技术领域Technical field
本发明涉及化疗药物技术领域，具体涉及一种化疗药物组合物及其应用。The invention relates to the technical field of chemotherapeutic drugs, and in particular to a chemotherapeutic drug composition and its application.
背景技术Background technique
化疗是治疗三阴性乳腺癌的主要方法之一，它是利用化学药物来阻止三阴性乳腺癌细胞的增殖、浸润、转移，直至最终杀灭三阴性乳腺癌细胞的一种治疗方式。但目前常用的一些临床一线化疗药物由于其选择性不强，在杀灭三阴性乳腺癌细胞的同时也会不可避免地损伤人体的正常细胞，从而出现药物的不良反应。且治疗三阴性乳腺癌时间相对较长，在长时间治疗过程中，容易产生抗药性或耐药性。Chemotherapy is one of the main methods for treating triple-negative breast cancer. It is a treatment method that uses chemical drugs to prevent the proliferation, invasion, and metastasis of triple-negative breast cancer cells, and ultimately kills triple-negative breast cancer cells. However, some currently commonly used clinical first-line chemotherapy drugs are not very selective and will inevitably damage normal cells in the human body while killing triple-negative breast cancer cells, resulting in adverse drug reactions. Moreover, the treatment of triple-negative breast cancer takes a relatively long time, and drug resistance or resistance is likely to develop during long-term treatment.
如何能够在不损伤人体正常细胞前提下，提高疗效，降低药物不良反应，并同时防止耐药性的出现，这是化疗药物治疗癌症亟待克服的难点。How to improve the efficacy, reduce adverse drug reactions, and prevent the emergence of drug resistance without damaging normal cells in the human body is an urgent difficulty that needs to be overcome in the treatment of cancer with chemotherapy drugs.
发明内容Contents of the invention
本发明意在提供一种化疗药物组合物及其应用，以解决现有治疗三阴性乳腺癌的化疗技术中因选择性不强导致治疗效果有限、不良反应严重的技术问题。The present invention is intended to provide a chemotherapeutic drug composition and its application to solve the technical problems of limited therapeutic effect and serious adverse reactions due to poor selectivity in the existing chemotherapy technology for treating triple-negative breast cancer.
为达到上述目的，本发明采用如下技术方案：一种化疗药物组合物，所述药物组合物的活性成分包括YM155和色瑞替尼。In order to achieve the above object, the present invention adopts the following technical solution: a chemotherapeutic pharmaceutical composition, the active ingredients of which include YM155 and ceritinib.
本方案的原理及优点是：色瑞替尼(Ceritinib，Cer，cas:1032900-25-6)用于治疗间变性淋巴瘤激酶(ALK)阳性、肿瘤病情有进展或不能耐受Crizotinib(克唑替尼)的转移性非小细胞肺癌(NSCLC)患者。YM155(Sepantronium Bromide)(Survivin抑制剂)是一种有效的survivin抑制药，通过抑制Survivin启动子活性而发挥作用，能有效抑制人类癌细胞系(突变p53或短小p53)。然而，YM155对肿瘤细胞的杀伤作用呈现浓度依赖性。为减少药物剂量与避免上述副作用，发明人在单独使用对正常细胞以及肿瘤细胞都没有细胞毒性的前提下，将两种药物进行药物组合；发明人实验发现，低剂量的两种药品组合即可有效抑制肿瘤细胞增殖，诱导肿瘤细胞凋亡，具有意想不到的技术效果。The principle and advantages of this program are: Ceritinib (Cer, cas: 1032900-25-6) is used to treat anaplastic lymphoma kinase (ALK)-positive, tumor progression, or intolerance to Crizotinib (Crazole) patients with metastatic non-small cell lung cancer (NSCLC). YM155 (Sepantronium Bromide) (Survivin inhibitor) is an effective survivin inhibitor that works by inhibiting the activity of the Survivin promoter and can effectively inhibit human cancer cell lines (mutated p53 or short p53). However, the killing effect of YM155 on tumor cells is concentration-dependent. In order to reduce the drug dosage and avoid the above-mentioned side effects, the inventor combined the two drugs on the premise that they have no cytotoxicity to normal cells and tumor cells when used alone. The inventor experimentally found that a low-dose combination of the two drugs is enough. It effectively inhibits tumor cell proliferation and induces tumor cell apoptosis, which has unexpected technical effects.
且相比于两者单独使用时抑制效果有限而言，YM155与色瑞替尼组合使用，可发挥协同增效的作用，提升色瑞替尼的抑制效果，以提高其抑制和杀灭三阴性乳腺癌细胞的效果。发明人实验表明，使用本方案的药物组合物对乳腺癌MDA-MB-231细胞、MCF-7细胞、BT549细胞进行抑制时，在使用YM155的情况下，色瑞替尼抑制和杀灭上述肿瘤细胞的效果均得到了很大提高，且YM155联合色瑞替尼的效果明显优于两者单独使用的效果，具有协同增效的作用。And compared with the limited inhibitory effect when used alone, YM155 and ceritinib can play a synergistic effect and enhance the inhibitory effect of ceritinib to improve its inhibition and killing of triple negative. effects on breast cancer cells. The inventor's experiments show that when the pharmaceutical composition of this solution is used to inhibit breast cancer MDA-MB-231 cells, MCF-7 cells, and BT549 cells, ceritinib inhibits and kills the above-mentioned tumors when YM155 is used. The effects of cells have been greatly improved, and the effect of YM155 combined with ceritinib is significantly better than the effect of the two alone, with a synergistic effect.
另外，本方案通过组合使用YM155与色瑞替尼，还能显著减弱色瑞替尼因不可避免的杀灭正常细胞而产生不良反应的情况，且能在长期治疗过程中，降低肿瘤细胞对色瑞替尼的耐药性，提升长期治疗的抑制效果。In addition, the combined use of YM155 and ceritinib can also significantly reduce the adverse reactions of ceritinib due to its inevitable killing of normal cells, and can reduce the color sensitivity of tumor cells during long-term treatment. Resistance to retinib increases the inhibitory effect of long-term treatment.
