WO2007030992A1 - Medicament de traitement de tumeurs et son utilisation dans la fabrication d'un medicament de traitement de tumeurs - Google Patents

Medicament de traitement de tumeurs et son utilisation dans la fabrication d'un medicament de traitement de tumeurs Download PDF

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Publication number
WO2007030992A1
WO2007030992A1 PCT/CN2006/001388 CN2006001388W WO2007030992A1 WO 2007030992 A1 WO2007030992 A1 WO 2007030992A1 CN 2006001388 W CN2006001388 W CN 2006001388W WO 2007030992 A1 WO2007030992 A1 WO 2007030992A1
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tumor
treatment
medicament
tumors
group
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PCT/CN2006/001388
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English (en)
French (fr)
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Jieguang Sun
Xueran Sun
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Jieguang Sun
Xueran Sun
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Publication of WO2007030992A1 publication Critical patent/WO2007030992A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/205—Rhabdoviridae, e.g. rabies virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/13—Tumour cells, irrespective of tissue of origin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/20011—Rhabdoviridae
    • C12N2760/20111—Lyssavirus, e.g. rabies virus
    • C12N2760/20134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2810/00—Vectors comprising a targeting moiety
    • C12N2810/50—Vectors comprising as targeting moiety peptide derived from defined protein
    • C12N2810/60—Vectors comprising as targeting moiety peptide derived from defined protein from viruses
    • C12N2810/6072—Vectors comprising as targeting moiety peptide derived from defined protein from viruses negative strand RNA viruses
    • C12N2810/6081—Vectors comprising as targeting moiety peptide derived from defined protein from viruses negative strand RNA viruses rhabdoviridae, e.g. VSV

Definitions

  • the invention relates to the field of medical technology, in particular to a medicament for treating tumors and a medicament (human rabies purified vaccine) for use in preparing a medicament for treating tumors.
  • a medicament human rabies purified vaccine
  • a tumor is a normal cell that is developing or matures in the human body. Under the long-term use of certain adverse factors, a new organism formed by excessive proliferation or abnormal differentiation of a certain cell group forms a mass locally. However, unlike normal tissues and cells, it does not grow according to the normal metabolism of normal cells, but becomes unconstrained and controlled. It does not cause normal death, resulting in abnormal morphology, function and metabolism of cells, so that it can destroy IH. The structure of tissues and organs affects their function. Malignant tumor cells can also infiltrate into the surrounding area, and even spread to other organs and tissues, continue to multiply geometrically, causing great threat to human body or life. For example, macrophages are important cells for defense and maintenance of homeostasis.
  • Cytokines When they encounter foreign body stimuli, various receptors on the cell surface and various enzymes in the cell are activated to different degrees, secreting various kinds of enzymes. Cytokines, presenting antigens, and removing foreign bodies or senescent cells by endocytosis. Both the drug and the chemotherapeutic agent can be regarded as foreign substances from outside the body, but these foreign substances are distinguished.
  • One is a biological product, which is similar to the structural component of the cell biofilm, and can protect and repair the cells.
  • One is a cytotoxic agent that causes the cells to be in an activated or inhibited state.
  • Cancer is a common disease that threatens people's lives and health. At present, there are no specific drugs for curing cancer at home and abroad. At present, the main methods for the treatment of swollen cancer include surgery, radiotherapy, chemotherapy and biological therapy. Other effective means include endocrine therapy, traditional Chinese medicine treatment, hyperthermia and radiofrequency ablation. Because each of the various treatments has its own best indications, it also has its own shortcomings.
  • alkylating agents anti-metabolites, anti-tumor antibiotics, anti-tumor botanicals, these are used in clinical anti-tumor drugs, in killing and inhibiting tumor cells. Growth, etc., have good curative effect, but the common shortcoming of chemotherapy drugs is that they damage the normal cells of the human body, such as Long-term use will bring certain side effects to cancer patients, which will greatly limit the widespread use of chemotherapy drugs.
