WO2019000163A1 - 精氨酸在制备抗肿瘤药物中的用途 - Google Patents

精氨酸在制备抗肿瘤药物中的用途 Download PDF

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WO2019000163A1
WO2019000163A1 PCT/CN2017/089988 CN2017089988W WO2019000163A1 WO 2019000163 A1 WO2019000163 A1 WO 2019000163A1 CN 2017089988 W CN2017089988 W CN 2017089988W WO 2019000163 A1 WO2019000163 A1 WO 2019000163A1
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arginine
preparation
fetoprotein
alpha
tumor
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余祖江
庄正平
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余祖江
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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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention relates to the field of new use of drugs, in particular to the use of arginine in the preparation of antitumor drugs, in particular to anti-hepatocarcinoma drugs.
  • Arginine hydrochloride is a basic amino acid that exerts biological functions in the form of physiologically active L-arginine in vivo. For a long time, people mainly used it to reduce blood ammonia concentration, which belongs to hepatoprotective drugs. Arginine promotes the formation of urea by participating in the ornithine cycle in the human body. It is the ammonia produced in the human body. It is converted into non-toxic urea by the ornithine cycle and discharged from the urine, thereby reducing the blood ammonia concentration. It is not only an essential amino acid for animal protein synthesis, but also a synthetic precursor for various biologically active substances, such as polyamines and NO.
  • Arginine is the only substrate for the synthesis of NO, and the arginine-NO pathway plays an important role in animals.
  • Acid produces ornithine and urea; third is polyamine produced by ornithine.
  • Polyamine is a general term for putrescine, spermidine and spermine, which plays an important role in regulating cell growth and development.
  • Anti-tumor drugs refer to drugs against malignant tumors, also known as anticancer drugs.
  • Traditional anti-tumor drugs mainly refer to drugs that directly kill tumor cells.
  • liver cancer refers to carcinogenesis in hepatocytes and intrahepatic bile duct epithelial cells, and is one of the most common malignant tumors in humans.
  • HCC hepatocellular carcinoma
  • cholangiocarcinoma hepatocellular cholangiocarcinoma mixed cancer.
  • Liver cancer has the characteristics of insidious onset, long incubation period, high malignancy, rapid progress, strong invasiveness, easy transfer, and poor prognosis.
  • Hepatocellular carcinoma is a high-mortality primary liver cancer.
  • AFP alpha fetoprotein
  • liver cancer is not sensitive to existing radiotherapy and chemotherapy drugs, and there is still no effective control means. Therefore, the treatment of liver cancer is one of the focuses of modern clinical medical research.
  • the present invention discloses The use of the acid in the preparation of an antitumor drug for treating liver cancer.
  • arginine for the preparation of a medicament for reducing the concentration of ammonia in liver cancer cells.
  • alpha-fetoprotein is alpha-fetoprotein, alpha-fetoprotein heterogeneity or PIVKA.
  • the present invention provides the use of arginine hydrochloride for the preparation of an anti-liver cancer drug.
  • the arginine as an anti-tumor drug can reduce the ammonia concentration of the liver cancer cells, and cut off the warburg effect of high ammonia metabolism in the cells on the tumor cells, thereby making the tumor cells lack the continuous supply and maintenance of energy, so that Apoptosis and necrosis occur soon or tumor cells are re-differentiated, inhibiting the growth, development and metastasis of tumor cells, and is a new method for the treatment of tumors and liver cancer.
  • the arginine mainly achieves an antitumor effect from the following two aspects.
  • arginine is metabolized by nitric oxide synthase (NOS) to produce NO, and citrulline is produced.
  • NOS nitric oxide synthase
  • the second is under the action of arginolytic enzyme.
  • Arginine produces ornithine and urea; the third is polyamine produced by ornithine, which is a general term for putrescine, spermidine and spermine, and plays an important role in regulating cell growth and development.
  • the antitumor drug is preferably an anti-liver cancer drug.
  • the use of a complex of arginine and aminoguanidine in the preparation of an antitumor drug is preferably an anti-liver cancer drug.
  • Aminoguanidine is a selective nitric oxide synthase inhibitor. After adding a certain concentration of aminoguanidine in the experiment, the metabolic pathway of arginine-NO is blocked, then the main arginine in the cell at this time.