优选的，所述YM155和色瑞替尼的质量比为4：2.025～3.24。Preferably, the mass ratio of YM155 and ceritinib is 4:2.025-3.24.
有益效果：本方案采用上述质量比的YM155和色瑞替尼可对肿瘤细胞形成有效的抑制作用，具有意想不到的技术效果。发明人实验发现，使用YM155和色瑞替尼组合对肿瘤进行治疗的时候，YM155的实际药量与色瑞替尼的实际用药的最低质量比为0.4mg∶0.2025mg；在两者协同增效作用下，可有效降低两种药物的用药剂量，降低成本，还能降低患者对色瑞替尼的不良反应及耐药性的治疗风险。发明人实验发现，若是高于此质量比(如选用4:1.5)则无法达到理想抑制效果；若低于此质量比，则不可避免的会对患者的正常细胞产生影响，从而造成不良反应，反而损害患者健康。Beneficial effects: This solution uses the above mass ratio of YM155 and ceritinib to form an effective inhibitory effect on tumor cells and has unexpected technical effects. The inventor's experiments found that when using a combination of YM155 and ceritinib to treat tumors, the lowest mass ratio of the actual dosage of YM155 to the actual dosage of ceritinib is 0.4mg:0.2025mg; when the two are synergistic, Under the action of ceritinib, the dosage of the two drugs can be effectively reduced, the cost can be reduced, and the risk of patients' adverse reactions and drug resistance to ceritinib can be reduced. The inventor found through experiments that if the mass ratio is higher than this (for example, 4:1.5), the ideal inhibitory effect cannot be achieved; if the mass ratio is lower than this, it will inevitably affect the patient's normal cells, resulting in adverse reactions. On the contrary, it harms the patient's health.
优选的，所述活性成分以分子或离子状态的游离形式存在。Preferably, the active ingredient exists in free form in a molecular or ionic state.
有益效果：本方案中YM155和色瑞替尼在使用前，均需使用生理盐水或者5％葡萄糖注射液将YM155配制为YM155注射液或将色瑞替尼配置为色瑞替尼溶液，使得两者溶解在溶液中，有助于分散，充分发挥药效。Beneficial effects: Before use of YM155 and ceritinib in this program, physiological saline or 5% glucose injection is required to prepare YM155 into YM155 injection or ceritinib into ceritinib solution, so that the two Dissolved in the solution, it helps to disperse and give full play to the medicinal effect.
本方案还提供一种化疗药物组合物在制备抗肿瘤药物中的应用，所述抗肿瘤药物针对的肿瘤为原位或复发三阴性乳腺癌。This solution also provides the application of a chemotherapeutic drug composition in the preparation of anti-tumor drugs. The tumors targeted by the anti-tumor drugs are in situ or recurrent triple-negative breast cancer.
有益效果：本方案的抗肿瘤药物由化疗药物组合物制备而成，而化疗药物组合物则由YM155和色瑞替尼组成，YM155和色瑞替尼联合使用对人三阴性乳腺癌细胞MDA-MB-231、BT549细胞有显著的抑制作用，而对非三阴性乳腺癌细胞MCF-7细胞增敏效果较弱，故可将YM155和色瑞替尼的用于治疗三阴性乳腺癌中。YM155和色瑞替尼的组合物显示出了良好的三阴性乳腺癌细胞抑制效果。三阴性乳腺癌是指癌组织免疫组织化学检查结果为雌激素受体(ER)、孕激素受体(PR)和原癌基因Her-2均为阴性的乳腺癌，本病预后较差，死亡风险较高。Beneficial effects: The anti-tumor drugs in this program are prepared from a chemotherapy drug composition, and the chemotherapy drug composition is composed of YM155 and ceritinib. The combination of YM155 and ceritinib has an effective effect on human triple-negative breast cancer cells MDA- MB-231 and BT549 cells have significant inhibitory effects, but have a weak sensitizing effect on non-triple-negative breast cancer cells MCF-7 cells. Therefore, YM155 and ceritinib can be used to treat triple-negative breast cancer. The combination of YM155 and ceritinib showed good inhibitory effect on triple-negative breast cancer cells. Triple-negative breast cancer refers to breast cancer in which the immunohistochemistry results of the cancer tissue are negative for estrogen receptor (ER), progesterone receptor (PR), and proto-oncogene Her-2. The prognosis of this disease is poor, including death. The risk is higher.
优选的，所述药物组合物的活性成分包括YM155和色瑞替尼。Preferably, the active ingredients of the pharmaceutical composition include YM155 and ceritinib.
有益效果：本方案通过组合使用YM155与色瑞替尼，一方面，YM155协同色瑞替尼对肿瘤细胞的抑制作用，提升化疗的治疗效果；另一方面，YM155还能显著减弱色瑞替尼因不可避免的杀灭正常细胞而产生不良反应的情况，且能在长期治疗过程中，降低肿瘤细胞对色瑞替尼的耐药性，提升长期用药时的治疗效果。Beneficial effects: This program combines the use of YM155 and ceritinib. On the one hand, YM155 cooperates with the inhibitory effect of ceritinib on tumor cells to improve the therapeutic effect of chemotherapy; on the other hand, YM155 can also significantly weaken ceritinib. Adverse reactions occur due to the inevitable killing of normal cells, and it can reduce the resistance of tumor cells to ceritinib during long-term treatment and improve the therapeutic effect during long-term medication.
优选的，所述药物组合物的给药方式为静脉给药。Preferably, the pharmaceutical composition is administered intravenously.