  • Biological or immunomodulatory agents which are biological products, are used for clinical treatment of diseases, and the main functions of regulating human immune function are to enhance the body's immunity.
  • interferon interleukin-II, etc.
  • Human rabies purified vaccine and its immune serum globin 1 have long been the only effective drugs for preventing or treating rabies, and the effect is better. He has not seen any reports on drug research and treatment of human tumors. Summary of the invention
  • the object of the present invention is to provide a medicament for treating tumor diseases, which has obvious therapeutic effects on tumors, has no toxic and side effects, and provides a medicament for use in the preparation of a medicament for treating tumors.
  • Drugs for the treatment of oncology A single component of a rabies purified vaccine (which may be liquid or lyophilized).
  • Application of human rabies purified vaccine in the preparation of drugs for treating tumor diseases using human rabies purified vaccine single component (may be liquid or lyophilized), human clinical dose per muscle intramuscular injection of 2.5 11; ⁇ 10 IU, 30 days A treatment.
  • the invention is a biological preparation, and the research finds that: as a medicine for treating tumor diseases, the human rabies purified vaccine has obvious anti-tumor effect, and the animal tumor model test and clinical observation have obtained satisfactory beneficial effects, as follows:
  • the present invention can enhance the phagocytic and digestive functions of macrophages in experiments.
  • Fig. 1 is a pathological photograph of a blank group in the H22 group experiment of the present invention.
  • Fig. 2 is a pathological photograph showing the killing effect of thymopentin on tumor cells in the H22 group experiment of the present invention.
  • Fig. 3 is a pathological photograph showing the killing effect of cyclophosphamide on tumor cells in the H22 group experiment of the present invention.
  • Fig. 4 is a pathological photograph showing the killing effect of the drug on tumor cells in the H22 group experiment of the present invention.
  • Fig. 5 is a pathological photograph of a blank group in the S180 group experiment of the present invention.
  • Fig. 6 is a pathological photograph showing the killing effect of thymopentin on tumor cells in the S180 group experiment of the present invention.
  • Fig. 7 is a pathological photograph showing the killing effect of cyclophosphamide on tumor cells in the S180 group experiment of the present invention.
  • Figure 8 is a pathological photograph of the killing effect of the drug on tumor cells in the S180 group experiment of the present invention. detailed description
  • Human clinical trial Human rabies purified vaccine (Vero cells) drug (commercially available product). Daily intramuscular injection of 2.5 IU, 30 days for a course of treatment, this example is two courses.
  • Pathological diagnosis of Lee Cervical squamous cell carcinoma, stage II B; After 2 courses of CAF chemotherapy, after local radiotherapy, the clinical symptoms improved, recovery was acceptable; the ratio of CEA was increased after re-examination; after treatment with the drug of the present invention, the condition Better, no abnormalities in pathological smears.
  • Zhao Unclear primary tumor, brain metastasis, pathological diagnosis: astrocytoma; gamma knife treatment, cerebral edema and coma, family members should use the drug for treatment: 2.5 IU of activity unit, Daily intramuscular injection of 10 IU, 30 days for a course of treatment, has been taken for 27 days, brain edema partially disappeared, in good condition.
  • Test drug The drug of the present invention, a commercially available product; a suspension having a concentration of 0.1 U/ml in physiological saline is used.
  • Gao Jusheng Biopharmaceutical, approval number: 20050703
  • Shenyang Xiehe Bio-Pharmaceutical Co., Ltd. formulated with normal saline to form lmg/ml solution.
  • Test methods According to the "Guidelines for Pre-clinical Antineoplastic Drugs of New Drugs" and the “Third Qufm Oncology Drugs and Chemotherapy Conference Development Plan".
  • the well-grown tumor-bearing mice were aspirated under sterile conditions and diluted with physiological saline to a cell suspension of 10 3 /ml.
