WO2024120523A1 - 一种治疗***癌的药物组合及其应用 - Google Patents
一种治疗***癌的药物组合及其应用 Download PDFInfo
- Publication number
- WO2024120523A1 WO2024120523A1 PCT/CN2023/137457 CN2023137457W WO2024120523A1 WO 2024120523 A1 WO2024120523 A1 WO 2024120523A1 CN 2023137457 W CN2023137457 W CN 2023137457W WO 2024120523 A1 WO2024120523 A1 WO 2024120523A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- prostate cancer
- compound
- drug
- enzalutamide
- androgen receptor
- Prior art date
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Classifications
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- 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
- A61K38/07—Tetrapeptides
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the androgen receptor belongs to the nuclear receptor superfamily and contains 918 amino acid residues, which form three important domains, namely the DNA binding domain (DBD), the ligand binding domain (LBD) and the N-terminal domain (NTD).
- DBD DNA binding domain
- LBD ligand binding domain
- NTD N-terminal domain
- the structural formula of the compound X is:
- the dosage form of the pharmaceutical combination includes tablets, granules, capsules, solutions, powders, injections or pills.
- the structural formula of the compound X is:
- the present disclosure further provides a drug for treating prostate cancer, the drug comprising a main active ingredient and a pharmaceutically acceptable excipient; the main active ingredient comprises the drug combination defined in the first aspect or the second aspect.
- the present disclosure has found through research that compound X and enzalutamide can synergistically enhance the efficacy when combined to treat prostate cancer, and can better inhibit the proliferation of prostate cancer cells and promote the apoptosis of prostate cancer cells.
- the present disclosure has verified the potential value of the combined treatment of compound X and enzalutamide through experiments, proving that the efficacy of the combined use of the two is far greater than that of the single drug, providing a better treatment plan for the treatment of prostate cancer, and has broad application prospects.
- FIG. 1 is a result of detecting the survival rate of each group of LNCAP cells treated in Example 1.
- Figure 5 shows the apoptosis detection results of LNCAP cells in the Control group, the Compound X 8 ng/ ⁇ L single treatment group, the Enzalutamide 200 ⁇ M single treatment group, and the Compound X 8 ng/ ⁇ L + Enzalutamide 200 ⁇ M combined treatment group in Example 3.
- Figure 6 shows the apoptosis rate of LNCAP cells in the Control group, the Compound X 8 ng/ ⁇ L single treatment group, the Enzalutamide 200 ⁇ M single treatment group, and the Compound X 8 ng/ ⁇ L + Enzalutamide 200 ⁇ M combined treatment group in Example 3.
- Example 7 shows the apoptosis detection results of LNCAP cells in the Control group, the Compound X 4 ng/ ⁇ L single treatment group, the Enzalutamide 100 ⁇ M single treatment group, and the Compound X 4 ng/ ⁇ L + Enzalutamide 100 ⁇ M combined treatment group in Example 3.
- FIG8 shows the 22Rv1 cells in the Control group, the Compound X 8 ng/ ⁇ L single treatment group, the Enzalutamide 200 ⁇ M single treatment group, and the Compound X 8 ng/ ⁇ L + Enzalutamide 200 ⁇ M combined treatment group in Example 4.
- Figure 9 shows the apoptosis rate of 22Rv1 cells in the Control group, the Compound X 8 ng/ ⁇ L single treatment group, the Enzalutamide 200 ⁇ M single treatment group, and the Compound X 8 ng/ ⁇ L + Enzalutamide 200 ⁇ M combined treatment group in Example 4.
- a and/or B may represent the following three situations: A exists alone, A and B exist at the same time, and B exists alone.
- the character "/" generally indicates that the associated objects are in an "or” relationship.
- prevention in this disclosure includes the inhibition or delay of the occurrence or frequency of a disease or disorder or its symptoms, and generally refers to the administration of a drug before the disorder or symptom occurs, particularly before the disorder or symptom occurs in an individual at risk.
