WO2022134325A1 - 抗癌组合物、组合产品及其制备方法和应用 - Google Patents

抗癌组合物、组合产品及其制备方法和应用 Download PDF

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WO2022134325A1
WO2022134325A1 PCT/CN2021/080468 CN2021080468W WO2022134325A1 WO 2022134325 A1 WO2022134325 A1 WO 2022134325A1 CN 2021080468 W CN2021080468 W CN 2021080468W WO 2022134325 A1 WO2022134325 A1 WO 2022134325A1
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cancer
cisplatin
transplatinum
anticancer
drug
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French (fr)
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王鹏业
刘玉如
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中国科学院物理研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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

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  • the invention belongs to the field of medicine, and in particular relates to a combined anticancer composition of transplatinum and cisplatin, a combined product, and a preparation method and application thereof.
  • Cisplatin is one of the most widely used chemotherapy drugs in clinic. In addition to testicular cancer that can be cured by cisplatin in 80-90% of patients without recurrence (known as the gold standard for cancer treatment), cisplatin is used in the treatment of other types of cancer, and sooner or later drug resistance and cancer recurrence occur, Can not achieve the effect of curing.
  • the basis of cisplatin as a chemotherapeutic drug is that it can hinge DNA, hinder DNA replication and transcription, and induce cancer cell death.
  • cancer types with DNA repair defects such as ovarian cancer and breast cancer patients with Brca-1/2 mutation
  • the initial response to cisplatin is very good (initial response)
  • the reduction of cancer tissue is significantly smaller, but Even in these patients who initially respond well, recurrence of cancerous tissue regrowth occurs over the next few years.
  • the prior art found through drug resistance induction that cisplatin resistance is inevitably generated in sensitive cells, of which about 50% is due to the restoration of function-reversing mutation of the mutated disease-causing gene, and the other half is caused by other reasons. In the prior art and clinical practice, many of them are cisplatin combined with inhibitors of drug resistance-related factors in cell regulatory pathways to overcome cisplatin resistance.
  • Olaparib is a PARP inhibitor in a new generation of chemotherapeutic small molecule inhibitors and the first marketed target for homologous recombination repair (HRR) pathway defects in cells/tumors due to DNA damage response (DDR) drug.
  • HRR homologous recombination repair
  • DDR DNA damage response
  • Olaparib produces a synthetic lethal effect in Brca-1/2-mutated cancer cells after inhibiting PARP repair of DNA single-strand damage, and olaparib has been approved for Brca-1/2-mutated advanced ovarian cancer and Metastatic breast cancer and various cancers of the prostate and pancreas.
  • the progression-free survival after olaparib is more than twice that of standard chemotherapy, and the toxic and side effects are small.
  • olaparib can only delay the growth of cancer tissue and prolong the life of patients, but it has not significantly improved the survival rate of patients with related cancer indications (like cisplatin for testicular cancer).
  • the purpose of the present invention is to overcome the defects in the prior art, and provide a new anti-cancer method that kills all cancer cells within a course of treatment, prevents the generation of drug resistance and is non-toxic to normal cells of the body.
  • BER refers to: base excision repair.
  • MMR Mismatch Repair
  • NER refers to: Nucleotide Excision Repair.
  • HRR refers to: Homologous Recombination Repair.
  • NHEJ refers to: non-homologous end joining repair.
  • FA refers to: Interchain Hinge Repair.
  • a first aspect of the present invention provides an anticancer composition, the anticancer composition comprising cisplatin and transplatinum.
  • the second aspect of the present invention provides an anti-cancer reagent combination product, the anti-cancer reagent includes a cisplatin reagent and a transplatinum reagent that exist independently.
  • anticancer composition according to the first aspect, wherein the anticancer composition, the cisplatin or the cisplatin reagent is in the form of a physiological saline solution of cisplatin, preferably, cisplatin in the physiological saline solution and/or
  • the transplatinum or transplatinum reagent is in the form of a physiological saline solution of transplatinum, preferably, the concentration of transplatinum in the physiological saline solution is 0.01-0.3 mg/ml, more preferably 0.05-0.3 mg/ml , more preferably 0.1 to 0.3 mg/ml.
  • a third aspect of the present invention provides a preparation method of the anticancer composition of the first aspect, and the preparation method may comprise the following steps:
  • step (2) Filter the drug solution obtained in step (1) with a 0.22 ⁇ m sterile filter.
  • step (1) the temperature of the water bath is 55-60°C; and/or
  • the heating time of the transplatinum solution is 10-60 minutes, preferably 20-40 minutes, and more preferably 30 minutes.
  • the heating time of the cisplatin solution is 1-10 minutes, preferably 2-6 minutes, more preferably 2-3 minutes.
  • the method further comprises the following steps:
  • step (3) separately packaging and preserving the drug solutions containing cisplatin or transplatinum prepared in step (2) to prepare the anticancer composition according to any one of claims 1 to 3;
  • the storage condition is -20°C.
  • the fourth aspect of the present invention provides the use of the anticancer composition of the first aspect or the anticancer agent of the second aspect in the preparation of a drug and/or a medical product for treating cancer.
  • the applicable cancer is a cancer with DNA damage repair function deficiency
  • the cancer is a cancer with defects in the homologous recombination repair pathway and interstrand hinge repair.
  • the cancer is a cisplatin-sensitive cancer with a cancer cell IC50 cisplatin concentration below 1 uM.