  • mice each batch of male and female experiments, 0.2ml of tumor fluid dilution was injected into the right sac of the mouse, the secondary bolts were randomly divided into groups, and the fourth day began to be administered once a day.
  • the tumor tissue was administered continuously for 5 times. Day (blank group - tumor tissue was injected with normal saline 0.2 ml). After 15 days of withdrawal, the animals were sacrificed, the subcutaneous tumor masses were dissected and weighed, and the tumor tissues were pathologically examined. The average tumor weight and inhibition rate of each group were calculated.
  • mice were taken, and each batch was divided into two parts: male and female. 0.2 ml of the diluted solution was injected into the abdominal cavity of the mice. The next day, the body weight was randomly divided into groups. The fourth day, the administration was started once a day, once a day, and administered intraperitoneally. The drug was administered for 5 consecutive days (blank group: intraperitoneal injection of physiological saline 0.2 ml). After stopping the drug, until all the mice died, the death time of each mouse was recorded, and the body weight was weighed.
  • H22 group anatomical macroscopic treatment:
  • the tumor tissue envelope is relatively intact, and some are spoiled.
  • the pathological film shows many necrotic changes in the tumor tissue, the nuclear stain is shallow, many structures in the cell disappear or degenerate, the tumor tissue shrinks, and the cancer cells become lightly stained.
  • the thymidine pentapeptide control group had a greater degree of necrosis (see Figure 1, pathological images of the H22 blank group, cancer cells with full field of view, nuclear deep staining, and few cytoplasms; see Figure 2, H22 thymus five Peptide pathological photographs showed a small amount of cancer cell necrosis and degeneration, and a large amount of cancer tissue was also visible locally; see Figure 3, H22 cyclophosphamide pathological photo, localized dispersion of cancer tissue, necrotic tissue dispersed therein; see Figure 4, H22 pathology of the invention Photographs, a large number of cancerous tissue degeneration and necrosis, local liquefaction, light nuclear staining, a small amount of cancer tissue centered).
  • the tumor tissue envelope is relatively intact, and some local macroscopic necrosis and variability can be seen. There is a large amount of liquid in the envelope, which is translucent and pale yellow, and a small part has a half-blood liquid.
  • Pathological findings There are a large number of light-stained areas in the tumor tissue, the nuclear membrane disappears, the nucleus is lightly stained, and the tissue structure is denatured or disappeared (see Figure 1, S180 blank group pathological photograph, cancer cells full of field of view, nuclear deep staining, less cell paddle; see Figure 2, S180 thymopentin pathological photograph, a small number of cancer cell necrosis, a large number of cancerous tissue can be seen locally; see Figure 3, S180 cyclophosphamide pathological photo, localized dispersion of cancer tissue, necrotic tissue dispersed in it; see figure 4, S180 The pathological photograph of the invention, a large number of cancer tissue degeneration and necrosis, local liquefaction, nuclear staining shallow, a small amount of cancer tissue centered).
  • the survival time of the experimental group was significantly longer than that of the control group and the blank group.
  • the experimental drugs have strong anti-tumor effect on H22 and S180, and the pathological film shows a strong killing and damaging effect on tumor cells.
  • the experimental drugs have a significant effect on the survival of tumor-bearing animals.
  • Test Conclusions By administering the epilepsy mice for 5 consecutive days, the solid tumor was observed for tumor weight, inhibition rate, and ascites type quality to observe the life extension rate, thereby confirming the efficacy of the drug.
  • the tumor inhibition rate is more than 30%, continuous test 3 times, the effect is stable, statistically significant difference PO.05, the drug is effective for solid tumors. '
  • the drug has stable and stable antitumor effect on solid tumor and ascites type carcinoma, and no other obvious side effects are found in the experiment.
  • Chemotherapeutic agents are cytotoxic agents that have a significant inhibitory effect on immune function. Through animal experiments such as immunization and anti-oxidation, the results suggest that inhibition of chemotherapeutic agents after administration can improve the formation of antibodies, promote chemotaxis and adhesion of phagocytic cells, promote the release of active substances in cells, and promote phagocytosis. Digestive function.