- treatment refers to the slowing, arresting or reversing of the progression of a disease such as cancer in a subject as evidenced by the alleviation or elimination of clinical or diagnostic symptoms of the disease. Treatment may include, for example, reducing the severity of symptoms, the number of symptoms or the frequency of recurrence, such as tumor growth inhibition, tumor growth retardation or regression of existing tumors.
- non-fixed combination means that the active ingredients (e.g., (a) Compound X or a pharmaceutically acceptable salt thereof, and (b) an androgen receptor antagonist or a pharmaceutically acceptable salt thereof) are administered to a patient simultaneously, without specific time restrictions, or at the same or different time intervals, sequentially as separate entities, wherein such administration provides preventive or therapeutically effective levels of the two active agents in the patient's body.
- fixed combination means that two active agents are administered to a patient simultaneously in the form of a single entity.
- the dosage and/or time interval of the two active agents are selected so that the combined use of the parts can produce an effect greater than that achieved by using either alone when treating a disease or condition, and each component can be in a separate formulation, which can be the same or different.
- therapeutically effective amount in the present disclosure refers to the amount of combined administration that, when administered in combination, induces the desired biological or medical response, i.e., inhibits or improves one or more cancers.
- therapeutically effective amount is the amount of antibody and the amount of chemotherapeutic drug that produce a therapeutically effective and/or synergistic combined effect when administered together (sequentially or simultaneously) on the same day or different days in a treatment cycle.
- the amount of the chemical drug alone may or may not be therapeutically effective.
- each active ingredient in the drug combination of the present disclosure refers to the physical introduction of each active ingredient in the drug combination of the present disclosure into an individual using any of a variety of methods and delivery systems known to those skilled in the art.
- the administration routes of each active ingredient in the drug combination of the present disclosure include oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other routes.
- each active ingredient in the drug combination of the present disclosure can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, etc.
- pharmaceutically acceptable salt in the present disclosure includes, but is not limited to, acid addition salts or base addition salts, such as acid addition salts formed by compound X with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts formed by compound X with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and salts with the formula HOOC-(CH 2 )n-COOH (wherein n
- the salts formed by the alkanedicarboxylic acid (0, 1, 2, 3 or 4) are also included.
- Enzalutamide in the present disclosure is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thione-1-imidazolidinyl]-2-fluoro-N-methylbenzamide.
- Enzalutamide is an androgen receptor antagonist that can competitively inhibit the binding of androgens to the receptor, and can inhibit the nuclear translocation of the androgen receptor and the interaction of the receptor with DNA.
- Enzalutamide was purchased from Selleck, item number S1250-5mg.
- the compound X treatment group had final concentrations of 9.6 ng/ ⁇ L (recorded as 5 groups), 4.8 ng/ ⁇ L (recorded as 4 groups), 2.4 ng/ ⁇ L (recorded as 3 groups), 1.2 ng/ ⁇ L (recorded as 2 groups), and 0.6 ng/ ⁇ L (recorded as 1 group);
- the enzalutamide treatment group had final concentrations of 400 ⁇ M (recorded as 5 groups), 200 ⁇ M (recorded as 4 groups), 100 ⁇ M (recorded as 3 groups), 50 ⁇ M (recorded as 2 groups), and 2 5 ⁇ M (recorded as group 1); compound X and enzalutamide combined treatment group, including the following concentrations: compound X 9.6ng/ ⁇ L+enzalutamide 400 ⁇ M (recorded as group 5), compound X 4.8ng/ ⁇ L+en
- the cells were treated with drugs, and the following experimental groups were set up: the compound X single treatment group, the final concentrations were 9.6 ng/ ⁇ L (recorded as 5 groups), 4.8 ng/ ⁇ L (recorded as 4 groups), 2.4 ng/ ⁇ L (recorded as 3 groups), 1.2 ng/ ⁇ L (recorded as 2 groups), and 0.6 ng/ ⁇ L (recorded as 1 group); the enzalutamide single treatment group, the final concentrations were 400 ⁇ M (recorded as 5 groups), 200 ⁇ M (recorded as 4 groups), 100 ⁇ M (recorded as 3 groups), 50 ⁇ M (recorded as 2 groups), 2 5 ⁇ M (recorded as group 1); compound X and enzalutamide combined treatment group, including the following concentrations: compound X 9.6ng/ ⁇ L+enzalutamide 400 ⁇ M (recorded as group 5), compound X 4.8ng/
- LNCAP cells were routinely cultured and then treated with drugs, and the following experimental groups were set up: compound X alone treatment group, the final concentrations were 8 ng/ ⁇ L and 4 ng/ ⁇ L, respectively; enzalutamide alone treatment group, the final concentrations were 200 ⁇ M and 100 ⁇ M, respectively; compound X and enzalutamide combined treatment group, including the following concentrations: compound X 8 ng/ ⁇ L + enzalutamide 200 ⁇ M, compound X 4 ng/ ⁇ L + enzalutamide 100 ⁇ M; Control group: treated with solvent DMSO, the volume concentration of DMSO in the culture system was 0.1%.