  • the metabolic pathway is involved in the process of ammonia reduction, that is, the reduction of ammonia and the metabolic disorder in the tumor cells will inevitably lead to an increase in apoptosis of tumor cells.
  • arginine has a significant anti-tumor effect in the indications, and the effect of reducing alpha-fetoprotein (including alpha-fetoprotein, alpha-fetoprotein heterogeneity, PIVKA) is significant, and it also delays tumors. Growth, the role of tumor shrinkage, or even disappear. In the treatment of liver cancer, it can significantly prolong the survival time of patients, improve the quality of life of patients, and has the advantages of convenient use, safety, and low treatment cost.
  • alpha-fetoprotein including alpha-fetoprotein, alpha-fetoprotein heterogeneity, PIVKA
  • Figure 1 is a metamap of metabolomics after normal ammonia cells treated with high ammonia
  • Figure 2 is a diagram of the glycolytic pathway
  • Figure 3 is a diagram of the cycle of the tricarboxylic acid cycle
  • Figure 4 is a diagram showing different liver cancer cell lines treated with different concentrations of ammonia
  • Figure 5 is a graph showing the apoptotic rate of the 7721 cell blank control
  • Figure 6 is a graph showing the apoptosis rate of 7721 cells after adding arginine
  • Figure 7 is a graph showing the apoptotic rate of 7721 cells after addition of arginine and aminoguanidine.
  • Arginine a new use of anti-tumor drugs in the treatment of liver cancer
  • the arginine as an anti-tumor drug can reduce the ammonia concentration of the liver cancer cells, and cut off the warburg effect of high ammonia metabolism in the cells on the tumor cells, thereby making the tumor cells lack the continuous supply and maintenance of energy, so that Apoptosis and necrosis occur soon or tumor cells are re-differentiated, It inhibits the growth, development and metastasis of tumor cells very well and is a new method for the treatment of tumors and liver cancer.
  • the drugs used to lower blood ammonia are mainly arginine and aspartate ornithine.
  • Arginine is a component of the ornithine cycle that helps to divert ammonia from the blood into urea.
  • arginine is commonly used in clinical practice to remove hyperammonemia and improve liver dysfunction.
  • Ornithine and aspartate produced by the hydrolysis of aspartate ornithine, acting on two major ammonia detoxification pathways - urea cycle and glutamine synthesis, ornithine almost involves the activation of urea cycle and ammonia The whole process of detoxification; however, due to the indirect promotion of aspartic acid on the metabolism of tricarboxylic acid in liver cancer cells, it may promote the energy synthesis in liver cancer cells and promote the proliferation and DNA synthesis of liver cancer cells. Therefore, we chose arginine as an anti-tumor drug.
  • the arginine mainly achieves anti-tumor effect from the following two aspects.
  • arginine is metabolized by nitric oxide synthase (NOS) to produce NO, and citrulline is produced.
  • NOS nitric oxide synthase
  • Arginine produces ornithine and urea; the third is polyamine produced by ornithine, which is a general term for putrescine, spermidine and spermine, and plays an important role in regulating cell growth and development.
  • Aminoguanidine is a selective nitric oxide synthase inhibitor. After adding a certain concentration of aminoguanidine in the experiment, the metabolic pathway of arginine-NO is blocked, then the main arginine in the cell at this time.
  • the metabolic pathway is involved in the process of ammonia reduction, that is, the reduction of ammonia and the metabolic disorder in the tumor cells will inevitably lead to an increase in apoptosis of tumor cells.
  • Case 1 Li XX Female 65 years old, found HBsAg positive for 10 years, began oral lamivudine antiviral treatment 6 years ago, during regular review, stable condition, 20 days ago due to lack of fatigue, poor appetite, local hospital review prompted virus Rebound, liver enzymes increased, and he was admitted to our hospital on November 17, 2015.