  • the invention studies the regulation of drugs on the repair of radiotherapy injury in tumor-bearing mice.
  • the changes in tumor inhibition rate, anti-radiation, anti-oxidation, anti-fatigue, and immune function of the mice after administration were mainly observed.
  • mice The function of mononuclear phagocytic cells in mice was significantly improved after administration, and the phagocytic index and phagocytic activity were 0.3480 and 8.2870, respectively. The results of the study were significantly different by data processing, see Table 1.
  • the phagocytosis rate of mouse peritoneal macrophages reached 35.02%, and the phagocytic index also increased significantly, reaching 1.02, which also increased the phagocytic digestion function; increased the half hemolysis value of serum, and had stronger antibody formation after chemotherapy. Regulatory effect (regulatory effect of immune function).
  • the tumor-inhibiting rate of tumor-bearing mice alone is 39.03%, and if used in combination with chemotherapy, it can reach 59.53% (synergistic effect).
  • SOD superoxide dismutase
  • the repair of radiation damage is also obvious.
  • the animal begins to die late, and the head skin and mucous membrane damage is lighter, while the control group is heavier, the head and face skin and mucous membrane are severely damaged, and most of the hair loss is accompanied by Have symptoms such as diarrhea.
  • the micronucleus rate of bone marrow in the experimental group was not significantly increased.
  • the 30-day survival rate was 82.07%, and the average monthly survival time was 24.62 days, which was consistent with the control group (regulatory effect of chemoradiotherapy injury repair).
  • the drug can prolong the swimming sputum of the mice by 75%, which significantly enhances the endurance (preventive effect).
  • the drug has a variety of biological mediation effects. It can improve the state of adverse reactions in the treatment of malignant tumors. Faced with a huge market for cancer treatment and rehabilitation, the application prospect is broad.

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Description

一种治疗肿痫的药物及该药物在制备治疗肿瘤药物中应用 技术领域
本发明涉及医药技术领域， 具体地说是一种治疗肿瘤的药物及该药物（人用狂犬 病纯化疫苗） 在制备治疗肿瘤药物中应用。 背景技术
恶性肿瘤严重威胁人类的健康与生命， 据世界卫生组织统计， 每年有近 700万人 死于癌症， 从 1996年以来全球每年新确诊的肿瘤病人在 1000万人以上， 全球肿瘤病 人总数已超过 4000万。掘卫生部的统计资料， 1§|前我国每年新确诊的肿痫患者约 160 万人， 年死亡 130万人， 癌症患者总数在 200万人以上。 随着癌症发病率的上升， 抗 肿瘤研究已成为国内外医学研究的重要课题。科学界预言， 找到癌症的超级抗原， 破 解癌基因的死亡密码， 人类将最终战胜癌症。
到目前为止尽管已有数十种化疗或辅助抗癌药物用于临床治疗。二十一世纪治疗 疾病， 合成药、 中草药、 生物制剂各占一个领地。 但大多数药物只能使病情缓节， 无 法达到治愈的目的。 近年来， 各国都在抗癌药物的研究与发展上投入了大量的人力、 物力， 希望在不久的将来能有所突破。 .