有益效果：本方案采用上述给药方式，既符合传统用药习惯，也更为方便。静脉注射给药是YM155和色瑞替尼的常规给药方式。在注射本发明组合药物中的色瑞替尼注射液时，实际上还是与单用色瑞替尼注射液一样的非连续用药方式。因为药物色瑞替尼在人体内的代谢时间较长，非连续用药方式能够减小毒副反应。即便用了YM155协同而组成了药物组合之后本来就已经能够减少一些色瑞替尼的使用剂量了，但仍沿用这样的用药方式，符合传统用药习惯。在应用本发明的药物组合时，只是多了注射YM155注射液这一步骤，没有其他的特别操作方法，更为方便。本发明药物组合中YM155的实际药量远比色瑞替尼的少。结合实验验证，不仅能够说明使用YM155协同色瑞替尼抑制和杀灭各种恶性肿瘤细胞，可以减少用药量、缩短治疗周期，减少毒副反应发生。甚至可以反过来讲，在现有临床化疗药物色瑞替尼媒介作用下，本申请发明人发现的具有能有效地诱导多种肿瘤细胞的自噬作用的YM155，也具有了效果可靠且具有实用价值的杀灭各种恶性肿瘤细胞的作用。。Beneficial effects: This program adopts the above-mentioned administration method, which is not only in line with traditional medication habits, but also more convenient. Intravenous administration is the conventional administration method of YM155 and ceritinib. When injecting the ceritinib injection in the combination medicine of the present invention, it is actually the same discontinuous administration method as the single use of ceritinib injection. Because the drug ceritinib takes a long time to be metabolized in the human body, discontinuous administration can reduce toxic and side effects. Even though the dosage of ceritinib can be reduced after using YM155 synergy to form a drug combination, this medication method is still used, which is in line with traditional medication habits. When applying the drug combination of the present invention, only the step of injecting YM155 injection is added, and there is no other special operation method, which is more convenient. The actual dosage of YM155 in the pharmaceutical combination of the present invention is much less than that of ceritinib. Combined with experimental verification, it not only shows that the use of YM155 in conjunction with ceritinib to inhibit and kill various malignant tumor cells can also reduce the dosage of drugs, shorten the treatment cycle, and reduce the occurrence of toxic and side effects. It can even be said conversely that under the mediated action of the existing clinical chemotherapy drug ceritinib, the YM155 discovered by the inventor of the present application can effectively induce autophagy in a variety of tumor cells, and has reliable and practical effects. It has great value in killing various malignant tumor cells. .
优选的，所述YM155的用药量为0.4mg/kg·bw。Preferably, the dosage of YM155 is 0.4 mg/kg·bw.
优选的，所述色瑞替尼的用药量为0.675～0.81mg/kg·bw。Preferably, the dosage of ceritinib is 0.675-0.81 mg/kg·bw.
有益效果：发明人经动物实验，将结果换算获得YM155和色瑞替尼的人体单次剂量。实验例2中，YM155的裸鼠单次剂量为5mg/kg·bw，色瑞替尼的裸鼠单次剂量为10mg/kg·bw。换算依据是美国食品药品监督管理局(FDA)在《药物临床实验中健康成人受试对象安全给药剂量的估算》(Estimating the Safe Starting Dose in Clinical Trials forTherapeutics in Adult Healthy Volunteers)中给出的，达到相同生物学效应所需的人体与小鼠(即实验验证中的裸鼠)的注射剂量换算比(1∶12.3)。Beneficial effects: The inventor conducted animal experiments and converted the results to obtain a single human dose of YM155 and ceritinib. In Experimental Example 2, the single dose of YM155 in nude mice was 5 mg/kg·bw, and the single dose of ceritinib in nude mice was 10 mg/kg·bw. The conversion basis is given by the US Food and Drug Administration (FDA) in "Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers" (Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers). The injection dose conversion ratio between humans and mice (i.e. nude mice in experimental verification) required to achieve the same biological effect (1:12.3).
优选的，所述YM155和色瑞替尼的给药频次比为10：3。Preferably, the administration frequency ratio of YM155 and ceritinib is 10:3.
有益效果：本方案采用上述的给药频次，低毒性YM155的使用可减少色瑞替尼的给药次数与剂量，在提升抑制效果的同时降低用药导致的不良反应和抗药性，提升色瑞替尼在长期治疗过程中的抑制效果。Beneficial effects: This protocol adopts the above-mentioned dosing frequency. The use of low-toxicity YM155 can reduce the dosing frequency and dosage of ceritinib, improve the inhibitory effect while reducing adverse reactions and drug resistance caused by medication, and improve the efficacy of ceritinib. The inhibitory effect of nil during long-term treatment.
附图说明Description of the drawings
图1为实验例1的色瑞替尼单用以及色瑞替尼联合YM155的癌细胞抑制曲线(实验对象为乳腺癌细胞，且YM155的浓度为定值)。Figure 1 shows the cancer cell inhibition curves of ceritinib alone and ceritinib combined with YM155 in Experimental Example 1 (the experimental subjects are breast cancer cells, and the concentration of YM155 is a constant value).
图2为实验例1的YM155单用以及YM155联合色瑞替尼的癌细胞抑制曲线(实验对象为乳腺癌细胞，且色瑞替尼的浓度为定值)。Figure 2 shows the cancer cell inhibition curves of YM155 alone and YM155 combined with ceritinib in Experimental Example 1 (the experimental subjects are breast cancer cells, and the concentration of ceritinib is a constant value).
图3为实验例2中处理21天后实验小鼠肿瘤体积图。Figure 3 is a graph of the tumor volume of experimental mice after 21 days of treatment in Experimental Example 2.
图4为实验例2的实验小鼠体重的变化曲线图。Figure 4 is a graph showing changes in body weight of experimental mice in Experimental Example 2.