  • HCV-RNA 5.08 ⁇ 10 5 Iu / ml, AFP 228.84 ng / ml
  • blood routine showed a decrease in three lines of cells, ALT27U / L, AST87U/L, A/G (white ball ratio) 1.43 (reduced)
  • November 24 check the abdominal magnetic resonance scan, no clear liver Space-occupying lesions, while giving liver and oral antiviral drugs
  • a week after intravenous administration of 15 g of arginine the alpha-fetoprotein was reduced to 122.75 ng/ml
  • the above treatment regimen was continued for 10 days. It was reduced to normal, and the general condition was significantly improved compared with the previous one.
  • Case 3 Xu XX male 57 years old, hepatitis B patients with three yang, oral adefovir dipivoxil capsule antiviral treatment for 3 years, the virus turned negative, liver function is normal. Two years ago, the upper abdominal magnetic resonance of our hospital showed the right posterior lobe of the liver (about 18mm in diameter), cirrhosis, splenomegaly, portal hypertension, ascites, and then underwent CT-guided HCC radiofrequency ablation. ,No abnormalities.
  • CT can accurately locate lesions and display the subtle structural changes of the lesions
  • PET/CT fusion images can comprehensively detect lesions, accurately locate and judge the benign and malignant lesions, so early, rapid, accurate and comprehensive detection of lesions.
  • PET imaging agents 18F-labeled FDG 18F-FDG fluorinated deoxyglucose
  • One of the important characteristics of tumor tissue is rapid growth, high metabolism, especially increased glucose glycolysis. Therefore, metabolic imaging It is one of the most sensitive methods for early diagnosis of malignant tumors.
  • PET-CT is performed by injecting 18F-FDG tracer into the human body, and the SUV value is used as a criterion for malignant lesions.