  • the cancer type is selected from one or more of the following: ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, melanoma, fallopian tube cancer, primary peritoneal cancer, colorectal cancer Cancer, leukemia.
  • a fifth aspect of the present invention provides a method for treating cancer, the method comprising: administering the anticancer composition or anticancer preparation of the first aspect to a subject in need thereof.
  • the cancer is a cancer with defects in the homologous recombination repair pathway and interstrand hinge repair.
  • the cancer is a cisplatin-sensitive cancer whose cancer cell IC50 cisplatin concentration is below 1 uM.
  • the cancer is selected from one or more of the following: ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, melanoma, fallopian tube cancer, primary peritoneal cancer, colorectal cancer ,leukemia.
  • Cisplatin is the most widely used chemotherapy drug in clinic and can successfully cure testicular cancer; however, it cannot cure other types of cancer due to drug resistance.
  • the invention aims at the problem that the current traditional chemotherapeutic drugs and the new generation of targeted drug small molecule inhibitors are widely developed drug resistance, which makes the cancer recur and is more difficult to treat and the obvious defect in medical intervention, and strives to develop a drug that kills the tumor within the course of treatment.
  • a new method of chemotherapy for all cancer cells preventing the formation of drug resistance and non-toxic to normal cells of the body.
  • the purpose of the present invention is to solve the urgent problem of recurrence in the current stage of cancer treatment, to provide new methods and strategies for related cancer treatment, and to understand the intervenability of cancer genome instability and the role of DNA damage repair function in cancer treatment.
  • the mechanism of action in the process, etc. provide answers and ideas.
  • the probability of sensitive cells producing drug resistance is very low.
  • the probability of cisplatin producing drug resistance is 87%, and the probability of the present invention producing drug resistance is 22%.
  • two platinum drug molecules are connected to hinge DNA, so that a difficult-to-repair barrier is formed on the skeleton of cancer cells (for sensitive cancer cell types that are inherently defective in DNA damage repair function), preventing gene transcription and chromatin replication, thereby depriving cancer cells
  • a difficult-to-repair barrier is formed on the skeleton of cancer cells (for sensitive cancer cell types that are inherently defective in DNA damage repair function), preventing gene transcription and chromatin replication, thereby depriving cancer cells
  • the invention is suitable for removing potential small lesions and sporadic cancer seed cells with latent metastasis after removing large solid tumors after surgery. Coupled with years of experience in clinical chemotherapy and drug development of cisplatin, the conduct of clinical human experiments and the prevention and treatment of side effects are more convenient, which may benefit related patients more quickly.
  • the present invention is not aimed at intracellular function executors (dynamic protein pools, whose production and degradation have random fluctuations; drug molecules have metabolic concentration fluctuations, which give cells a certain opportunity to transfer from inhibited state to life function activities. , so that there is a chance to develop drug resistance), but for the genetic material chromatin DNA in the cell, the content in the cell is basically stable, and it is indispensable in the most basic activities of the cell - gene transcription and cell replication, so the source is locked. , locks the possibility of cell dynamic evolution.
  • the scope of utility of the present invention is clinically "cisplatin-sensitive" cancer types, plus genetic sequencing of molecular markers containing DNA homologous recombination repair deficiency (HRR-deficiency) and DNA interstrand hinge repair deficiency (FA-deficiency).
  • HRR-deficiency DNA homologous recombination repair deficiency
  • FA-deficiency DNA interstrand hinge repair deficiency
  • the new chemotherapy method of the present invention is mainly applicable to cancer types with defects in DNA damage repair function, specifically with homologous recombination repair pathway (homologous recombination repair, HRR) and interchain hinge repair defects (Fanconi anemia, FA), these mutations are more common in ovarian, breast, pancreatic and prostate cancers.
  • the scope of administration of the present invention is not limited to specific cancer types, but rather to specific gene mutation types. Since the factors that cause the resistance of platinum drugs in cells are considered to be a combination of factors, in addition to DNA repair ability, other factors play a role.
  • Phenotype - "cisplatin-sensitive" cancer cell IC50 cisplatin concentration below 1uM
  • Molecular markers mainly include:
  • FANCI,FANCG,FANCA,etc. key gene in FA system.
  • the application prospect of the present invention is based on the existing cell level, animal safety experiments and theoretical analysis, which will benefit applicable cancer patients, and the cancer recurrence probability after effective treatment is very low. Due to the important chemotherapeutic drugs cisplatin and olaparib in cancer research at home and abroad, a large number of intensive clinical applications, molecular screening and basic mechanism of action have been comprehensively studied in clinical and basic research. Non-toxic isomers have also been used as negative controls in drug development in the past few decades to do a lot of in vivo and in vitro experimental studies.
  • the anticancer composition of the present invention may have, but is not limited to, the following beneficial effects:
  • the present invention comprehensively and in detail studies the effectiveness and using method of the combined application of cisplatin and transplatinum on sensitive tumors, the reliability for overcoming the generation of drug resistance, and the safety for experimental animals.
  • the probability of sensitive cells developing drug resistance is very low.
  • the probability of cisplatin producing resistance is 87%
  • the probability of mitomycin producing resistance is 92%
  • the probability of producing olaparib is 95%
  • the probability of producing drug resistance in the present invention at 22%.
  • FIG 1 shows an overview of the scope of application of the present invention.