- apoptosis rate was detected using an apoptosis kit (GOONIE; catalog number: 100-101) combined with flow cytometry. The operation was carried out strictly in accordance with the instructions of the kit.
- 22Rv1 cells were routinely cultured and then treated with drugs.
- the following experimental groups were set up: compound X alone treatment group, with final concentrations of 8 ng/ ⁇ L and 4 ng/ ⁇ L, respectively; enzalutamide alone treatment group, with final concentrations of 200 ⁇ M and 100 ⁇ M, respectively; compound X and enzalutamide combined treatment group, including the following concentrations: compound X 8 ng/ ⁇ L + enzalutamide 200 ⁇ M, compound X 4 ng/ ⁇ L + enzalutamide 100 ⁇ M; Control group: treated with solvent DMSO, and the volume concentration of DMSO in the culture system was 0.1%.
- apoptosis rate was detected using an apoptosis kit (GOONIE; catalog number: 100-101) combined with flow cytometry. The operation was carried out strictly in accordance with the instructions of the kit.
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Abstract
本公开提供了一种治疗***癌的药物组合及其应用,所述药物组合包含(a)化合物X或其可药用盐;和(b)雄激素受体拮抗剂或其可药用盐。本公开还提供了一种治疗***癌药物,所述药物包含了所述药物组合。本公开经过研究发现,化合物X和雄激素受体拮抗剂联合治疗***癌时能协同增效,可以更好地抑制***癌细胞的增殖和促进***癌细胞的凋亡。本公开通过实验验证了化合物X与雄激素受体拮抗剂联合治疗的潜在价值,证明了当两者联合应用时疗效远大于单独用药,为***癌的治疗提供了一种更优的治疗方案,应用前景广阔。
Description
相关申请的引用
本公开要求于2022年12月09日提交中国专利局、申请号为202211585939.X、发明名称为“一种治疗***癌的药物组合及其应用”的发明专利申请,以及于2023年12月01日提交中国专利局、申请号为202311643355.8、发明名称为“一种治疗***癌的药物组合及其应用”的发明专利申请的优先权,通过引用将其全部内容结合在本公开中。
本公开属于生物医药技术领域,具体涉及一种治疗***癌的药物组合及其应用。