图5为实验例2的实验小鼠存活率的变化曲线图。Figure 5 is a change graph of the survival rate of experimental mice in Experimental Example 2.
具体实施方式Detailed ways
实施例1Example 1
本方案的一种化疗药物组合物是由有效成分YM155和色瑞替尼组成，YM155的结构式参见式(Ⅰ)，色瑞替尼的结构式参见式(Ⅱ)。A chemotherapy drug composition in this program is composed of active ingredients YM155 and ceritinib. The structural formula of YM155 is shown in formula (Ⅰ), and the structural formula of ceritinib is shown in formula (Ⅱ).
在了解到本发明提供的药物组合能够提高疗效和降低不良反应之后，为避免抗药性或耐药性而采用本发明的药物组合时，对本领域的技术人员来讲，完全有能力针对具体的恶性肿瘤，通过系统的常规试验来确定YM155和色瑞替尼这两种组分之间的配比。针对本发明做实验验证时所选择的几种恶性肿瘤细胞而言，该药物组合物采用这样的配比为宜，一个疗程中(10天)，YM155的总药量与色瑞替尼总药量的质量比为4mg∶2.025～2.43mg。上述剂量比例是根据动物实验剂量(实验例2)换算。换算依据是美国食品药品监督管理局(FDA)在《药物临床实验中健康成人受试对象安全给药剂量的估算》(Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers)中给出的，达到相同生物学效应所需的人体与小鼠(即实验验证中的裸鼠)的注射剂量换算比(1∶12.3)。After understanding that the drug combination provided by the present invention can improve the efficacy and reduce adverse reactions, when using the drug combination of the present invention to avoid drug resistance or resistance, those skilled in the art are fully capable of targeting specific malignant diseases. Tumors, the ratio between the two components YM155 and ceritinib is determined through systematic routine trials. For several malignant tumor cells selected during the experimental verification of the present invention, it is appropriate for the pharmaceutical composition to adopt such a ratio. In one course of treatment (10 days), the total dosage of YM155 and the total dosage of ceritinib The mass ratio of the amount is 4mg:2.025~2.43mg. The above dosage ratio is converted based on the animal experimental dosage (Experimental Example 2). The conversion basis is given by the U.S. Food and Drug Administration (FDA) in "Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers" (Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers). The injection dose conversion ratio between humans and mice (i.e. nude mice in experimental verification) required for the same biological effect (1:12.3).
本方案中活性成分以游离形式或可药用盐的形式存在。具体的，本方案中YM155和色瑞替尼在使用前，均需使用生理盐水或者5％葡萄糖注射液将YM155配制为YM155注射液或将色瑞替尼配置为色瑞替尼溶液，使得两者溶解在溶液中，有助于分散，充分发挥药效。The active ingredients in this regimen are present in free form or in the form of pharmaceutically acceptable salts. Specifically, in this protocol, before use of YM155 and ceritinib, it is necessary to use normal saline or 5% glucose injection to prepare YM155 as YM155 injection or ceritinib as ceritinib solution, so that the two Dissolved in the solution, it helps to disperse and give full play to the medicinal effect.
本方案还提供一种化疗药物组合物在制备抗肿瘤药物中的应用，药物组合物的活性成分包括YM155和色瑞替尼，抗肿瘤药物针对的肿瘤为原位或复发三阴性乳腺癌。药物组合物的给药方式为静脉给药；YM155的用药量为0.4mg/kg·bw，色瑞替尼的用药量为0.81mg/kg·bw；YM155和色瑞替尼的给药频次比为10:3。This solution also provides the application of a chemotherapy drug composition in the preparation of anti-tumor drugs. The active ingredients of the drug composition include YM155 and ceritinib. The tumors targeted by the anti-tumor drugs are in situ or recurrent triple-negative breast cancer. The dosage of the pharmaceutical composition is intravenous administration; the dosage of YM155 is 0.4 mg/kg·bw, and the dosage of ceritinib is 0.81 mg/kg·bw; the dosage frequency ratio of YM155 and ceritinib is 10:3.
具体的，在应用本方案的药物组合物在制备抗肿瘤药物并对原位或复发三阴性乳腺癌进行治疗的时候，YM155和色瑞替尼均分次给药(但总药量之比保持为4mg：2.025～2.43mg，本实施例具体以4mg：2.43mg为例，对本方案的药物组合物在制备抗肿瘤药物并对原位或复发三阴性乳腺癌的治疗效果进行说明)，具体的应用方法如下：Specifically, when applying the pharmaceutical composition of this protocol to prepare anti-tumor drugs and treat in situ or recurrent triple-negative breast cancer, both YM155 and ceritinib are administered in divided doses (but the ratio of the total drug dosage remains is 4mg: 2.025~2.43mg. This embodiment specifically takes 4mg: 2.43mg as an example to illustrate the pharmaceutical composition of this solution in preparing anti-tumor drugs and explaining the therapeutic effect of in situ or recurrent triple-negative breast cancer), specifically The application method is as follows:
①按照YM155∶患者体重＝0.4mg/kg的剂量(需使用生理盐水或者5％葡萄糖注射液将YM155配制为YM155注射液，本实施例使用的是生理盐水)，通过静脉每日注射一次YM155注射液；①According to the dose of YM155: patient weight = 0.4mg/kg (normal saline or 5% glucose injection is required to prepare YM155 into YM155 injection, this example uses normal saline), inject YM155 once a day through intravenous injection liquid;
②在按照步骤①注射YM155注射液的当日，按照色瑞替尼∶患者体重＝0.81mg/kg的剂量(需使用生理盐水或者5％葡萄糖注射液将色瑞替尼配制为色瑞替尼注射液，本实施例使用的葡萄糖注射液)，通过静脉注射一次色瑞替尼注射液；② On the day of injecting YM155 injection according to step ①, follow the dosage of ceritinib: patient weight = 0.81 mg/kg (normal saline or 5% glucose injection is required to prepare ceritinib for injection) Liquid, glucose injection used in this embodiment), inject ceritinib injection once intravenously;
③到第五日时，按照步骤②所述剂量，通过静脉再注射一次同剂量色瑞替尼注射液；按照步骤①～③循环；③ On the fifth day, inject the same dose of ceritinib injection intravenously according to the dosage mentioned in step ②; cycle according to steps ① to ③;
④从第十一日起，根据患者身体的承受能力和治疗效果，确定是否再按照步骤①～③的方法循环，以及循环次数和中间停药时间。④ From the 11th day onwards, based on the patient's body tolerance and treatment effect, determine whether to follow steps ① to ③ again, as well as the number of cycles and the intervening drug withdrawal time.