  • Figure 2 shows the relationship between the probability of the effect of "killing all cancer cells without producing drug resistance" of the present invention and the concentration of cisplatin, wherein Figure 2(a) is the result of breast cancer MDA-MB-436 cells; Figure 2(b) ) for pancreatic cancer Capan-1 cells.
  • Figure 3 shows the comparison effect of several drugs in killing all cancer seed cells in the cancer cell population under the same conditions, in which Figure 3(a) is three consecutive drug treatments, and the concentration of each drug is 4 ⁇ IC50; Figure 3(b) ) are four consecutive drug treatments, the first concentration is 2 ⁇ IC50, and the subsequent three concentrations are 4 ⁇ IC50.
  • Figure 4 shows the probability of drug resistance of sensitive cells in the present invention under conventional drug resistance induction conditions.
  • Fig. 5 shows the experimental result of the safety experiment of the drug concentration adopted in the present invention in human normal cells and rats; wherein Fig. 5(a) is the experimental result of the drug concentration adopted in the present invention in human normal cells; Fig. 5(b) ) is the experimental result of the safety experiment of the drug concentration used in the present invention in rats.
  • Cisplatin, transplatinum purchased from Sigma-Aldrich Company, MDA-MB-436 cells, Capan-1 cells, purchased from National Experimental Cell Resource Sharing Platform (Institute of Basic Medicine, Chinese Academy of Medical Sciences, Beijing) and ATCC (Beijing, United States) Zhongyuan Heju Economic and Trade Co., Ltd. purchasing).
  • This example is used to illustrate the treatment results of different cancer cells by the method of the present invention.
  • Drug dissolution cisplatin and transplatinum powder are directly dissolved in sterile normal saline, and the concentration of cisplatin can easily reach 0.3-0.6mg/ml; Shake continuously for 30 min in a water bath at °C. The dissolved drug solution is filtered with a 0.22 ⁇ m sterile filter and used fresh or stored at -20 °C for use within one week.
  • Cancer cells select MDA-MB-436 breast cancer cells and Capan for appropriate cancer types.
  • Pancreatic cancer cells the culture method is that the first 3 generations after cell recovery are carried out in full compliance with the commercial instructions for culture and passage, and the medium and other reagents used are directly purchased from the cell source company.
  • the fourth generation of cells gradually transitioned to RPMI- 1640 medium + 10% FBS (Corning, hereinafter referred to as 1640 medium) culture that is, the 4th and 5th generation medium is 1:1 commercial recommended medium: 1640 medium, 5th and 6th generation medium is 1 : 2 commercial recommended medium: 1640 medium, changed to 100% 1640 medium after the 7th passage.
  • the cells used were no longer used after 20 passages), the cancer cells were treated with drugs for a total of 3 to 4 times, and the time interval was about 3 weeks.
  • Cisplatin (2-3 ⁇ M, ⁇ 4 ⁇ IC50 cisplatin for sensitive cancer cells) first acts on the cancer cells, aspirates the ordinary medium, and directly adds the fresh medium containing the required concentration of cisplatin.
  • the bottle was placed in a 37°C, CO 2 incubator for 2 hours, after which it was washed three times with PBS; then a medium containing 10 ⁇ M transplatinum was added (that is, a corresponding trace volume of transplatinum saline solution was added to the fresh medium, for example: Add 100 ⁇ l of 0.3 mg/ml transplatinum physiological saline solution to 10 ml of medium, shake well) for 2 hours, add fresh medium after washing, culture for 3 weeks, and replace the medium every 3 days.
  • a medium containing 10 ⁇ M transplatinum was added (that is, a corresponding trace volume of transplatinum saline solution was added to the fresh medium, for example: Add 100 ⁇ l of 0.3 mg/ml transplatinum physiological saline solution to 10 ml of medium, shake well) for 2 hours, add fresh medium after washing, culture for 3 weeks, and replace the medium every 3 days.
  • the transplatinum concentration was 10 ⁇ M, which was lower than the highest non-toxic dose of transplatinum (the highest nontoxic dose of transplatinum varies with cell types, according to the inventors’ experiments
  • the highest non-toxic dose of transplatinum for different cancer cells is ⁇ 10-150 ⁇ M; the highest non-toxic dose of transplatinum for normal human primary cells is ⁇ 120-200 ⁇ M), and 10 ⁇ M is the maximum possible concentration in vivo during intravenous injection— -
  • 1mM is the concentration of the highest physiological saline solution of transplatinum.
  • intravenous injection ratio of 1:100 the highest concentration of transplatinum that can be reached in the body is 10 ⁇ M.
  • Figure 2 shows the relationship between the probability of the effect of "killing all cancer cells without producing drug resistance" of the present invention and the concentration of cisplatin, wherein Figure 2(a) is the result of MDA-MB-436 cells; Figure 2(b) is Results for Capan-1 cells.
  • olaparib olaparib group
  • mitomycin mitomycin
  • cisplatin C group
  • C+T group transplatinum
  • Figure 3 shows the comparison effect chart of killing all cancer seed cells in the cancer cell population under the same conditions of several drugs, and the specific probability values of the C+T group are marked on the figure.
  • Figure 3(a) shows three consecutive drug treatments, each with a concentration of 4 ⁇ IC50;
  • Figure 3(b) shows four consecutive drug treatments, the first concentration is 2 ⁇ IC50, and the subsequent three concentrations are 4 ⁇ IC50.