  • SUV is the standard intake value, the Standardized Uptake Value Abbreviation, is a semi-quantitative method for the static aggregation of 18F-FDG widely used in tissues. It is often used in clinical practice as SUV2.5. It is the criterion for the determination of malignant lesions.
  • HCC radiofrequency ablation, after cholecystectomy changes compared with the 2016.01.05 (709399) old film, suspicious new appearance in the liver parenchyma Abnormal signal 2, cirrhosis, splenomegaly, a small amount of ascites 3, gallbladder is not clearly shown, consistent with postoperative changes.
  • Alpha-fetoprotein 4.2ng/mL considering the recurrence of HCC, patients refused the relevant surgical and interventional treatment, arginine treatment began on 2016-06-10.
  • arginine has a significant anti-tumor effect in the indications, and the effect of reducing alpha-fetoprotein (including alpha-fetoprotein, alpha-fetoprotein heterogeneity, PIVKA) is significant, and it also delays tumors. Growth, the role of tumor shrinkage, or even disappear. In the treatment of liver cancer, the survival time of patients can be significantly prolonged, and the survival treatment of patients can be improved.
  • the arginine of the present invention can effectively inhibit the growth, development and metastasis of tumor cells as an antitumor drug, and is a new method for treating tumors and liver cancer.

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Abstract

精氨酸在制备抗肿瘤药物中的用途，尤其是抗肝癌药物中的用途。临床研究和试验结果显示，精氨酸具有抗肿瘤作用，降低甲胎蛋白（包括甲胎蛋白、甲胎蛋白异质体、PIVKA）疗效显著，同时具有延缓肿瘤生长，使肿瘤缩小、甚至消失的作用，可延长患者生存时间，提高患者生存质量，且使用方便、安全，治疗费用低。

Description

精氨酸在制备抗肿瘤药物中的用途 技术领域
本发明涉及药物新用途领域，具体为精氨酸在制备抗肿瘤药物中的用途，尤其是抗肝癌药物的用途。
背景技术