***癌是指发生在***的上皮性恶性肿瘤。2004年WHO《泌尿***及***官肿瘤病理学和遗传学》中***癌病理类型上包括腺癌(腺泡腺癌)、导管腺癌、尿路上皮癌、鳞状细胞癌、腺鳞癌。其中***腺癌占95%以上,因此,通常我们所说的***癌就是指***腺癌。目前,***癌已成为威胁老年男性健康的重要疾病,其发病率在西方国家较高且呈逐年上升的趋势,而在过去发病率较低的亚洲国家,近年来患病人数增长也在加快。临床治疗***癌常用的方法有手术切除、放射治疗以及阻断雄激素的内分泌疗法等。雄激素与***的生长以及***癌的发生密切相关,因此内分泌疗法已成为治疗***癌的有效途径。该方法包括睾丸切除法、***疗法、***释放激素类似物疗法、***释放激素拮抗剂疗法、雄激素拮抗疗法等,其中雄激素拮抗疗法既可单独治疗早期***癌也可配合手术进行辅助治疗,是当前临床治疗***癌的主要手段之一。而雄激素受体作为雄激素发挥生物学效应的靶点,已成为生物医学领域研究的
重要内容。
雄激素受体(androgen receptor,AR)属于核受体超家族,包含918个氨基酸残基,由此组成3个重要的结构域,分别是DNA结合域(DNA binding domain,DBD)、配体结合域(ligand binding domain,LBD)和氮端结合域(N-terminal domain,NTD)。临床实验表明,给予***癌病人外源性雄激素会导致患者的病情加重;但相反,若通过切除睾丸,降低患者体内雄激素水平则会使病情缓解,这表明雄激素对***癌的发展有重要影响。根据受体学说,雄激素必须与AR结合后才能引起后续的生理和病理效应,这就为应用雄激素受体拮抗剂治疗***癌奠定了理论基础。雄激素受体抑制是为患有***癌的患者提供的治疗策略之一。
化合物X是一种双配体小分子药物偶联体。其中,双配体的2个分支分别特异性识别叶酸受体α和***特异性膜蛋白(prostate specific membrane antigen,PSMA)受体,小分子毒素为一甲基澳瑞他汀E(Monomethyl auristatin E,MMAE),二者通过一个连接子进行偶联。连接子在细胞外液中相对稳定,化合物X被肿瘤细胞内吞后,该连接子即可被组织蛋白酶剪切并释放MMAE。MMAE可与微管结合,使细胞分化周期停滞在G2/M周期,进而诱导细胞凋亡,发挥抗肿瘤作用。
PSMA在***癌细胞表面特异性高表达,在***癌分子影像学及靶向治疗领域具有极为重要的研究价值,特别是核素标记PSMA小分子化合物已显示出较传统方法更良好的临床应用前景。另外,PSMA在肾细胞癌、肺鳞癌等其他实体瘤的肿瘤组织或肿瘤新生血管中,也存在较高表达。目前,已有多种靶向PSMA的药物处于早期临床研发阶段。叶酸是真核细胞核苷酸合成的必需物质,叶酸受体1(folate receptor 1,FLOR1)是介导细胞对叶酸内吞的一种糖蛋白,在多种恶性肿瘤细胞表面高表达,使其成为肿瘤诊疗领域广泛研究的新靶点。MMAE为海兔毒素衍生物,目前已有多种以MMAE为载药的抗体药物偶联物(antibody-drug conjugate,ADC)被国内外监管机构批准上市或处于研发阶段,治疗领域涵盖乳腺癌、淋巴瘤、妇科肿瘤和消
化道肿瘤等多种恶性肿瘤。FLOR1和PSMA双靶向的化合物X在临床前研究中表现出显著的抗肿瘤活性和良好的安全性,支持其进入临床阶段开发。
尽管化合物X单独治疗显示出了良好的疗效,但并非所有病人都有PSMA和FOLR1的高表达,这意味着对于受体低表达的病人来说单独治疗并不能达到期望的疗效。因此,需要探索更优的治疗方案。
发明内容
基于此,本公开的目的在于提供一种治疗***癌的药物组合及其应用,所述药物组合在用于治疗***癌时能协同增效。
为达到上述目的,本公开采用如下技术方案:
第一方面,本公开提供了一种药物组合在制备用于治疗***癌的药物中的应用,所述药物组合包含(a)化合物X或其可药用盐;和(b)雄激素受体拮抗剂或其可药用盐;其中化合物X的结构式为:
在一个优选实施方案中,所述化合物X的结构式为:
在一个优选实施方案中,所述雄激素受体拮抗剂为恩杂鲁胺。
在一个优选实施方案中,所述药物组合协同抑制***癌细胞的增殖。
在一个优选实施方案中,所述药物组合协同促进***癌细胞的凋亡。
在一些实施例中,所述药物组合的剂型包括片剂、颗粒剂、胶囊剂、溶液剂、粉剂、注射剂或丸剂。
第二方面,本公开还提供了一种治疗***癌的药物组合,所述药物组合包含(a)化合物X或其可药用盐;和(b)雄激素受体拮抗剂或其可药用盐;其中化合物X的结构式为:
在一个优选实施方案中,所述化合物X的结构式为:
在一个优选实施方案中,所述雄激素受体拮抗剂为恩杂鲁胺。
在一个优选实施方案中,所述化合物X和雄激素受体拮抗剂可分开或同时施用。
第三方面,本公开还提供了一种治疗***癌的药物,所述药物包含主要活性成分和药物学上可接受的辅料;所述主要活性成分包含第一方面或第二方面中所定义的药物组合。
在一个优选实施方案中,所述辅料包括填料、增容剂、粘合剂、保湿剂、崩解剂、缓溶剂、吸附剂、稀释剂、增溶剂、乳化剂、润滑剂、润湿剂、悬浮剂、矫味剂和香料中的至少一种。
第四方面,本公开还提供了一种用于预防或治疗***癌的方法,所述方法包括向有需要的患者施用治疗有效量的第一方面或第二方面中所定义的药物组合或第三方面所定义的药物。
第五方面,本公开还提供了一种成套药盒,其包含治疗有效量的第一方面或第二方面中所定义的药物组合或第三方面所定义的药物。
本公开经过研究发现,化合物X和恩杂鲁胺联合治疗***癌时能协同增效,可以更好地抑制***癌细胞的增殖和促进***癌细胞的凋亡。本公开通过实验验证了化合物X与恩杂鲁胺联合治疗的潜在价值,证明了当两者联合应用时疗效远大于单独用药,为***癌的治疗提供了一种更优的治疗方案,应用前景广阔。
图1为实施例1处理各组LNCAP细胞的存活率检测结果。
图2为实施例1处理各组LNCAP细胞的药物协同指数计算结果。
图3为实施例2中处理各组22Rv1细胞的存活率检测结果。
图4为实施例2中处理各组22Rv1细胞的药物协同指数计算结果。
图5为实施例3中Control组、化合物X 8ng/μL单独处理组、恩杂鲁胺200μM单独处理组、化合物X 8ng/μL+恩杂鲁胺200μM联合处理组LNCAP细胞的凋亡检测结果。
图6为实施例3中Control组、化合物X 8ng/μL单独处理组、恩杂鲁胺200μM单独处理组、化合物X 8ng/μL+恩杂鲁胺200μM联合处理组LNCAP细胞的凋亡率。
图7为实施例3中Control组、化合物X 4ng/μL单独处理组、恩杂鲁胺100μM单独处理组、化合物X 4ng/μL+恩杂鲁胺100μM联合处理组LNCAP细胞的凋亡检测结果。
图8为实施例4中Control组、化合物X 8ng/μL单独处理组、恩杂鲁胺200μM单独处理组、化合物X 8ng/μL+恩杂鲁胺200μM联合处理组22Rv1细胞
的凋亡检测结果。
图9为实施例4中Control组、化合物X 8ng/μL单独处理组、恩杂鲁胺200μM单独处理组、化合物X 8ng/μL+恩杂鲁胺200μM联合处理组22Rv1细胞的凋亡率。
本公开下列实施例中未注明具体条件的实验方法,通常按照常规条件进行,或按照制造厂商所建议的条件进行。实施例中所用到的各种常用化学试剂,均为市售产品。
除非另有定义,本公开所使用的所有的技术和科学术语与属于本公开的技术领域的技术人员通常理解的含义相同。本公开的说明书中所使用的术语只是为了描述具体的实施例的目的,不用于限制本公开。