  • This example is used to illustrate the safety experiment of the method of the present invention.
  • the drug concentration of the method of the present invention is within the low dose range (2-3 ⁇ M) in clinical applications, and does not cause any observable effects on human primary normal cells and rats. toxicity.
  • Human primary normal cells were purchased from the National Experimental Cell Resource Sharing Platform (Institute of Basic Medicine, Chinese Academy of Medical Sciences, Beijing) and ATCC (purchased by Beijing Zhongyuan Heju Economic and Trade Co., Ltd. in the United States), and cultured according to the method of purchasing the product manual. , used within 6-8 passages.
  • the drug treatment method is the same as the "cancer drug treatment protocol" described above.
  • the drug concentration was selected in a series of doses that can cause cytotoxicity, and in a series of concentrations far higher than the clinical physiological concentration of cisplatin by 80 ⁇ M, it was not tested because it had no practical significance.
  • the transplatinum concentration was the highest non-toxic dose for each cell determined in this experimental system (range 100-150 ⁇ M).
  • Fig. 5 shows the experimental results of the safety experiment of the drug concentration used in the present invention in human normal cells and rats.
  • This example is used to illustrate the effectiveness test of the method of the present invention - overcoming the generation of drug resistance.

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Abstract

提供一种抗癌组合物，所述抗癌组合物包括顺铂和反铂，还提供了抗癌组合物的应用，并全面研究顺铂、反铂联合应用对动物机体内的安全性和杀灭敏感肿瘤细胞的有效性：在抗药性常规诱导条件下，敏感细胞产生抗药性的几率很低；在同等条件平行对比实验中，顺铂产生抗药性的几率为87％，丝裂霉素(mitomycin-C)和奥拉帕尼(olaparib)都高于90％大概率地诱导出了抗药性，所述抗癌组合物产生抗药性的几率为22％。

Description

抗癌组合物、组合产品及其制备方法和应用
相关申请的交叉引用
本申请要求2020年12月21日提交的第CN202011518936.5号中国发明专利申请的优先权，所述申请以引用的方式整体并入本文。
技术领域
本发明属于医药领域，具体涉及一种反铂和顺铂联合的抗癌组合物、组合产品及其制备方法和应用。
背景技术