肿瘤是人体中正在发育的或成熟的正常细胞，在某些不良因素的长期使用下， 某 部的细胞群出现的过度增生或异常分化而生成的新生物，在局部形成肿块。但它与正 常的组织和细胞不同， 不按正常细胞的新陈代谢规律生长， 而变得不受约束和控制， 不会正常死亡导致了细胞呈现异常的形态、功能和代谢， 以致可以破坏 IH常的组织器 官的结构并影响其功能。恶性肿瘤细胞还能向周围浸润蔓延，甚至扩散转移到其他器 官组织， 继续成几何倍数增生， 造成对人体或生命极大的威胁。 如： 巨噬细胞是机体 防御和维持自稳性的重要细胞， 当其遇到异物刺激时， 细胞表面的各种受体及胞内的 多种酶类均被不同程度的激活， 分泌各种细胞因子， 提呈抗原， 通过内吞外排等方式 清除异物或衰老细胞。可将该药物和化疗剂均视为来自体外的异物，但这些异物又有 所区别， 一种是生物制品， 与细胞生物膜的结构成分相似， 可保护和修复细胞。 一种 为细胞毒剂， 导致细胞处于活化或抑制状态。
癌症是危及人们生命与健康的常见病， 目前国内、 外没有根治癌症的特效药物。 目前用于肿癌治疗的主要手段有手术、放疗、化疗和生物治疗， 其他有效手段还包括 内分泌治疗、 中医中药治疗、热疗和射频消融治疗等。 由于现有各种治疗手段各有其 最佳适应症， 也各有其不足。
现在治疗肿瘤的药物中用于临床的较多的有： 烷化剂类， 抗代谢类， 抗肿瘤抗生 素类， 抗肿瘤植物药类， 这些用于临床的抗肿瘤药物， 在杀伤和抑制肿瘤细胞生长等 方面， 均有较好的疗效， 但化疗药物的共同缺点是对人体正常细胞损害较大， 如 长时间使用，均会给肿瘤患者带来一定的毒副作用，这样就使化疗药物的广泛使用受 到了极大限制。 生物或免疫调节剂， 是生物制品， 用于临床治疗疾病， 主耍可调节人 体免疫功能， 起到机体免疫增强作用。 如千扰素、 白介素 -II等， 对部分肿瘤如肾癌、 黑色素瘤等有一定的疗效，但价格较品贵，许多肿瘤疗效不确切，不: έ〔用作一线治疗。 现在人用狂犬病纯化疫苗及其免疫血清球蛋 1长期以来是用于预防或治疗狂犬病的 唯一有效药物， 且效果较好。伹其关于对人治疗肿瘤方面的药物研究和应 ffl还尚未见 任何报道。 . 发明内容
本发明的目的是提供一种治疗肿瘤病的药物， 该药物对肿瘤具有明显的治疗作 用， 无毒副作用； 并提供一种该药物在制备治疗肿瘤药物中应用。 '
本发明技术方案是：
治疗肿瘤病的药物： 釆用人用狂犬病纯化疫苗单一成分 （可为液体或冻干型）。 人用狂犬病纯化疫苗在制备治疗肿瘤病药物中的应用：采用人用狂犬病纯化疫苗 单一成分 （可为液体或冻干型）， 人临床用量每 R肌肉注射 2.5 11；〜 10 IU， 30天为一 个疗程。
本发明为生物制剂， 研究发现： 作为治疗肿瘤病的药物， 人用狂犬病纯化疫苗具 有明显的抗肿瘤作用， 通过动物肿瘤模型试验和临床观察， 均获得满意的有益效果， 具体如下：
与对照组相比， 本发明在实验中可增强巨噬细胞的吞噬和消化功能。
从本发明对药物开展的药理、药效实验中可见： 该药物对荷瘤动物的体内实验及 对癌细胞的组织细胞病理观察中均可证实药物的抑瘤疗效，相关的实验研究工作也探 讨了药物对机体免疫和抗氧化等多种功能的影响。大量的实验研究工作， 也为了进一 步的开发该药功能提供了可靠的科学理论依据。 - 附图说明
图 1为本发明 H22组实验中空白组病理照片。
图 2为本发明 H22组实验中胸腺五肽对肿瘤细胞杀伤作用病理照片。