本领域的技术人员十分清楚，注射液的浓度应当根据患者身体的承受能力等因素确定，在步骤④中所说的“循环次数”通常可以为1～4遍，“中间停药时间”通常可以为1～2周；对于身体特别差的患者，甚至可以只以步骤①和②为一用药周期或一个疗程(即从第六日起就暂停用药)。Those skilled in the art know very well that the concentration of the injection should be determined based on factors such as the patient's body tolerance. The "number of cycles" mentioned in step ④ can usually be 1 to 4 times, and the "intermediate withdrawal time" can usually be 1 to 2 weeks; for patients with particularly poor health, you can even only use steps 1 and 2 as a medication cycle or course of treatment (that is, suspend medication from the sixth day).
实验例1：细胞实验Experimental example 1: Cell experiment
1.细胞选择与活性培养1. Cell selection and active culture
实验选择有，人乳腺癌细胞MDA-MB-231、MCF-7、BT549。其中，人乳腺癌细胞MDA-MB-231、MCF-7、BT549细胞养在DMEM+10％ FBS完全培养基中，以上细胞均在37℃，5％浓度的CO2，饱和湿度的细胞培养箱中培养。Experimental options include human breast cancer cells MDA-MB-231, MCF-7, and BT549. Among them, human breast cancer cells MDA-MB-231, MCF-7, and BT549 were cultured in DMEM+10% FBS complete culture medium. The above cells were cultured in a cell culture incubator at 37°C, 5% concentration CO2 and saturated humidity. culture in.
2.实验方法以及结果2. Experimental methods and results
各肿瘤细胞系状态稳定后，将细胞铺于96孔板中，每孔5000个细胞，每孔含完全培养基90μL，然后使用药物处理细胞。对处理后的细胞进行MTT法检测，以确定药物对细胞活性的影响：加药处理48小时后，每孔中加入20μL磷酸盐缓冲溶液(PBS溶液)配制的5mg/mL的噻唑蓝(MTT)溶液继续培养4小时。吸走上层培养基，每孔中加入150μL二甲亚砜(DMSO)进行溶解，振荡器上溶解10分钟后，用酶标仪在A495处检测吸光度值，细胞存活率根据以下公式计算：After the status of each tumor cell line is stable, the cells are plated in a 96-well plate, with 5,000 cells in each well and 90 μL of complete culture medium in each well, and then the cells are treated with drugs. Conduct MTT assay on the treated cells to determine the effect of the drug on cell activity: 48 hours after drug addition, add 20 μL of 5 mg/mL thiazole blue (MTT) prepared in phosphate buffer solution (PBS solution) to each well. The solution was incubated for another 4 hours. Aspirate the upper culture medium and add 150 μL dimethyl sulfoxide (DMSO) to each well for dissolution. After dissolving on a oscillator for 10 minutes, use a microplate reader to detect the absorbance value at A495. The cell survival rate is calculated according to the following formula:
细胞存活百分率＝(处理组吸光度－空白孔吸光度)÷(对照组吸光度－空白孔吸光度)×100％。Cell survival percentage = (absorbance of treatment group - absorbance of blank well) ÷ (absorbance of control group - absorbance of blank well) × 100%.
具体的实验分组方式如下：The specific experimental grouping method is as follows:
人乳腺癌细胞MDA-MB-231、MCF-7、BT549细胞按以下方式分组并处理：Human breast cancer cells MDA-MB-231, MCF-7, and BT549 cells were grouped and processed as follows:
(1)对照组：完全培养基溶液10μL处理。(1) Control group: treated with 10 μL of complete medium solution.
(2)色瑞替尼组：用完全培养基配制浓度为0、1、2、4、6、8、10μM(μmol/L)的色瑞替尼溶液，每孔中加10μL处理，使其作用终浓度为0、0.1、0.2、0.4、0.6、0.8、1.0μM。实验结果参见图1。(2) Ceritinib group: Use complete culture medium to prepare ceritinib solutions with concentrations of 0, 1, 2, 4, 6, 8, and 10 μM (μmol/L), and add 10 μL to each well to make it The final concentrations are 0, 0.1, 0.2, 0.4, 0.6, 0.8, and 1.0 μM. The experimental results are shown in Figure 1.
(3)YM155组：用完全培养基配制浓度为0、0.5、1、2、4、6、8、10、20μM(μmol/L)的YM155溶液，每孔中加10μL处理，使其作用终浓度为0、0.05、0.1、0.2、0.4、0.6、0.8、1.0、2.0μM。实验结果参见图2。(3) YM155 group: Use complete culture medium to prepare YM155 solutions with concentrations of 0, 0.5, 1, 2, 4, 6, 8, 10, and 20 μM (μmol/L). Add 10 μL to each well for final treatment. The concentrations are 0, 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 2.0μM. The experimental results are shown in Figure 2.