癌症是目前造成我国和世界人类死亡的首要因素。基因组不稳定性和DNA损伤修复能力下降是癌症发生过程中的重要原因。顺铂(cisplatin)是临床上最广泛应用的化疗药物之一。除了睾丸癌可以被顺铂治愈80-90％的病人且不复发(被称为癌症治疗的金标准)，顺铂在治疗其他类型的癌症上，都或早或晚出现抗药性和癌症复发，不能达到治愈的效果。顺铂作为化疗药物的基础是由于其能铰链DNA，妨碍DNA的复制和转录，诱导癌细胞死亡。其中，具有DNA修复功能缺陷的癌症类型(如Brca-1/2突变的卵巢癌和乳房癌患者)，对顺铂的最初应答很好(initial response),出现癌组织的明显削减变小，但是即使这些最初疗效很好的患者，也会在接下来的几年时间内发生癌组织重新生长的复发问题。现有技术通过抗药性诱导发现，顺铂抗药性不可避免地在敏感细胞中生成，其中约50％是由于突变致病基因的恢复功能反转突变，另一半是其他原因引起。现有技术和临床实践中很多是顺铂联合细胞调控通路中抗药相关因子的抑制剂，来克服顺铂抗药性。短期效果可能使得耐药癌细胞重新获得敏感性，但是长期联合诱导还会不可避免地出现对新处理的抗药性，是现在医学干预体系的难题和未解决的问题。为了克服顺铂抗药性，现有技术尝试运用纳米颗粒等运转药物的小微囊提高肿瘤组织的药物含量，提高杀伤抗药癌细胞效率，但此类方法的安全性还有待于进一步深入广泛研究来证实(毕竟正常组织中也含有相当量的微囊)。如果能有比较显著的效果来区分癌组织和正常组织，现有技术并没有足够的能力来区分出转移到正常组织潜伏下来的零星癌症种子细胞，这些癌症转移细胞将和正常细胞一样免除光热损伤。
奥拉帕尼(olaparib)是新一代化疗药物小分子抑制剂中的PARP抑制剂，也是针对细胞/肿瘤中DNA损伤应答(DDR)导致同源重组修复(HRR)途径缺陷的首个上市靶向药物。奥拉帕尼抑制PARP的DNA单链损伤修复后，在Brca-1/2突变的癌细胞内产生合成致死效应，奥拉帕尼已被批准用于Brca-1/2突变的晚期卵巢癌和转移性乳腺癌以及前列腺癌和胰腺癌的多种癌症。奥拉帕尼适用后的无进展生存期是标准化疗的2倍多， 且毒副作用小。但是在奥拉帕尼化疗过程中，几乎所有的患者在大概几个月或更长时间之后(平均8.4个月左右)，出现耐药性，使得药物失效，封闭的靶蛋白具有显著机会反转突变成野生型蛋白。目前，奥拉帕尼只能延缓癌组织的生长，延长患者生命，但还不能显著改善相关癌症适应症患者的生存率(像顺铂之于睾丸癌)。
发明内容
因此，本发明的目的在于克服现有技术中的缺陷，提供一种在疗程内杀灭所有癌细胞、防止抗药性生成并对机体正常细胞无毒性的抗癌新方法。
在阐述本发明内容之前，定义本文中所使用的术语如下：
术语“BER”是指：碱基切除修复。
术语“MMR”是指：错配修复。
术语“NER”是指：核苷酸切除修复。
术语“HRR”是指：同源重组修复。
术语“NHEJ”是指：非同源末端连接修复。
术语“FA”是指：链间铰链修复。
为实现上述目的，本发明的第一方面提供了一种抗癌组合物，所述抗癌组合物包括顺铂和反铂。
本发明的第二方面提供了一种抗癌试剂组合产品，所述抗癌试剂包括各自独立存在的顺铂试剂和反铂试剂。
根据第一方面的抗癌组合物，其中，所述抗癌组合物，所述顺铂或顺铂试剂是以顺铂的生理盐水溶液的形式存在，优选地，所述生理盐水溶液中顺铂的浓度为0.1～2mg/ml，更优选为0.2～1.5mg/ml，进一步优选为0.3～0.6mg/ml；和/或
所述反铂或反铂试剂是以反铂的生理盐水溶液的形式存在，优选地，所述生理盐水溶液中反铂的浓度为0.01～0.3mg/ml，更优选为0.05～0.3mg/ml，进一步优选为0.1～0.3mg/ml。
本发明的第三方面提供了第一方面的抗癌组合物的制备方法，该制备方法可以包括以下步骤：
(1)将顺铂、反铂粉末分别溶于无菌生理盐水中，水浴加热且连续摇动；
(2)将步骤(1)所得药物溶液用0.22μm无菌滤膜过滤。
根据本发明第一方面的制备方法，其中，步骤(1)中，所述水浴温度为55～60℃；和/或
反铂溶液所述加热时间为10～60min，优选为20～40min，进一步优选为30min。顺铂溶液所述加热时间为1～10min，优选为2～6min，进一步优选为2-3min。
根据本发明第三方面的制备方法，其中，所述方法进一步包括以下步骤：
(3)将步骤(2)制得的包含顺铂或反铂的药物溶液分别独立包装保存以制得权利要求1至3中任一项所述的抗癌组合物；
优选地，所述保存条件-20℃。
本发明的第四方面提供了第一方面的抗癌组合物或第二方面的抗癌试剂在制备治疗癌症的药物和/或医疗产品中的应用。
根据本发明第四方面的应用，其中，所述适用癌症为DNA损伤修复功能缺陷的癌症；
优选地，所述癌症为具有同源重组修复途径和链间铰链修复缺陷的癌症。
根据本发明第四方面的应用，其中，所述癌症为癌细胞IC50 cisplatin浓度在1uM以下的顺铂敏感癌症。
根据本发明第四方面的应用，其中，所述癌症类型选自以下一种或多种：卵巢癌、乳腺癌、胰腺癌、前列腺癌、黑色素瘤、输卵管癌、原发性腹膜癌、结直肠癌、白血病。
本发明的第五方面提供了一种用于治疗癌症的方法，所述方法包括：对有需要的受试者给予第一方面所述的抗癌组合物或抗癌制剂。
根据本发明第五方面的方法，其中，所述癌症为DNA损伤修复功能缺陷的癌症；
优选地，所述癌症为具有同源重组修复途径和链间铰链修复缺陷的癌症。
根据本发明第五方面的方法，其中，所述癌症为癌细胞IC50 cisplatin浓度在1uM以下的顺铂敏感癌症。
根据本发明第五方面的方法，其中，所述癌症选自以下一种或多种：卵巢癌、乳腺癌、胰腺癌、前列腺癌、黑色素瘤、输卵管癌、原发性腹膜癌、结直肠癌、白血病。