图 3为本发明 H22组实验中环磷酰胺对肿瘤细胞杀伤作用病理照片。
图 4为本发明 H22组实验中该药对肿瘤细胞杀伤作用病理照片。
图 5为本发明 S180组实验中空白组病理照片。
图 6为本发明 S180组实验中胸腺五肽对肿瘤细胞杀伤作用病理照片。
图 7为本发明 S180组实验中环磷酰胺对肿瘤细胞杀伤作用病理照片。
图 8为本发明 S180组实验中该药对肿瘤细胞杀伤作用病理照片。 具体实施方式
下面通过实施例对本发明作进一歩说明。
实施例 1
人临床实验： 取人用狂犬病纯化疫苗 （Vero细胞） 药物 （市购产品）。 每日肌肉 注射 2.5 IU, 30天为一个疗程， 本实施例为两个疗程。
李某 病理诊断： 宫颈鳞癌， II期 B; 经 CAF化疗方案 2个疗程， 局部放射 治疗后， 临床征状改善， 恢复尚可； 复查吋 CEA比值升高； 用本发明药物治疗后， 病情好转， 病理涂片未见异常。
实施例 2
人临床实验： 取该药物， 每日肌肉注射 · 7.5 ΐυ， 30天为一个疗程， 共 1个疗程。 应某： 病理诊断： 食管鳞癌， III期 Α; 局部放射治疗 20天后， 临床征状改善， , 饮食尚可； 放射治疗 3个月后， 用本发明药物治疗后， 病情好转， Τ细胞亚群比值明 显提高， 生理指标正常。
实施例 3
赵某： 原发灶不清， 脑转移， 病理诊断： 星形细胞癌； 伽玛刀治疗后， 出现脑水 肿及昏迷现象， 家属要示改用该药物进行治疗： 以活性单位 2.5 IU计， 每日肌肉注射 10 IU, 30天为一个疗程， 现已服用 27天， 脑水肿部分消失、 状态良好。
实施例 4 (用荷瘤小鼠验证该药物对肿瘤的抑制作用）
考察该药物对小鼠 Η22肝癌和小鼠 S180实体瘤的抑制作用， 及提高小鼠艾氏腹 水癌的生命延长率作用。
受试药物： 本发明药物， 市购产品； 用生理盐水配成浓度为 0.1U/ml的混悬液备 用。
实验材料：
1. 动物昆明种小鼠， 体重 20±2g， 每实验组 20只， 山中国医科大学实验动物室 提供。 实验动物合格证号： 辽实动字第 521号。
2. 小鼠 S180肉瘤和 H22肝癌瘤株、 艾氏腹水癌瘤株， 均 |±|北京中国医学科学 院药物所提供。
3. 饲料小鼠颗粒料， 由沈阳实验动物颗粒饲料厂提供。'
4. 对照药：
1 )环磷酰胺（化疗药； 批号： 05060721 )， 注射用针剂， ώ江苏恒医药有限公司 提供。 用生理盐水配制成 3mg/ml水溶液。 '
2)高聚生（生物药， 批准文号： 20050703 )， 沈阳协和生物制药股份有限公司生 产， 用生理盐水配成 lmg/ml液备用。
3 ) 闩达仙注射剂 （生物药， 注册证号： H20050339 产品批号： P005D) 美国 赛生药品 （香港） 股份国际有限公司。 5. 空白对照组： 生理盐水。
试验方法： 按 〈新药临床前抗肿瘤药指导原则〉 和 〈第三屈全 ffl肿瘤药现及化疗 会议制定方案〉 进行。 将生长良好的荷瘤小鼠， 在无菌条件下抽取瘤液， 用生理盐水 稀释成 103个 /ml的细胞悬液。
一、 抑瘤试验
1 . 实体瘤抑瘤试验
取小鼠， 每批实验用雌雄各半， 将 0.2ml瘤液稀释液注入小鼠右腋皮下， 次闩称 体重随机分组， 第四天开始给药， 每天一次， 肿瘤组织注射给药连续 5天 （空白组- 肿瘤组织注射生理盐水 0.2ml)。 停药 15天后处死动物， 解剖分离皮下瘤块， 称重， 瘤组织做病理检査， 计箕各组平均瘤重和抑制率。