本公开的术语“包括”或“包含”指包括所有的要素、整数或步骤,但是不排除任意其他要素、整数或步骤。在本文中,当使用术语“包含”或“包括”时,除非另有指明,否则也涵盖由所述及的要素、整数或步骤组成的情形。
在本公开中提及的“多个”是指两个或两个以上。“和/或”,描述关联对象的关联关系,表示可以存在三种关系,例如,A和/或B,可以表示:单独存在A,同时存在A和B,单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
本公开中术语“预防”包括对疾病或病症或其症状的发生或发生频率的抑制或推迟,其通常是指在病症或症状发生前,特别是具有风险个体的病症或症状发生前的药物施用。
本公开中术语“治疗”指通过疾病的临床或诊断症状的减轻或消除来证明的对象癌症等疾病进展的减缓、阻止或逆转。治疗可包括例如,降低症状严重程度、症状数量或复发频率,例如肿瘤生长抑制、肿瘤生长阻滞或已有肿瘤的消退。
本公开中术语“药物组合”是指非固定组合产品或固定组合产品,例如药盒。术语“非固定组合”意指活性成分(例如(a)化合物X或其可药用盐、和(b)雄激素受体拮抗剂或其可药用盐)以分开的实体被同时、无特定时间限制或以相同或不同的时间间隔、依次地施用于患者,其中这类施用在患者体内提供预防或治疗有效水平的所述两种活性剂。术语“固定组合”意指两种活性剂以单个实体的形式被同时施用于患者。优选对两种活性剂的剂量和/或时间间隔进行选择,从而使各部分的联合使用能够在治疗疾病或病症时产生大于单独使用任何一种所能达到的效果,各成分可以各自呈单独的制剂形式,其制剂形式可以相同也可以不同。
本公开中术语“治疗有效量”指联合给药时联合作用引发所需的生物学或医学反应,即抑制或改善的一种或多种癌症的联合给药量,例如,提到联合治疗时,本文所用术语“治疗有效量”是在治疗周期中的同一天或不同天一起给药(依次或同时)时,产生治疗有效和/或协同性的联合作用的抗体用量和化疗药物用量。而且,本领域技术人员应认识到,在用治疗有效量联合治疗的情况下(如上述实例),单独的化学药用量可能是或不是治疗有效的。
本公开中术语“施用”指用本领域技术人员已知的多种方法和递送***中的任一种将本公开的药物组合中的各活性成分物理导入至个体。本公开的药物组合中的各活性成分的施用途径包括口服、静脉内(例如输注(又称滴注)或注射)、肌内、皮下、腹膜内、脊髓、局部或其他途径。相应地,本公开的药物组合中的各活性成分可以被配制成胶囊剂、片剂、注射剂(包括输液或注射液)、糖浆、喷雾剂、锭剂、脂质体或栓剂等。
本公开中术语“可药用盐”包括但不限于酸加成盐或碱加成盐,例如化合物X与无机酸形成的酸加成盐,例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等;以及化合物X与有机酸形成的酸加成盐,例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH2)n-COOH(其中n
是0、1、2、3或4)的链烷二羧酸形成的盐等。还包括带有酸性基团的化合物X与药学上可接受的阳离子如钠、钾、钙、铝、锂和铵形成的碱加成盐。
本公开中术语“恩杂鲁胺(enzalutamide)”化学式为4-[3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫酮-1-咪唑烷基]-2-氟-N-甲基苯甲酰胺。恩杂鲁胺是雄激素受体拮抗剂,能够竞争性地抑制雄激素与受体的结合,并且能抑制雄激素受体的核转运以及该受体与DNA的相互作用。
下面结合具体实施例进行说明。以下实施例中使用的试剂信息如下:恩杂鲁胺购于Selleck,货号S1250-5mg。
实施例1