顺铂是临床上使用最广泛的化疗药物，能成功治愈睾丸癌；但是由于抗药性产生，尚不能治愈其他类型癌症。本发明针对目前传统化疗药物和新一代靶向药物小分子抑制剂等广泛产生耐药性，使得癌症复发并更难以治疗的难题和医学干预中这一明显缺陷，力图研发出在疗程内杀灭所有癌细胞、防止抗药性生成并对机体正常细胞无毒性的化疗新方法。我们前期致力于通过DNA与铂类药物的单分子动态作用规律研究，发现微观作用机理，即顺铂和反铂共同作用有效形成DNA复杂铰链，明显增强顺铂的抗癌效果，超越癌细胞修复能力，并且对机体正常细胞没有明显毒性作用。在此微观分子基础上，本发明力图通过综合运用单分子、细胞生化、生物医学和理论分析等研究方法，全面详细研究顺铂反铂联合应用对动物机体内的安全性和杀灭敏感肿瘤的有效性和使用方法。本发明目的集中在解决现阶段癌症治疗中的急需解决的复发难题，为相关癌症治疗提供可能治愈的新方法和策略，对理解癌症基因组不稳定性的可干预性和DNA损伤修复功能在癌症治疗过程中的作用机制等，提供答案和思路。
本发明在抗药性常规诱导条件下，敏感细胞产生抗药性的几率很低。在同等条件平 行对比实验中，顺铂产生抗药性的几率为87％，本发明产生抗药性的几率在22％。
本发明是两种铂类药物分子接连铰链DNA，使得癌细胞骨架上形成难以修复的障碍(对于天生具有DNA损伤修复功能缺陷的敏感癌细胞类型)，防止基因转录和染色质复制，从而剥夺癌细胞适应进化的机会，免除长期抗药突变发生。
本发明适用于手术后摘除了大实体肿瘤之后，潜在微小病灶和转移潜伏的零星癌种子细胞的去除。加上顺铂临床化疗和药物研发多年的经验，临床人体实验的进行、副作用防治都比较便利，可能更为迅速使相关患者受益。
本发明不是针对细胞内功能执行者(动态蛋白池，其产生和降解存在随机波动；药物分子存在新陈代谢的浓度波动，这样就给细胞以一定可趁之机从抑制状态下转入进行生命功能活动，从而有机会产生抗药性)，而是针对细胞内遗传物质染色质DNA，在细胞内的含量基本稳定，在细胞最基本活动——基因转录和细胞复制中不可或缺，所以锁住了源头，就锁住了细胞动态进化可能性。
本发明的实用范围是临床上“顺铂敏感”癌症类型，加上基因测序含有DNA同源重组修复缺陷(HRR-deficiency)和DNA链间铰链修复缺陷(FA-deficiency)的分子标记物。这些癌症类型目前较常见于(但不限于)卵巢癌、乳腺癌、胰腺癌和前列腺癌等。
如图1所示，本发明化疗新方法主要适用于具有DNA损伤修复功能缺陷的癌症类型，具体是同时具有同源重组修复途径(homologous recombination repair,HRR)和链间铰链修复缺陷(Fanconi anemia，FA)，这些突变较常见于卵巢癌、乳腺癌、胰腺癌和前列腺癌等。本发明施用范围不限于具体癌症类型，而是限于具体的基因突变类型。由于铂类药物在细胞内引起抗药性的因素被认为是多种因素共同影响，除了DNA修复能力还有其他因子起作用，本发明适用范围除了基因型上HRR和FA缺陷外，还带有临床表型——“顺铂敏感”(癌细胞IC50 cisplatin浓度在1uM以下)这一参数指标。
分子标记物主要包括：
BRCA1and/or BRCA2,etc.(key gene in HRR system)；
FANCI,FANCG,FANCA,etc.(key gene in FA system)。
本发明的应用前景从目前已有的细胞层面、动物安全实验和理论分析来看，将会使适用型癌症患者从中受益，有效治疗后癌症复发几率很低。由于国内外癌症研究中关于重要化疗药物顺铂和奥拉帕尼，临床和基础研究已经做了大量密集的临床应用、分子筛选和基础作用机理等方面的全面研究；而反铂作为顺铂的无毒同分异构体，也在前几十年药物研发中作为阴性对照做了大量体内和体外的实验研究。在这些比较明朗的研究背景之下，本发明的体内有效性实验和临床试验就有了比较明确的实施方法，临床试验容易展开，“有的放矢”的精准医疗方案相对容易得到确定结果，为达到顺铂治愈睾丸癌之外的其他癌症患者，提供了较大几率的成功可能性。
本发明抗癌组合物可以具有但不限于以下有益效果：
本发明全面详细研究顺铂反铂联合应用对敏感肿瘤的有效性和使用方法，对克服药 物抗药性生成的可靠性，和对实验动物的安全性。在抗药性常规诱导条件下，敏感细胞产生抗药性的几率很低。在同等条件平行对比实验中，顺铂产生抗药性的几率为87％，丝裂霉素产生抗药性几率为92％，奥拉帕尼产生抗药性几率为95％，本发明产生抗药性的几率在22％。
附图的简要说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1示出了本发明适用范围框架一览图。
图2示出了本发明“杀灭所有癌细胞不产生抗药性”作用结果几率与顺铂浓度关系图，其中图2(a)为乳腺癌MDA-MB-436细胞的结果；图2(b)为胰腺癌Capan-1细胞的结果。
图3示出了几种药物同等条件下杀灭癌细胞群体中所有癌症种子细胞对比效果图，其中图3(a)为连续三次药物处理，各药物浓度均为4×IC50；图3(b)为连续四次药物处理，首次浓度为2×IC50，随后三次浓度均为4×IC50。
图4示出了本发明在抗药性常规诱导条件下敏感细胞产生抗药性的几率。
图5示出了本发明所采用药物浓度在人体正常细胞和大鼠体内安全实验的实验结果；其中图5(a)为本发明所采用药物浓度在人体正常细胞的实验结果；图5(b)为本发明所采用药物浓度在大鼠体内安全实验的实验结果。