(4)联合用药组：色瑞替尼和YM155组合药物组(4) Combination drug group: Ceritinib and YM155 combination drug group
色瑞替尼和YM155联合用药采用两种实验方案：The combination of ceritinib and YM155 adopts two experimental protocols:
方案一：用完全培养基配制浓度为0、1、2、4、6、8、10μM的色瑞替尼溶液及20μM的YM155混合药液，每孔中加混合药液10μL处理，使色瑞替尼作用终浓度分别为0、0.1、0.2、0.4、0.6、0.8、1μM，YM155的作用终浓度为2μM，实验结果参见图1。Plan 1: Use complete culture medium to prepare ceritinib solutions with concentrations of 0, 1, 2, 4, 6, 8, and 10 μM and 20 μM YM155 mixed drug solution. Add 10 μL of mixed drug solution to each well to make ceritinib. The final concentrations of tinib were 0, 0.1, 0.2, 0.4, 0.6, 0.8, and 1 μM, and the final concentration of YM155 was 2 μM. The experimental results are shown in Figure 1.
由图1可知，色瑞替尼本身在高剂量时具有一定的浓度依赖的癌细胞抑制效果，然而在YM155的作用下，同一浓度的色瑞替尼的癌细胞抑制效果增强。As can be seen from Figure 1, ceritinib itself has a certain concentration-dependent inhibitory effect on cancer cells at high doses. However, under the action of YM155, the inhibitory effect on cancer cells of ceritinib at the same concentration is enhanced.
方案二：用完全培养基配制浓度为0、0.5、1、2、4、6、8、10、20μM的YM155溶液及5μM的色瑞替尼混合药液，每孔中加混合药液10μL处理，使YM155的作用终浓度分别为0、0.05、0.1、0.2、0.4、0.6、0.8、1.0、2.0μM，色瑞替尼的作用终浓度为0.5μM，实验结果参见图2。Scheme 2: Use complete culture medium to prepare YM155 solutions with concentrations of 0, 0.5, 1, 2, 4, 6, 8, 10, 20 μM and 5 μM ceritinib mixed solution, and add 10 μL of the mixed solution to each well. , so that the final concentrations of YM155 are 0, 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, and 2.0 μM, respectively, and the final concentration of ceritinib is 0.5 μM. The experimental results are shown in Figure 2.
由图2可知，YM155本身不具有显著的癌细胞抑制效果，随着YM155的用量增加，YM155也没有显示出癌细胞抑制作用。但在加入0.5μM的色瑞替尼之后，组合物具有显著的抑制癌细胞的效果，这种抑制效应不是仅仅只通过色瑞替尼产生，而是通过色瑞替尼和YM155的协同效应实现。As can be seen from Figure 2, YM155 itself does not have a significant cancer cell inhibitory effect. As the dosage of YM155 increases, YM155 does not show any cancer cell inhibitory effect. However, after adding 0.5 μM ceritinib, the composition has a significant inhibitory effect on cancer cells. This inhibitory effect is not only produced by ceritinib, but is achieved through the synergistic effect of ceritinib and YM155. .
结合图1和图2，YM155单用时对细胞存活率无明显影响。YM155协同色瑞替尼组与单独使用色瑞替尼组相比较，YM155协同色瑞替尼组的肿瘤细胞存活率均不同程度地低于单独使用色瑞替尼组，两者联用的效果不是相加，而是1+1大于2的效果，两者协同增效，对癌症细胞的抑制具有意想不到的技术效果。Combining Figure 1 and Figure 2, YM155 has no significant effect on cell survival rate when used alone. Compared with the YM155 combined with ceritinib group and the ceritinib alone group, the tumor cell survival rate of the YM155 combined with ceritinib group was lower than that of the ceritinib alone group to varying degrees. The effect of the combination of the two It is not the addition, but the effect of 1+1 greater than 2. The two synergize and have unexpected technical effects on the inhibition of cancer cells.
综合图1和图2的实验结果，YM155和色瑞替尼联合使用对人三阴性乳腺癌细胞MDA-MB-231、BT549细胞有显著的抑制作用，而对非三阴性乳腺癌细胞MCF-7细胞增敏效果较弱，故可将YM155和色瑞替尼的用于治疗三阴性乳腺癌中。YM155和色瑞替尼的组合物显示出了良好的三阴性乳腺癌细胞抑制效果。Based on the experimental results in Figures 1 and 2, the combination of YM155 and ceritinib has a significant inhibitory effect on human triple-negative breast cancer cells MDA-MB-231 and BT549 cells, while it has a significant inhibitory effect on non-triple-negative breast cancer cells MCF-7 The cell sensitizing effect is weak, so YM155 and ceritinib can be used to treat triple-negative breast cancer. The combination of YM155 and ceritinib showed good inhibitory effect on triple-negative breast cancer cells.
另外，在图1～图2中，纵坐标表示细胞存活率，即处理组相对于对照组的细胞存活率。横坐标为各种人肿瘤细胞株(注：仅由对应肿瘤细胞的区别符号表示)。图柱对应的值为各组的平均值，图中“Ⅰ”形符号指出了上下偏差。In addition, in Figures 1 and 2, the ordinate represents the cell survival rate, that is, the cell survival rate of the treated group relative to the control group. The abscissa represents various human tumor cell lines (note: only represented by the distinguishing symbols of the corresponding tumor cells). The value corresponding to the graph column is the average value of each group, and the "I" shaped symbol in the graph points out the upper and lower deviations.