本实施例研究化合物X和恩杂鲁胺联合使用对***癌细胞LNCAP活力的影响。
常规培养LNCAP细胞后用药处理,设置以下实验组:化合物X单独处理组,终浓度分别为9.6ng/μL(记作5组)、4.8ng/μL(记作4组)、2.4ng/μL(记作3组)、1.2ng/μL(记作2组)、0.6ng/μL(记作1组);恩杂鲁胺单独处理组,终浓度分别为400μM(记作5组)、200μM(记作4组)、100μM(记作3组)、50μM(记作2组)、25μM(记作1组);化合物X和恩杂鲁胺联合处理组,包括以下浓度:化合物X 9.6ng/μL+恩杂鲁胺400μM(记作5组)、化合物X 4.8ng/μL+恩杂鲁胺200μM(记作4组)、化合物X 2.4ng/μL+恩杂鲁胺100μM(记作3组)、化合物X 1.2ng/μL+恩杂鲁胺50μM(记作2组)、化合物X 0.6ng/μL+恩杂鲁胺25μM(记作1组)。
药物处理48h后,收集各组细胞,使用CCK8试剂盒(APEXBIO;货号:K1018-500T)检测OD值(操作严格按照试剂盒说明书进行)计算细胞存活率,再使用混合药物分析软件CalcuSyn计算药物协同指数(当协同指数<1时表示药物存在协同作用)。
结果如图1-2所示,与化合物X单独处理组和恩杂鲁胺单独处理组相比,化合物X和恩杂鲁胺联合处理组对LNCAP细胞活力的抑制作用更强,化合物X和恩杂鲁胺在不同浓度联合加药时协同指数<1,均表现出协同作用,说明
两者在抑制***癌时可以协同增效。
实施例2
本实施例研究化合物X和恩杂鲁胺联合使用对***癌细胞22Rv1活力的影响。
常规培养22Rv1细胞后用药处理,设置以下实验组:化合物X单独处理组,终浓度分别为9.6ng/μL(记作5组)、4.8ng/μL(记作4组)、2.4ng/μL(记作3组)、1.2ng/μL(记作2组)、0.6ng/μL(记作1组);恩杂鲁胺单独处理组,终浓度分别为400μM(记作5组)、200μM(记作4组)、100μM(记作3组)、50μM(记作2组)、25μM(记作1组);化合物X和恩杂鲁胺联合处理组,包括以下浓度:化合物X 9.6ng/μL+恩杂鲁胺400μM(记作5组)、化合物X 4.8ng/μL+恩杂鲁胺200μM(记作4组)、化合物X 2.4ng/μL+恩杂鲁胺100μM(记作3组)、化合物X 1.2ng/μL+恩杂鲁胺50μM(记作2组)、化合物X 0.6ng/μL+恩杂鲁胺25μM(记作1组)。
药物处理48h后,收集各组细胞,使用CCK8试剂盒检测OD值计算细胞存活率,再使用混合药物分析软件CalcuSyn计算药物协同指数。
结果如图3-4所示,与化合物X单独处理组和恩杂鲁胺单独处理组相比,化合物X和恩杂鲁胺联合处理组对22Rv1细胞活力的抑制作用更强,化合物X和恩杂鲁胺在不同浓度联合加药时协同指数<1,均表现出协同作用,说明两者在抑制***癌时可以协同增效。
实施例3
本实施例研究化合物X和恩杂鲁胺联合使用对***癌细胞LNCAP凋亡的影响。
常规培养LNCAP细胞后用药处理,设置以下实验组:化合物X单独处理组,终浓度分别为8ng/μL、4ng/μL;恩杂鲁胺单独处理组,终浓度分别为200μM、100μM;化合物X和恩杂鲁胺联合处理组,包括以下浓度:化合物X 8ng/μL+恩杂鲁胺200μM、化合物X 4ng/μL+恩杂鲁胺100μM;Control组:使用溶剂DMSO处理,DMSO在培养体系中的体积浓度为0.1%。
药物处理48h后,收集各组细胞,使用凋亡试剂盒(GOONIE;货号:100-101)结合流式分析技术检测凋亡率,操作严格按照试剂盒说明书进行。