实施发明的最佳方式
下面通过具体的实施例进一步说明本发明，但是，应当理解为，这些实施例仅仅是用于更详细具体地说明之用，而不应理解为用于以任何形式限制本发明。
本部分对本发明试验中所使用到的材料以及试验方法进行一般性的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚，在上下文中，如果未特别说明，本发明所用材料和操作方法是本领域公知的。
以下实施例中使用的试剂和仪器如下：
试剂：
顺铂，反铂，购自Sigma-Aldrich公司，MDA-MB-436细胞，Capan-1细胞，购自国家实验细胞资源共享平台(中国医学科学院基础医学研究所，北京)和ATCC(美国，北京中原合聚经贸有限公司代购)。
实施例1
本实施例用于说明本发明方法对不同癌细胞的处理结果。
(1)药物溶解：顺铂、反铂粉末直接溶于无菌生理盐水中，顺铂浓度可以容易到0.3～0.6mg/ml；反铂最高溶解度为0.3mg/ml,在加热到55～60℃的水浴中连续摇动30min.溶解后的药物溶液用0.22μm无菌滤膜过滤后新鲜使用或者保存于-20℃一周之内使用。
(2)癌细胞药物处理方案：
模拟临床化疗程序中多次给药方案(即用药3-4次，根据癌细胞生长情况每次用药 间隔为3到4周。癌细胞选取适用癌症类型的MDA-MB-436乳腺癌细胞和Capan-1胰腺癌细胞，培养方法是细胞复苏后前3代完全遵照商品化说明书的培养和传代方法进行，所用培养基等试剂均直接从细胞来源公司购买。随后第四代细胞逐渐过渡为RPMI-1640培养基+10％FBS(康宁公司，以下简称1640培养基)培养，即第4和5代培养基为1：1的商品推荐培养基：1640培养基，第5和6代培养基为1：2的商品推荐培养基：1640培养基，第7代后改为100％1640培养基。所用细胞在传代20次后，不再使用)，癌细胞总共药物处理3～4次，时间间隔为3周左右。
每次药物处理时间为2小时，即药物和癌细胞有效充分接触时间为2小时。顺铂(2～3μM，为敏感类型癌细胞的～4×IC50 cisplatin)先与癌细胞作用，吸去普通培养基，直接加入含有所需浓度顺铂的新鲜培养基，把细胞培养板/培养瓶放入37℃,CO 2培养箱中孵育2小时，其后用PBS洗涤三次；然后加入含有10μM反铂培养基(即向新鲜培养基中加入相应微量体积的反铂生理盐水溶液，例如：10ml培养基中加入100μl的0.3mg/ml反铂生理盐水溶液，摇匀)，作用2小时，洗涤后加入新鲜培养基，培养3周，每3天更换一次培养基。
本实施例中所有针对适用型癌细胞的实验过程中反铂浓度均为10μM，此浓度低于反铂最高无毒剂量(反铂最高无毒剂量因细胞种类而异，据本发明人的实验体系摸索，不同癌细胞的反铂最高无毒剂量范围为～10-150μM；正常人体原代细胞的反铂最高无毒剂量为～120-200μM)，10μM为静脉注射时最大可能体内达到浓度——具体来算，1mM为反铂最高生理盐水溶液的浓度，按照1：100的实际操作静脉注射比例，反铂体内可能达到的最高浓度为10μM。
图2示出了本发明“杀灭所有癌细胞不产生抗药性”作用结果几率与顺铂浓度关系图，其中图2(a)为MDA-MB-436细胞的结果；图2(b)为Capan-1细胞的结果。
本发明人还采用同等条件进行了平行对比实验(图3)，其中，分别采用奥拉帕尼(olaparib组)、丝裂霉素(mito-C组)、顺铂(C组)以及顺铂和反铂的协同作用(C+T组)。
图3示出了几种药物同等条件下杀灭癌细胞群体中所有癌症种子细胞对比效果图，C+T组的具体几率数值标注在图上。图3(a)为连续三次药物处理，各药物浓度均为4×IC50；图3(b)为连续四次药物处理，首次浓度为2×IC50，随后三次浓度均为4×IC50。
相比之下，顺铂(cisplatin)、丝裂霉素(mitomycin-C)和奥拉帕尼(olaparib)处理都大概率地存活癌症种子细胞。
实施例2
本实施例用于说明本发明方法的安全性实验。
经过人体正常原代细胞和大鼠药物安全性实验，本发明方法药物浓度在临床应用中低剂量范围之内(2-3μM)，对人体原代正常细胞和大鼠未造成任何可观测到的毒性。
具体步骤：人体原代正常细胞购自国家实验细胞资源共享平台(中国医学科学院基础医学研究所，北京)和ATCC(美国，北京中原合聚经贸有限公司代购)，按照购买商品说明书的方法进行培养，在传代6-8代之内使用。药物处理方法与前所述“癌细胞药物处 理方案”相同。药物浓度选择在可出现细胞毒性的系列剂量，在远高于临床生理浓度顺铂80μM之上的系列浓度，因没有实际意义而未进行检测。反铂浓度为本实验体系所测定各细胞的最高无毒剂量(范围在100-150μM)。
大鼠药物安全性实验在中国检验检疫科学院化学品安全研究所(北京)进行。所有实验程序均为中国检验检疫科学院院属“实验动物保护和使用委员会”审查和批准，以对实验动物的痛苦和伤害降到最低。