本领域的技术人员十分清楚，在细胞实验中，药物作用效果只与药物浓度存在对应关系，而不是与药物的总量，同时，细胞层面的药物浓度不能够与动物实验的浓度进行换算，因此，细胞层面实验只能够验证YM155协同色瑞替尼的药物组合与单独使用色瑞替尼相比较有没有显著差异。当然，通过这一验证也充分证明了本发明药物组合的有效性和可靠性。再通过裸鼠实验进一步验证本发明药物组合的效果时，仅只针对一种肿瘤细胞进行研究。Those skilled in the art know very well that in cell experiments, the drug effect only corresponds to the drug concentration, not the total amount of the drug. At the same time, the drug concentration at the cellular level cannot be converted to the concentration in animal experiments. Therefore, , Cell-level experiments can only verify whether there is any significant difference between the drug combination of YM155 and ceritinib compared with the use of ceritinib alone. Of course, this verification also fully proves the effectiveness and reliability of the pharmaceutical combination of the present invention. When further verifying the effect of the drug combination of the present invention through nude mouse experiments, only one type of tumor cell was studied.
实验例2：裸鼠移植瘤模型实验(仅以移植人乳腺癌MDA-MB-231细胞为例)Experimental Example 2: Nude mouse transplanted tumor model experiment (only transplanting human breast cancer MDA-MB-231 cells as an example)
在本实验过程中，是通过腹腔向裸鼠体内注射各种药物以进行比较的(即并不是通过静脉注射)。因此，其剂量通过了换算，换算依据是美国食品药品监督管理局(FDA)在《药物临床实验中健康成人受试对象安全给药剂量的估算》(Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers)中给出的，达到相同生物学效应所需的人体与小鼠(即实验验证中的裸鼠)的注射剂量换算比(1∶12.3)。During this experiment, various drugs were injected into nude mice through the abdominal cavity for comparison (that is, not through intravenous injection). Therefore, its dose passed the conversion based on the U.S. Food and Drug Administration (FDA)'s "Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adults" (Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers), the injection dose conversion ratio of humans and mice (i.e. nude mice in experimental verification) required to achieve the same biological effect (1:12.3).
1.裸鼠的选择1. Selection of nude mice
取6～8周龄无特异病原微生物(SPF)级裸鼠24只，体重范围为20±2g，在昼夜交替、室温(20℃～23℃)环境饲养，自由饮水、进食。Twenty-four specific pathogen-free (SPF) grade nude mice aged 6 to 8 weeks, with a weight range of 20±2g, were raised in a day-night alternating, room temperature (20°C to 23°C) environment, with free access to water and food.
2.实验分组及给药剂量(共4组)2. Experimental grouping and dosage (4 groups in total)
所有裸鼠随机分为四组，每组6只，每只右大腿外侧接种1×107个用人乳腺癌MDA-MB-231细胞所制悬液0.2mL(人乳腺癌MDA-MB-231细胞的培养与前述“细胞实验”相同)，待瘤体形成后开始按以下方式给药。All nude mice were randomly divided into four groups, with 6 mice in each group. Each mouse was inoculated with 1 × 107 suspensions of 0.2 mL of human breast cancer MDA-MB-231 cells on the outside of the right thigh (human breast cancer MDA-MB-231 cells). The culture is the same as the aforementioned "cell experiment"), and after the tumor is formed, administration is started in the following manner.
(1)对照组：与处理组体积相同的生理盐水腹腔注射，1次/日；(1) Control group: intraperitoneal injection of normal saline with the same volume as the treatment group, once a day;
(2)YM155组：按裸鼠体重5mg/kg的剂量，腹腔注射YM155，1次/日；(2) YM155 group: YM155 was injected intraperitoneally at a dose of 5 mg/kg body weight of nude mice, once a day;
(3)色瑞替尼组：按裸鼠体重10mg/kg的剂量，腹腔注射色瑞替尼，2次/5日(即间隔3日注射1次)；(3) Ceritinib group: Inject ceritinib intraperitoneally at a dose of 10 mg/kg body weight of nude mice, 2 times/5 days (i.e., once every 3 days);
(4)YM155和色瑞替尼的药物组合组：按裸鼠体重5mg/kg的剂量，腹腔注射YM155，1次/日；在第一次注射YM155的同日，按裸鼠体重10mg/kg的剂量，腹腔注射色瑞替尼，间隔3日注射1次(YM155和色瑞替尼的给药频次比为10:3)。(4) Drug combination group of YM155 and ceritinib: Inject YM155 intraperitoneally at a dose of 5 mg/kg body weight of nude mice, once a day; on the same day of the first injection of YM155, dose 10 mg/kg body weight of nude mice Dosage: intraperitoneal injection of ceritinib once every 3 days (the dosage frequency ratio of YM155 and ceritinib is 10:3).
上述各组中YM155和色瑞替尼的剂量中，均只是指药物本身的剂量。配制成注射针剂时应当达到的浓度，对本领域的技术人员而言，应当是十分清楚的，故不详述。The doses of YM155 and ceritinib in each of the above groups only refer to the doses of the drugs themselves. The concentration that should be achieved when formulating it into an injection should be very clear to those skilled in the art, so it will not be described in detail.
3.测量与记录3. Measurement and recording
(1)每7天后测量、记录一次各组裸鼠的体重；(1) Measure and record the body weight of nude mice in each group after every 7 days;
(2)每21天后用游标卡尺测量肿瘤的长度和宽度、记录一次各组裸鼠肿瘤体部分的体积；肿瘤体积按照以下公式计算：(2) After every 21 days, use a vernier caliper to measure the length and width of the tumor, and record the volume of the tumor body part of the nude mice in each group; the tumor volume is calculated according to the following formula:
肿瘤体积(mm3)＝肿瘤长度(mm)×肿瘤宽度的平方(mm2)Tumor volume (mm3) = Tumor length (mm) × Tumor width squared (mm2 )
实验结果参见图3-5，在图3中纵坐标表示各组裸鼠的肿瘤体积；横坐标表示分组；各点的数值为各组肿瘤体积的实际值(图中“Ⅰ”形符号指出了上下偏差)。在图4中纵坐标表示各组裸鼠的平均体重；横坐标表示测量时间点；各种线条节点表示各处理组；各点的数值为各组平均体重。在图5中纵坐标表示各组裸鼠的存活率；横坐标表示时间节点；各种线条节点表示各处理组。The experimental results are shown in Figure 3-5. In Figure 3, the ordinate represents the tumor volume of each group of nude mice; the abscissa represents the grouping; the value of each point is the actual value of the tumor volume of each group (the "I" shaped symbol in the figure points out upper and lower deviation). In Figure 4, the ordinate represents the average weight of nude mice in each group; the abscissa represents the measurement time point; various line nodes represent each treatment group; the value of each point is the average weight of each group. In Figure 5, the ordinate represents the survival rate of nude mice in each group; the abscissa represents time nodes; various line nodes represent each treatment group.