盐酸精氨酸，是一种碱性氨基酸，在生物体内以具有生理活性的L-精氨酸形式发挥生物学功能。长期以来，人们主要将其用于降低血氨浓度，属于保肝类药物。精氨酸通过在人体内参与鸟氨酸循环，促进尿素形成，是人体内产生的氨，经鸟氨酸循环转变成无毒的尿素，从尿中排出，从而降低血氨浓度。它不仅是动物体蛋白合成的必需氨基酸，同时也是多种生物活性物质的合成前体，如多胺和NO等。精氨酸是合成NO的唯一底物，精氨酸--NO途径在动物体内发挥着重要的作用。精氨酸代谢在体内有3条途径，一是精氨酸在一氧化氮合酶(NOS)催化下代谢产生NO，并生成瓜氨酸；二是在精氨酸分解酶作用下，精氨酸生成鸟氨酸和尿素；三是由鸟氨酸生成多胺，多胺是腐胺、亚精胺和精胺的统称，对于调控细胞生长和发育具有重要作用。
抗肿瘤药物，是指抗恶性肿瘤的药物，又称抗癌药。传统抗肿瘤药物，主要指直接杀灭肿瘤细胞而起作用的药物，根据目前临床上使用的抗肿瘤药物的作用机理，可以大致将其分为四类：直接作用于DNA破坏其结构和功能的药物；干扰DNA合成的药物；抗有丝分裂的药物；基于肿瘤生物学机制的药物。
传统抗肿瘤药物都是通过影响DNA合成和细胞有丝分裂而发挥作用的，这些肿瘤药物的作用比较强，但缺乏选择性，毒副作用极大。因而，癌症的药物治疗仍然是世界性难题。随着医学的发展，有关肿瘤发生和发展的生物学机 制逐渐被人们所认识，新型抗肿瘤药物应运而生。目前，靶向抗肿瘤药物、抗肿瘤转移药物、基因治疗等等多种新型抗肿瘤药物的研发，都为癌症患者带来了新的希望。
众所周知，原发性肝癌是指发生于肝细胞与肝内胆管上皮细胞的癌变，是人类最常见的恶性肿瘤之一，我国肝癌中，肝细胞癌(hepatocellular carcinoma，HCC)约占80％－90％，其次为胆管细胞癌和肝细胞胆管细胞混合癌。临床可见肝区疼痛，上腹部肿块，进行性消瘦等。肝癌具有起病隐匿、潜伏期长、高度恶性、进展快、侵袭性强、易转移、预后差等特点。肝细胞肝癌是一种高死亡率的原发性肝癌，它是一种全球范围最常见的恶性肿瘤，其发病率有逐年上升趋势，每年超过600,000患者死于肝细胞肝癌。自60年代肝癌细胞系的建立、乙型肝炎病毒和黄曲霉素的发现，尤其是甲胎蛋白(AFP)在肝癌病人血中的检出，越来越多证据表明AFP是肝细胞肝癌发生的重要标记，AFP降低也是判断肝细胞肝癌的治疗预后的重要标志。肝细胞从静息状态转化为持续复制的恶性细胞就标志着肝脏癌变的开始，AFP增高，相反如果肝癌细胞被重新诱导分化，AFP则降低。
另外近期多项肝细胞肝癌的代谢组学研究表明，肝癌细胞内呈现典型的warburg效应：即葡萄糖代谢至丙酮酸(pyruvate)后不再通过线粒体的三羧酸循环进行有氧氧化，而是通过乳酸脱氢酶(LDH)，转变成乳酸排出细胞，细胞主要能量依赖糖酵解和谷氨酰胺回补途径。
肝癌对现有的放疗和化疗药物均不敏感，目前仍无有效的控制手段，因此肝癌的治疗是现代临床医学研究的重点之一。
发明内容
针对上述研究情况，为了克服上述现有技术中的不足，本发明公开了精 氨酸在制备治疗肝癌的抗肿瘤药物中的用途。
精氨酸在制备抗肝癌药物中的用途。
精氨酸在制备降低肝癌细胞内氨浓度的药物中的用途。
精氨酸在制备降低甲胎蛋白的药物中的用途。
其中，所述甲胎蛋白为甲胎蛋白、甲胎蛋白异质体或PIVKA。
另外本发明提供了盐酸精氨酸在制备抗肝癌药物中的用途。
所述的精氨酸作为抗肿瘤药物，可以使肝癌细胞的氨浓度的降低，切断了细胞内高氨代谢对于肿瘤细胞的warburg效应，进而使肿瘤细胞缺乏了能量的持续供应和维持，使之很快出现凋亡和坏死或者肿瘤细胞被重新诱导分化，抑制了肿瘤细胞生长、发展、转移，是肿瘤和肝癌治疗的新方法。
所述的精氨酸作为抗肿瘤药物，主要从以下两个方面达到抗肿瘤作用。
(1)细胞内高氨代谢对于肿瘤细胞的warburg效应形成维持作用，因此，通过精氨酸作为降低肝癌细胞内氨浓度的药物对肿瘤细胞进行新的治疗，很好的实现了肿瘤细胞在缺乏氨的持续供应和维持后，出现凋亡和坏死，或者肿瘤细胞被重新诱导分化，使肿瘤生长得到控制。
(2)精氨酸代谢在体内有3条途径，一是精氨酸在一氧化氮合酶(NOS)催化下代谢产生NO，并生成瓜氨酸；二是在精氨酸分解酶作用下，精氨酸生成鸟氨酸和尿素；三是由鸟氨酸生成多胺，多胺是腐胺、亚精胺和精胺的统称，对于调控细胞生长和发育具有重要作用。
另外本发明还提供了一种氨基胍的用途。
氨基胍在制备抗肿瘤药物中的用途。所述抗肿瘤药物优选为抗肝癌药物。
精氨酸和氨基胍的复合物在制备抗肿瘤药物中的用途。所述抗肿瘤药物优选为抗肝癌药物。