7周龄雄性Sprague Dawley大鼠(维通利华，北京)随机分为3组(顺铂组，顺铂+反铂组，对照生理盐水组)，每组10只。每周尾静脉注射药物：顺铂组，每只大鼠按体重注射0.9mg/kg顺铂生理盐水溶液；顺铂+反铂组，顺铂首先注射，方法和剂量同顺铂组，注射顺铂2小时后，尾静脉注射按体重3mg/kg反铂生理盐水溶液；对照组注射方法同顺铂+反铂组，用同样体积的生理盐水代替药物溶液。注射后6个小时内连续观察动物行为，在6小时之后每天再观察两次。每周注射一次，总共三次。随后，第四周观察一周后，动物CO 2麻醉气体麻醉，由专业资质人员常规剖检和取肾组织作H.E.染色组织学观察。在实验过程中，每隔一天测体重和每日详尽观察外观、动作、精神状态等生理指标，来比较用药动物和对照动物的细微差别。本安全性实验目的是检测本发明相比于顺铂的平行实验中，有没有发生高于顺铂单独使用的毒性症状。
图5示出了本发明所采用药物浓度在人体正常细胞和大鼠体内安全实验的实验结果。
实施例3
本实施例用于说明本发明方法的有效性实验——克服抗药性生成。
适用敏感型癌细胞如前所述，～10,000个癌细胞(同一批次解冻，低传代细胞p3-p5)接种到25cm 2细胞培养瓶内，在37℃,CO2培养箱中孵育贴壁2小时，向瓶内加入相应药物溶液，使终浓度～2×IC50，再放入培养箱中药物作用2小时(顺铂，丝裂霉素和本发明，方法同前所述)或7天(奥拉帕尼，方法同前所述)，随后，PBS清洗，再加入新鲜培养基。根据细胞生长速度培养3-5周后，传代细胞，再接种～10,000癌细胞/25cm 2细胞培养瓶，用逐渐升高的药物浓度处理细胞后，观察幸存癌细胞克隆，整个实验过程一般为8-10个月到更长，每三天更换一次新鲜培养基。
结果如图4所示，本发明在抗药性常规诱导条件下，敏感细胞产生抗药性的几率很低。在同等条件平行对比实验中，顺铂产生抗药性的几率为87％，本发明产生抗药性的几率在22％。相比之下，丝裂霉素(mitomycin-C)和奥拉帕尼(olaparib)处理都高于90％大概率地诱导出了抗药性细胞株。
尽管本发明已进行了一定程度的描述，明显地，在不脱离本发明的精神和范围的条件下，可进行各个条件的适当变化。可以理解，本发明不限于所述实施方案，而归于权利要求的范围，其包括所述每个因素的等同替换。

Claims (14)

  1. 一种抗癌组合物，其特征在于，所述抗癌组合物包括顺铂和反铂。
  2. 一种抗癌试剂组合产品，其特征在于，所述抗癌试剂包括各自独立存在的顺铂试剂和反铂试剂。
  3. 根据权利要求1所述的抗癌组合物或权利要求2所述的抗癌试剂，其特征在于，所述抗癌组合物或抗癌试剂中，所述顺铂或顺铂试剂是以顺铂的生理盐水溶液的形式存在，优选地，所述生理盐水溶液中顺铂的浓度为0.1～2mg/ml，更优选为0.2～1.5mg/ml，进一步优选为0.3～0.6mg/ml；和/或
    所述反铂或反铂试剂是以反铂的生理盐水溶液的形式存在，优选地，所述生理盐水溶液中反铂的浓度为0.01～0.3mg/ml，更优选为0.05～0.3mg/ml，进一步优选为0.1～0.3mg/ml。
  4. 根据权利要求1至3中任一项所述的抗癌组合物或抗癌试剂的制备方法，其特征在于，所述方法包括以下步骤：
    (1)将顺铂、反铂粉末分别溶于无菌生理盐水中，水浴加热且连续摇动；
    (2)将步骤(1)所得药物溶液用0.22μm无菌滤膜过滤。
  5. 根据权利要求4所述的方法，其特征在于，步骤(1)中，所述水浴为55～60℃；
    顺铂溶液的所述加热时间为1～10min，优选为2～6min，进一步优选为2-3min；和/或
    反铂溶液所述加热时间为10～60min，优选为20～40min，进一步优选为30min。
  6. 根据权利要求4或5所述的方法，其特征在于，所述方法进一步包括以下步骤：
    (3)将步骤(2)制得的包含顺铂或反铂的药物溶液分别独立包装保存以制得权利要求1至3中任一项所述的抗癌组合物或抗癌试剂；优选地，所述保存条件为-20℃。
  7. 权利要求1至3中任一项所述的抗癌组合物或抗癌试剂在制备治疗癌症的药物和/或医疗产品中的应用。
  8. 根据权利要求7所述的应用，其特征在于，所述癌症为DNA损伤修复功能缺陷的癌症；
    优选地，所述癌症为具有同源重组修复途径和链间铰链修复缺陷的癌症。
  9. 根据权利要求7所述的应用，其特征在于，所述癌症为癌细胞IC50 cisplatin浓度在1uM以下的顺铂敏感癌症。
  10. 根据权利要求8或9所述的应用，其特征在于，所述癌症选自以下一种或多种： 卵巢癌、乳腺癌、胰腺癌、前列腺癌、黑色素瘤、输卵管癌、原发性腹膜癌、结直肠癌、白血病。
  11. 一种用于治疗癌症的方法，其特征在于，所述方法包括：对有需要的受试者给予权利要求1至3中任一项所述的抗癌组合物或抗癌制剂。
  12. 根据权利要求11所述的方法，其特征在于，所述癌症为DNA损伤修复功能缺陷的癌症；
    优选地，所述癌症为具有同源重组修复途径和链间铰链修复缺陷的癌症。
  13. 根据权利要求11所述的方法，其特征在于，所述癌症为癌细胞IC50 cisplatin浓度在1uM以下的顺铂敏感癌症。
  14. 根据权利要求12或13所述的方法，其特征在于，所述癌症选自以下一种或多种：卵巢癌、乳腺癌、胰腺癌、前列腺癌、黑色素瘤、输卵管癌、原发性腹膜癌、结直肠癌、白血病。
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