2. 生命延长率试验 '
取小鼠， 每批实验用雌雄各半， 将 0.2ml稀释液注入小鼠的腹腔， 次日称体重随 机分组， 第四天开始给药， 每天一次， 每天给药一次， 腹腔注射给药， 连续 5天给药 (空白组： 腹腔注射生理盐水 0.2ml)。停药后观察， 直至小鼠全部死亡， 记录每只鼠 的死亡吋间， 称体重。
实验结果：
H22组， 解剖肉眼处理： 肿瘤组织包膜较完整， 个别呈腐败状。 包膜内存大量液 体 （血性液体居多）， 肿瘤组织许多呈腐烂状， 病理片见瘤组织中许多坏死变化， 核 染浅， 细胞内许多结构消失或变性， 瘤组织缩小， 癌细胞核染变浅。 从病理片见较环 '磷酰胺， 胸腺五肽对照组坏死性程度大 （参见图 1， H22空白组病理照片， 癌细胞满 视野， 核深染， 胞桨少； 参见图 2, H22胸腺五肽病理照片， 可见少量癌细胞坏死变 性， 局部还可见大量的癌组织； 参见图 3, H22环磷酰胺病理照片， 癌组织局部分散， 坏死变性组织分散在其中； 参见图 4， H22本发明病理照片， 大量癌组织变性坏死， 局部液化， 核染变浅， 癌组织少量居中）。 - S180 组， 解剖肉眼外可见： 肿瘤组织包膜较完整， 个别局部肉眼可见坏死， 变 性。 包膜内有大量液体， 呈半透明淡黄色， 少部有半血性液休。
病理片见：瘤组织存在大量浅染区，核膜消失，核浅染，组织结构变性或消失（参 见图 1， S180 空白组病理照片， 癌细胞满视野， 核深染， 胞桨少； 参见图 2， S180 胸腺五肽病理照片，可见少量癌细胞坏死变性，局部还可见大量的癌组织；参见图 3， S180环磷酰胺病理照片，癌组织局部分散，坏死变性组织分散在其中；参见图 4， S180 本发明病理照片， 大量癌组织变性坏死， 局部液化， 核染变浅， 癌组织少量居中）。
艾氏腹水癌组， 实验组生存期较对照组与空白组明显延长。
实验结论： 实验药物对 H22， S180有较强的抑瘤作用， 病理片可见对肿瘤细胞 有较强大的杀伤破坏作用。 实验药物对荷瘤动物生存期延长.有明显作用。
试验结论： 通过对荷痫小鼠连续 5天注射给药， 实体瘤观察瘤重、抑制率， 腹水型质量观察 生命延长率， 从而验定了药物的疗效。
1. 实体瘤疗效评价： 抑瘤率均大于 30 % , 连续试验 3次， 疗效稳定， 经统计学 处理有显著差异 PO.05 , 该药对实体瘤疗效较好。 '
2. 腹水型疗效评价： 生命延长率 >50%。 实验连续 3次， 疗效较稳定， 统计学 处理有显著差异 PO.05, 该药对腹水癌疗效较好。
根据上述试验结果认为： 该药对实体瘤及腹水型癌瘤疗效稳定较好，抑瘤作用较 强， 实验中未发现其它明显毒副作用。
腹腹腹腹腹腹腹
二、 免疫功能的调节作w用w H H S空六空空六、增效解毒作用， 对放化疗损伤修复的调节作用及预防 注注注注注注注
作用
化疗剂是细胞毒剂， 可对免疫功能产生了明显的抑制作用。通过免疫和抗氧化等 动物实验， 结果提示， 用药后对化疗剂的抑制， 使抗体的形成有所提高， 促进吞噬细 胞的趋化、 黏附作用， 促进细胞内活性物质的释放， 进而促进吞噬和消化功能。
本发明研究了药物对荷瘤小鼠放疗损伤修复的调节作甩。主要观察了用药后的小 鼠体内的肿瘤抑制率、 抗辐射、 抗氧化、 抗疲劳、 提髙免疫功能的变化。
动物实验证明：
1. 用药后小鼠单核吞噬细胞功能明显提高， 吞噬指数与吞噬活性分别为 0.3480 和 8.2870。 其研究结果经数据处理具有显著性差异， 参见表 1。