氨基胍是一种选择性一氧化氮合酶抑制剂，在实验中加入一定浓度的氨基胍后，精氨酸—NO的代谢途径就被阻断，那么此时精氨酸在细胞内的主要代谢途径就是参与降氨的过程，即氨降低，肿瘤细胞内代谢紊乱，必然会导致肿瘤细胞的凋亡增加。
临床研究和试验结果显示，在用于适应症方面，精氨酸具有明显的抗肿瘤作用，降低甲胎蛋白(包括甲胎蛋白、甲胎蛋白异质体、PIVKA)疗效显著，同时具有延缓肿瘤生长，使肿瘤缩小、甚至消失的作用。在肝癌治疗中，可明显延长患者生存时间，提高患者生存质量，且具有使用方便、安全，治疗费用低等优点。
附图说明
图1为正常肝细胞高氨处理后代谢组学Heatmap图；
图2为糖酵解途径图；
图3为三羧酸循环途径图；
图4为不同浓度的氨处理不同肝癌细胞系图；
图5为7721细胞空白对照的凋亡率图；
图6为7721细胞加入精氨酸后的细胞凋亡率图；
图7为7721细胞加入精氨酸及氨基胍后的细胞凋亡率图。
具体实施方式
下面结合具体实施例，对本发明做进一步的说明：
精氨酸，在肝癌治疗中具有抗肿瘤药物的新用途；
所述的精氨酸作为抗肿瘤药物，可以使肝癌细胞的氨浓度的降低，切断了细胞内高氨代谢对于肿瘤细胞的warburg效应，进而使肿瘤细胞缺乏了能量的持续供应和维持，使之很快出现凋亡和坏死或者肿瘤细胞被重新诱导分化， 很好的抑制了肿瘤细胞生长、发展、转移，是肿瘤和肝癌治疗的新方法。用于降低血氨的药物主要有精氨酸及门冬氨酸鸟氨酸。精氨酸是鸟氨酸循环中的一个组成成分，有助于将血液中的氨转变为尿素而排泄出去。所以精氨酸是临床常用的去除高氨血症，改善肝脏机能障碍等常用药物。门冬氨酸鸟氨酸水解产生的鸟氨酸和门冬氨酸，作用于两个主要的氨解毒途径——尿素循环和谷氨酰胺合成，鸟氨酸几乎涉及尿素循环的活化和氨的解毒的全过程；但由于门冬氨酸对肝癌细胞内三羧酸循环代谢过程的间接促进作用，有可能促进肝癌细胞内的能量合成，促进肝癌细胞的增殖及DNA合成。故我们选择精氨酸作为抗肿瘤的药物。
所述的精氨酸作为抗肿瘤药物，主要从以下两个方面达到抗肿瘤作用
(1)细胞内高氨代谢对于肿瘤细胞的warburg效应形成维持作用，因此，通过精氨酸作为降低肝癌细胞内氨浓度的药物对肿瘤细胞进行新的治疗，很好的实现了肿瘤细胞在缺乏氨的持续供应和维持后，出现凋亡和坏死或者肿瘤细胞被重新诱导分化，使肿瘤生长得到控制。
(2)精氨酸代谢在体内有3条途径，一是精氨酸在一氧化氮合酶(NOS)催化下代谢产生NO，并生成瓜氨酸；二是在精氨酸分解酶作用下，精氨酸生成鸟氨酸和尿素；三是由鸟氨酸生成多胺，多胺是腐胺、亚精胺和精胺的统称，对于调控细胞生长和发育具有重要作用。氨基胍是一种选择性一氧化氮合酶抑制剂，在实验中加入一定浓度的氨基胍后，精氨酸—NO的代谢途径就被阻断，那么此时精氨酸在细胞内的主要代谢途径就是参与降氨的过程，即氨降低，肿瘤细胞内代谢紊乱，必然会导致肿瘤细胞的凋亡增加。
具体临床病例
病例1：李XX 女 65岁，发现HBsAg阳性10年，6年前开始口服拉米夫定抗病毒治疗，期间定期复查，病情稳定，20天前因乏力、食欲欠佳，当地医院复查提示病毒反弹，肝酶升高，遂于2015年11月17日入我院住院治疗，次日复查结果回示：乙肝大三阳，HBV-DNA：1.33×104Iu/ml，甲胎蛋白(AFP)>2000ng/ml,HBV耐药突变：基因分型C检测到M204I/L类型，因患者AFP明显升高，为排除肝脏恶性病变，给予肝脏磁共振平扫及马根维显动态增强后提示：1.肝右后叶异常信号影，考虑退变结节，需结合临床进一步明确诊断 2.肝硬化 3.右肾小囊肿。因患者乙肝病史时间长合并肝硬化，抗病毒治疗出现临床耐药，甲胎蛋白异常升高，谨慎起见，请磁共振室主任会诊，会诊意见：肝右后叶可见片状短T1、短T2信号影，直径约10mm，动态增强扫描未见明显强化，考虑肝硬化发育不良性结节？因AFP高，建议行磁共振平扫+普美显动态增强扫描进一步诊断。于11月25日MRI普美显增强提示：1.肝右后叶异常信号，表现欠典型，考虑高级别发育不良性结节伴局部癌变，早期HCC不除外，建议结合临床病理协诊 2.肝实质内多发短T2信号影，考虑肝硬化结节 3.肝硬化、少量腹水 4.胆囊结石 5、双肾小囊肿 6、肝门部淋巴结显影。因患者不愿行肝脏活检，故在给予联合抗病毒治疗的同时，11月22日开始给予精氨酸针20g静脉滴注直至12月25号患者出院，期间复查AFP逐渐下降，由最初的AFP>2000ng/ml(11.18)-1839ng/ml(11.25)-1213ng/ml(12.1)-768ng/ml(12.8)-625ng/ml(12.15)-529ng/ml(12.22)，于12月24号再次复查MRI普美显增强提示：肝右后叶异常信号，与2015.11.25MRI比较原病变内小点状长T2信号未见明确显示。该患者乙肝病史时间长，肝硬化，甲胎蛋白异常升高，磁共振可见直径10mm的发育不良结节伴局部癌变，精氨酸治疗后，病变未见明确显示，甲胎蛋白明显下降，治疗有效。