由图3可知，YM155协同色瑞替尼组与单独使用色瑞替尼、单独使用YM155组相比较，YM155协同色瑞替尼组的肿瘤体积在治疗21天后显著低于各单独使用药物组。图3中的“**”同样表示p＜0.01，同样可以认定使用YM155协同色瑞替尼组的肿瘤体积小于单独药物组和对照组出现错误的可能性小，这一验证结果也是准确而可靠。As can be seen from Figure 3, compared with the YM155 plus ceritinib group, the ceritinib alone, and the YM155 alone group, the tumor volume of the YM155 plus ceritinib group was significantly lower than that of the individual drug groups after 21 days of treatment. The “**” in Figure 3 also indicates p<0.01. It can also be determined that the tumor volume of the YM155 combined with ceritinib group is smaller than that of the drug alone group and the control group. The possibility of errors is small. This verification result is also accurate and reliable. .
由图4可见，YM155协同色瑞替尼组与单独使用色瑞替尼、单独使用YM155组、对照组相比较，YM155协同色瑞替尼组的小鼠体重与其他各单独使用药物组及对照组比较未见显著差异。n.s代表p＞0.05，即认定YM155协同色瑞替尼组的体重与单独药物组或对照组有差异而出现错误的可能性大于0.05，因p＝0.05是统计学中可接受最大出错概率，所以本处大于0.05的出错概率是不能认定YM155协同色瑞替尼组的体重与单独药物组或对照组有差异的，即未见显著差异。As can be seen from Figure 4, the YM155 synergistic ceritinib group is compared with the ceritinib alone, the YM155 alone group, and the control group. The weight of the mice in the YM155 synergistic ceritinib group is different from that of the other drug alone groups and the control group. No significant differences were found in group comparisons. n.s represents p>0.05, that is, it is determined that the weight of the YM155 combined with ceritinib group is different from that of the drug alone group or the control group and the possibility of error is greater than 0.05. Since p=0.05 is the maximum acceptable error probability in statistics, so If the error probability here is greater than 0.05, it cannot be determined that the weight of the YM155 combined with ceritinib group is different from that of the drug alone group or the control group, that is, no significant difference is found.
图5记载的验证结果证明了，YM155协同色瑞替尼化疗的药物组合，抑制和杀灭人乳腺癌MDA-MB-231细胞的确优于单独使用色瑞替尼，导致老鼠模型生存周期延长，自然可以减少用药量、缩短治疗周期，减少毒副反应发生。图5中的“**”同样表示p＜0.01，同样可以认定使用YM155协同色瑞替尼组的治疗效果优于单独药物组和对照组出现错误的可能性小，这一验证结果也是准确而可靠。The verification results recorded in Figure 5 prove that the combination of YM155 and ceritinib chemotherapy is indeed better at inhibiting and killing human breast cancer MDA-MB-231 cells than using ceritinib alone, resulting in a longer survival period of the mouse model. Naturally, it can reduce the dosage of medication, shorten the treatment cycle, and reduce the occurrence of toxic and side effects. “**” in Figure 5 also indicates p<0.01. It can also be concluded that the therapeutic effect of the YM155 combined with ceritinib group is better than that of the drug alone group and the control group. The possibility of errors is small. This verification result is also accurate and reliable.
由于在图4的记载未见明显毒副反应，其验证结果证明，YM155协同色瑞替尼化疗的药物组合，至少不会有单独使用色瑞替尼那样明显的毒副反应。Since there are no obvious toxic and side effects recorded in Figure 4, the verification results prove that the drug combination of YM155 and ceritinib chemotherapy will at least not have as obvious toxic and side effects as using ceritinib alone.
本领域的技术人员清楚，在通过了前述细胞实验的验证之后，现经过针对人乳腺癌MDA-MB-231细胞的裸鼠移植瘤模型实验，就完全能够说明，YM155协同色瑞替尼化疗的药物组合对人乳腺癌细胞治疗效果较好，特别是三阴性乳腺癌(有差别，也极其微小)。It is clear to those skilled in the art that after passing the verification of the aforementioned cell experiments and the nude mouse transplanted tumor model experiments on human breast cancer MDA-MB-231 cells, it can be fully demonstrated that YM155 synergizes with ceritinib chemotherapy. The drug combination has a better therapeutic effect on human breast cancer cells, especially triple-negative breast cancer (the difference is very small).
以上所述的仅是本发明的实施例，方案中公知的具体技术方案和/或特性等常识在此未作过多描述。应当指出，对于本领域的技术人员来说，在不脱离本发明技术方案的前提下，还可以作出若干变形和改进，这些也应该视为本发明的保护范围，这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准，说明书中的具体实施方式等记载可以用于解释权利要求的内容。The above are only embodiments of the present invention, and common knowledge such as specific technical solutions and/or characteristics that are known in the scheme are not described in detail here. It should be pointed out that for those skilled in the art, several modifications and improvements can be made without departing from the technical solution of the present invention. These should also be regarded as the protection scope of the present invention and will not affect the implementation of the present invention. The effect and practicality of the patent. The scope of protection claimed in this application shall be based on the content of the claims, and the specific implementation modes and other records in the description may be used to interpret the content of the claims.
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