表 1 小鼠单核吞噬细胞功能的实验结果
" ~~ 绗别 "~ 动物数 . 给药途径 ~剂量 （mg/kg) 吞噬指数 K ~吞噬活性 α 空 R组 10 0.2 mL生理盐水 /只 0.0867±0.0058 5.1542±0.3016 化疗组 10 20mg/kg/只 0.0744±0.0081 4.4614±0.2413 高聚生治疗组 10 100mg/kg/只 0.333 Π0.0177 7.8440±0.5096 高聚生 +化疗组 10 100mg+20 mg /kg/只 0.2868±0.0348 7.0877±0.4307 疫苗组 10 0.625U/kg/只 0.3480±0.0120 8.2870±0.3221 疫苗 +化疗组 10 0.625U+20mg/kg/只 0.2969±0.0115 7.2141±0.3674 日达仙组 10 0.3 mg/kg/只 0.3473±0.0130 7.95_83±0.5069 百 ; Ϊ0 腹腔注射 0.3rag+20 mg /kg/只 0.2923±0.0041 '7 80Ϊ8±03 Ϊ5 其中： 组间比较 Ρ <0.1。
2.用药后使小鼠腹腔巨噬细胞吞噬率达 35.02%，吞噬指数亦明显提高，达 1.02， 还可增加吞噬细胞消化功能； 使血清半数溶血值增加，对化疗后抗体形成有较强的调 节作用 （免疫功能的调节作用）。
3. 可迅速回升外周血白细胞总数达 ΪΗ常水平、 使用环磷酰胺大剂鹭化疗降白细 胞， 通常要经相当长一段时间才可恢复正常，而用药后可使白细胞在 7-10天回升至正 常水平 （解毒作用）。
4. 荷瘤小鼠单用药物抑瘤率为 39.03 %， 如与化疗并用， 可达 59.53% (增效作 用）。 . 5 . ffl药后可增强小鼠肝脏超氧化物歧化酶 （SOD ) 的活性， SOD 水平为 662.97ug/mL 化疗吋并用为 452.69 ug/ml ， 高于对照组， 与正常对照组相当 （抗氧 化作用）。
对辐射损伤的修复也较明显，如照射后动物开始出现死亡较晚， 出现头部皮肤及 粘膜损伤较轻， 而对照组损伤较重， 头面部皮肤、 粘膜渙疡严重， 大部脱毛并伴有腹 泻等症状。 实验组小鼠骨髓微核率未见明显升高。 而且 30天存活率为 82.07%， 平均 月生存吋间为 24.62天， 均髙于对照组 （放化疗损伤修复的调节作用）。
药物可延长小鼠游泳吋间达 75%， 明显增强耐力 （预防作用）。
通过上述实验研究发现，该药物具有多种生物调解作用。能改善恶性肿瘤治疗中 的不良反应状态。 面临肿瘤治疗与康复的庞大市场， 应用前景广阔。

Claims

权 利 耍 求 书
1. 一种治疗肿瘤病的药物， 其特征在于： 其活性成分为人用狂犬病纯化疫苗。
2. 按权利要求 1所述治疗肿瘤病的药物， 其特征在于： 其中所述人用狂犬病纯 化疫苗为液体或冻千型。
3. —种权利耍求 1所述药物在制备治疗肿瘤病药物中的应用， 其特征在于： 其 活性成分为人用狂犬病纯化疫苗。
4. 按权利要求 3所述的应用， 其特征在于： 其中所述人用狂犬病纯化疫苗为液 体或冻干型。
5. 按权利要求 3所述的应用， 其特征在于： 人临床用量每 FI肌肉注射 2.5 IU ~10 IU， 30天为一个疗程。
1
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