病例2：邓XX 女 44岁，丙肝抗体阳性10余年，既往曾给予“派罗欣针180ug”联合“利巴韦林片9片/天”抗病毒治疗5个月，效果较差，病毒未见明显下降，遂停用，后定期复查。因乏力、腹胀伴牙龈出血于2015年11月20号入院，次日结果回示：HCV-RNA：5.08×105Iu/ml，AFP228.84ng/ml，血常规示三系细胞减少，ALT27U/L,AST87U/L,A/G(白球比)1.43(降低),诊断为慢性丙型肝炎肝硬化甲胎蛋白升高原因待查，11月24查上腹部磁共振平扫，未见明确肝脏占位性病变，在给予保肝及口服抗病毒药物的同时，给予精氨酸15g静滴1周后复查甲胎蛋白降为122.75ng/ml，继续上述治疗方案治疗10天，患者甲胎蛋白降为正常，一般状况较前明显改善，办理出院。
病例3：徐XX 男 57岁，乙肝大三阳患者，口服阿德福韦酯胶囊抗病毒治疗3年，病毒转阴，肝功正常。2年前我院上腹部磁共振提示肝右后叶占位性病变(直径约18mm)，肝硬化，脾大，门脉高压，腹水，后在CT引导下行HCC射频消融术，术后恢复可，未见异常。2月前复查上腹部磁共振平扫加动态增强提示：门脉主干癌栓形成，第VI段异常信号，表现不典型，可疑HCC复发，再次行HCC介入治疗，为进一步复查于2015年11月1号入院，2号检查结果回示：病毒低于检测试剂盒下限，ALT64U/L,AST88U/L,AFP484.30ng/ml，血常规三系减少，凝血酶原时间活动度69％，磁共振提示肝内肿瘤进展，门脉侵犯，介入行肝动脉栓塞效果预计不佳，与患者家属沟通病情后，建议穿刺门脉粒子置入，4号在手术过程中发现穿刺针在导管配合下不能沿门脉下行，手术失败。后给予保肝、抗病毒药物、精氨酸15g/天静滴保守治疗，9号复查AFP297.76ng/ml，ALT45U/L,AST61U/L，继续精氨酸治疗1月后复查AFP26.14ng/ml，ALT32U/L,AST67U/L，对比影像学检 查发现门脉主干癌栓较前有所缩小，患者尚可维持日常生活，目前仍在应用精氨酸。
病例4  朱XX 女 62岁，4月前体检发现肝占位，于河南某医院行“肝多发肿瘤切除术+胆囊切除术”，术后病理提示肝细胞肝癌，术后一般状况可。1月余前来我院复查，上腹部CT检查回示：肝右后叶强化结节，平扫呈低密度，动脉期强化，门脉期呈等密度，不除外HCC可能，与患者家属沟通病情后建议行MRI增强或PET-CT检查有无微小病灶或远处转移灶，家属要求行PET-CT(2015年10月9日)提示肝右叶稍低密度结节影代谢较活跃，考虑转移，遂以“HCC切除术后复发慢乙肝”收入院于10月14号局麻下行TACE术，术后转入我科给予保肝及精氨酸20g静脉应用数天，病情稳定后出院，院外继续口服精氨酸20g/天。患者发现“乙肝”病史1年，自体检发现肝占位后开始给予恩替卡韦抗病毒治疗至今，糖尿病3年，规律应用胰岛素，血糖控制可。患者介入术后1月余，遵医嘱于2015年11月23日再次入院复查，查肝功基本正常，病毒阴性，血象提示三系降低，甲胎蛋白阴性，复查磁共振提示：肝右叶病变未见明显动脉期血供，边缘肝实质异常强化考虑灌注异常，肝右叶多发点、片状异常强化信号，HCC不除外，对比以往影响学检查结果，无法确诊，故再次行PET-CT检查(2015年12月4号)提示肝右叶见片状稍低密度影放射性分布稍浓聚，SUVmax约3.6，边界欠清晰，但与2015年10月9日PET-CT比较，原肝右叶病灶放射性浓聚程度减低(既往SUVmax约7.3)，后仔细对比以往所检查的影像学结果发现，代谢降低的低密度影在1月前的介入中并未被碘油覆盖，但1个多月的时间，在口服精氨酸的作用下，其代谢值明显降低，现患者未再选择继续行TACE术，而是继续应用精氨酸，目前一般状况良好， 继续规律随访中。