4μM。单用5μM索拉非尼，两株细胞存活率分别为88.4±1.6％和76.3±4.7％，联合50μM的3-HAA之后，两株细胞存活率分别下降至43.8±2.1％及23.5±2.3％。图5的凋亡检测进一步证实两者连用具有协同作用。
实施例4
3-HAA与索拉非尼协同抑制SMMC-7721移植瘤
实验方法
构建SMMC-7721细胞的裸鼠移植瘤模型。4组移植瘤裸鼠分别作为对照组(给 予DMSO)、3-HAA给药组(100mg/kg.day)、索拉非尼给药组(10mg/kg.day)和3-HAA和索拉非尼联合给药组(3-HAA和索拉非尼的给药量分别为100mg/kg.day和10mg/kg.day)，给药方式为腹腔注射给药，每天给药。连续8天。
实验结果
从图6中可以看出，在对荷瘤小鼠体重无明显影响的情况下，索拉非尼和3-HAA联用可以发挥协同抑制SMMC-7721细胞移植瘤的生长。腹腔注射10mg/Kg.day的索拉非尼，对索拉非尼低应答肝癌细胞肿瘤生长曲线抑制作用不明显，当联合100mg/Kg.day的3-HAA，肿瘤生长得到了明显的抑制(图6A)。肿瘤重量也有类似的结果，联合使用索拉非尼和3-HAA，肿瘤平均重量为0.15±0.05g，仅为对照组(0.41±0.08g)的27％(图6B)。
实施例5
3-HAA与索拉非尼协同抑制PDX(病人来源的移植瘤)移植瘤
实验方法
在2个索拉非尼耐药临床病人的PDX模型上验证3-HAA与索拉非尼协同抑制肿瘤作用，分别设立对照组(给予DMSO)、3-HAA给药组(100mg/kg.day)、索拉非尼给药组(30mg/kg.day)和3-HAA和索拉非尼联合给药组(3-HAA和索拉非尼的给药量分别为100mg/kg.day和30mg/kg.day)。
实验结果
结果如图7所示，可以看出，3-HAA亦可增强索拉非尼对临床耐药肝癌PDX模型的治疗敏感性。本研究构建的PDX模型对30mg/Kg.day的索拉非尼仍呈现治疗抵抗，结果显示单独注射30mg/Kg.day的索拉非尼或100mg/Kg.day的3-HAA，对PDX移植瘤生长曲线抑制作用不明显，两者联合后，肿瘤生长得到了明显的抑制(图7A-B)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (11)

  1. 一种组合物，其特征在于，所述组合物包括：
    (a)治疗有效量的第一活性成分，所述第一活性成分3-羟基氨基苯甲酸或其药学上可接受的盐；和
    (b)治疗有效量的第二活性成分，所述第二活性成分为激酶抑制剂类抗癌药物。
  2. 如权利要求1所述的组合物，其特征在于，所述3-羟基氨基苯甲酸或其药学可接受的盐与激酶抑制剂类抗癌药物的重量比为1-50：0.5-15，较佳地1-30：0.5-10，更佳地1-20：0.5-5，最佳地5-15：0.5-5。
  3. 如权利要求1所述的组合物，其特征在于，所述的激酶抑制剂类抗癌药物为索拉非尼或其药学上可接受的盐。
  4. 一种药物组合物，其特征在于，所述的药物组合物包括如权利要求1所述的组合物；和药学上可接受的载体。
  5. 一种药盒，其特征在于，所述药盒包括：
    (A)含有3-羟基氨基苯甲酸或其药学可接受的盐的第一制剂；
    (B)含有激酶抑制剂类抗癌药物的第二制剂；和
    (C)使用说明书。
  6. 一种活性成分组合，其特征在于，所述的活性成分组合包括以下组分：
    (1)第一活性成分，所述第一活性为3-羟基氨基苯甲酸或其药学上可接受的盐；和
    (2)第二活性成分，所述第二活性成分为激酶抑制剂类抗癌药物。
  7. 如权利要求5所述的药盒和/或如权利要求6所述的活性成分组合，其特征在于，所述3-羟基氨基苯甲酸或其药学可接受的盐与所述激酶抑制剂类抗癌药物的重量比为1-50：0.5-15，较佳地1-30：0.5-10，更佳地1-20：0.5-5，最佳地5-15：0.5-5。
  8. 一种如权利要求1所述的组合物，或如权利要求4所述的药物组合物，或如权利要求5所述的药盒，或如权利要求6所述的活性成分组合的用途，其特征在于，用于制备预防和/或治疗癌症的药物。
  9. 如权利要求8所述的用途，其特征在于，所述的癌症选自下组：肝癌、肾癌、白血病。
  10. 一种体外非治疗性的抑制癌细胞生长的方法，其特征在于，所述的方法包括步骤：将癌细胞与如权利要求1所述的组合物，或如权利要求4所述的药物 组合物，或如权利要求6所述活性成分组合接触，来抑制癌细胞的生长。
  11. 一种预防和/或治疗癌症的方法，其特征在于，所述的方法包括步骤：给所需的受试者如权利要求1所述的组合物，或如权利要求4所述药物组合物，或如权利要求5所述药盒，或如权利要求6所述活性成分组合。
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WO2009063241A1 (en) * 2007-11-13 2009-05-22 Ludwig Institut Fur Krebsforschung Ag 3-hydroxyanthranilic acid or salts thereof1 for treating cancer or infections
CN102836160A (zh) * 2012-10-10 2012-12-26 武汉大学 一种治疗癌症的组合药物

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WO2009063241A1 (en) * 2007-11-13 2009-05-22 Ludwig Institut Fur Krebsforschung Ag 3-hydroxyanthranilic acid or salts thereof1 for treating cancer or infections
CN102836160A (zh) * 2012-10-10 2012-12-26 武汉大学 一种治疗癌症的组合药物

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