如图5-6所示,与化合物X 8ng/μL单独处理组和恩杂鲁胺200μM单独处理组相比,化合物X 8ng/μL+恩杂鲁胺200μM联合处理组LNCAP细胞凋亡比例明显提高。如图7所示,与化合物X 4ng/μL单独处理组和恩杂鲁胺100μM单独处理组相比,化合物X 4ng/μL+恩杂鲁胺100μM联合处理组LNCAP细胞凋亡比例明显提高。说明两者在促进***癌细胞凋亡时可以协同增效。
实施例4
本实施例研究化合物X和恩杂鲁胺联合使用对***癌细胞22Rv1凋亡的影响。
常规培养22Rv1细胞后用药处理,设置以下实验组:化合物X单独处理组,终浓度分别为8ng/μL、4ng/μL;恩杂鲁胺单独处理组,终浓度分别为200μM、100μM;化合物X和恩杂鲁胺联合处理组,包括以下浓度:化合物X 8ng/μL+恩杂鲁胺200μM、化合物X 4ng/μL+恩杂鲁胺100μM;Control组:使用溶剂DMSO处理,DMSO在培养体系中的体积浓度为0.1%。
药物处理48h后,收集各组细胞,使用凋亡试剂盒(GOONIE;货号:100-101)结合流式分析技术检测凋亡率,操作严格按照试剂盒说明书进行。
如图8-9所示,与化合物X 8ng/μL单独处理组和恩杂鲁胺200μM单独处理组相比,化合物X 8ng/μL+恩杂鲁胺200μM联合处理组22Rv1细胞凋亡比例明显提高。说明两者在促进***癌细胞凋亡时可以协同增效。
上述结果表明,化合物X和恩杂鲁胺联合治疗***癌时能协同增效,可以更好地抑制***癌细胞的增殖和促进***癌细胞的凋亡。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以上实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本公开的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本公开专利范围的限制。应当指出的是,对于
本领域的普通技术人员来说,在不脱离本公开构思的前提下,还可以做出若干变形和改进,这些都属于本公开的保护范围。因此,本公开专利的保护范围应以所附权利要求为准。
Claims (11)
- 一种药物组合在制备用于治疗***癌的药物中的应用,其特征在于,所述药物组合包含(a)化合物X或其可药用盐;和(b)雄激素受体拮抗剂或其可药用盐;其中化合物X的结构式为:
- 如权利要求1所述的应用,其特征在于,所述雄激素受体拮抗剂为恩杂鲁胺。
- 如权利要求1或2所述的应用,其特征在于,所述药物组合协同抑制***癌细胞的增殖。
- 如权利要求1或2所述的应用,其特征在于,所述药物组合协同促进***癌细胞的凋亡。
- 如权利要求1或2所述的应用,其特征在于,所述药物组合的剂型包括片剂、颗粒剂、胶囊剂、溶液剂、粉剂、注射剂或丸剂。
- 一种治疗***癌的药物组合,其特征在于,所述药物组合包含(a)化合物X或其可药用盐;和(b)雄激素受体拮抗剂或其可药用盐;其中化合物X的结构式为:
- 如权利要求6所述的药物组合,其特征在于,所述雄激素受体拮抗剂为恩杂鲁胺。
- 如权利要求6或7所述的药物组合,所述化合物X和雄激素受体拮抗剂可分开或同时施用。
- 一种治疗***癌的药物,其特征在于,所述药物包含主要活性成分和药物学上可接受的辅料;所述主要活性成分包含如权利要求6~8任一项所述的药物组合。
- 如权利要求9所述的治疗***癌的药物,其特征在于,所述辅料包括填料、增容剂、粘合剂、保湿剂、崩解剂、缓溶剂、吸附剂、稀释剂、增溶剂、乳化剂、润滑剂、润湿剂、悬浮剂、矫味剂和香料中的至少一种。
- 一种成套药盒,其包含治疗有效量的根据权利要求6~8任一项所述的药物组合或根据权利要求9或10所述的药物。
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