(注释：PET采用正电子核素作为示踪剂，通过病灶部位对示踪剂的摄取了解病灶功能代谢状态，可以宏观的显示全身各脏器功能，代谢等病理生理特征，更容易发现病灶。CT可以精确定位病灶及显示病灶细微结构变化；PET/CT融合图像可以全面发现病灶，精确定位及判断病灶良恶性，故能早期，快速，准确，全面发现病灶。目前最常用的PET显像剂为18F标记的FDG(18F-FDG氟化脱氧葡萄糖)，是一种葡萄糖的类似物。肿瘤组织的重要特点之一就是生长迅速、代谢旺盛，特别是葡萄糖酵解速率增高。因此，代谢显像是早期诊断恶性肿瘤的最灵敏的方法之一。PET-CT检查通过在人体注入18F-FDG示踪剂，通过SUV值作为恶性病变的判定标准。SUV即标准摄入值，the Standardized Uptake Value的简称，是目前广泛使用的18F-FDG在组织中静态聚集的半定量的测定方法，临床上常将SUV2.5作为恶性病变的判定标准。)
病例5 戴XX 女 59岁，乙肝肝硬化失代偿期患者，2年余前(2014-06-02)于我院行CT增强回示：1.肝硬化，脾大，门脉高压。2.肝左叶小结节影，小肝癌？3.胆囊切除术后改变。于2014-06-05行“经皮肝穿肝占位射频消融术”。1月余前至我院复查MRI(2016-6-01)示：1、“HCC射频消融术后，胆囊切除术后”改变与2016.01.05(709399)老片对比，肝实质内可疑新出现异常信号 2、肝硬化，脾大，少量腹水 3、胆囊未见明确显示，符合术后改变。甲胎蛋白4.2ng/mL，考虑为HCC复发，患者拒绝相关外科及介入治疗，2016-06-10开始给予精氨酸治疗。应用精氨酸治疗1月后(2016-07-05)复查MRI增强示：1、“HCC射频消融术后，胆囊切除术后”改变，与2016.06.04(788059)老片对比，前片所见肝实质内多发异常强化灶，此次未见明确显示， 建议结合临床病史随访复查  2、肝硬化、脾大、门静脉高压  3、左肾小囊肿；复查AFP 1.92ng/mL。患者应用精氨酸治疗1月余后，肝脏内原HCC病灶消失，AFP较前下降。2016-07-11再次复查磁共振增强，示：1、“HCC射频消融术后，胆囊切除术后”改变，与2016.07.05(804598)老片对比变化不大，建议结合临床并动态复查  2、肝硬化、脾大、门静脉高压  3、腹腔积液  4、左肾小囊肿。肝脏内仍未见原HCC病灶。现患者一般情况良好，已办理出院。
临床研究和试验结果显示，在用于适应症方面，精氨酸具有明显的抗肿瘤作用，降低甲胎蛋白(包括甲胎蛋白、甲胎蛋白异质体、PIVKA)疗效显著，同时具有延缓肿瘤生长，使肿瘤缩小、甚至消失的作用。在肝癌治疗中，可明显延长患者生存时间，提高患者生存治疗。
如图4-7，通过不同浓度的氨处理不同肝癌细胞系图、加入精氨酸后的细胞凋亡率图、加入精氨酸及氨基胍后的细胞凋亡率图以及临床肝癌患者给药后得到有效治疗的结果可知，本发明精氨酸作为抗肿瘤的药物，可以很好的抑制肿瘤细胞生长、发展、转移，是肿瘤和肝癌治疗的新方法。
以上实施案例仅用于说明本发明的优选实施方式，但本发明并不限于上述实施方式，在所述领域普通技术人员所具备的知识范围内，本发明的精神和原则之内所作的任何修改、等同替代及改进等，均应视为本申请的保护范围。

Claims (9)

  1. 精氨酸在制备抗肝癌药物中的用途。
  2. 精氨酸在制备降低肝癌细胞内氨浓度的药物中的用途。
  3. 精氨酸在制备降低甲胎蛋白的药物中的用途。
  4. 根据权利要求4所述的用途，其特征在于：所述甲胎蛋白为甲胎蛋白、甲胎蛋白异质体或PIVKA。
  5. 盐酸精氨酸在制备抗肝癌药物中的用途。
  6. 根据权利要求1所述的用途，其特征在于：精氨酸使肿瘤细胞的氨浓度的降低，切断细胞内高氨代谢对于肿瘤细胞的warburg效应，进而使肿瘤细胞缺乏了能量的持续供应和维持，使肿瘤细胞很快出现凋亡和坏死或者肿瘤细胞被重新诱导分化，抑制肿瘤细胞生长、发展、转移。
  7. 氨基胍在制备抗肿瘤药物中的用途。
  8. 精氨酸和氨基胍的复合物在制备抗肿瘤药物中的用途。
  9. 根据权利要求7或8所述的用途，其特征在于：所述抗肿瘤药物为抗肝癌药物。
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