WO2018098804A1 - 含有亚铁氨基酸螯合物的组合物用于制造防止癌症转移的医药品的用途 - Google Patents

含有亚铁氨基酸螯合物的组合物用于制造防止癌症转移的医药品的用途 Download PDF

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WO2018098804A1
WO2018098804A1 PCT/CN2016/108366 CN2016108366W WO2018098804A1 WO 2018098804 A1 WO2018098804 A1 WO 2018098804A1 CN 2016108366 W CN2016108366 W CN 2016108366W WO 2018098804 A1 WO2018098804 A1 WO 2018098804A1
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cancer
amino acid
ferrous
use according
tumor
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PCT/CN2016/108366
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English (en)
French (fr)
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林村源
陈木桂
陈沧泽
傅嘉慧
詹勋锦
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普惠德生技股份有限公司
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Priority to PCT/CN2016/108366 priority Critical patent/WO2018098804A1/zh
Priority to CN201680091337.5A priority patent/CN110035747B/zh
Priority to JP2019529158A priority patent/JP6774126B2/ja
Publication of WO2018098804A1 publication Critical patent/WO2018098804A1/zh

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the use of a composition comprising a ferrous amino acid chelate compound, in particular to a medicament for the manufacture of a medicament for preventing cancer metastasis.
  • Cancer metastasis also known as malignant metastasis, is the leading cause of cancer incurable. Cancer metastasis refers to the transfer of cancer cells from the original location to the growth of other organs and tissues in the body, making cancer treatment more difficult, usually unable to eradicate, only radiation therapy or chemotherapy can inhibit cancer cells to continue to proliferate to prolong the life of patients.
  • Cancer metastasis is an extremely complicated process. At present, it is pointed out that the main reason why cancer cells can be transferred to other organ tissues is the ability of cancer cells to have invasion.
  • the cancer cells are abnormally activated and secrete massive matrix metalloproteinase (matrix metalloproteinase, MMP), a matrix metalloproteinase that decomposes the extracellular matrix (ECM), allowing cancer cells to invade surrounding tissues and metastasize to other organs, where MMP-1 and MMP-3 have been shown to be associated with cancer cell metastasis.
  • MMP matrix metalloproteinase
  • ECM extracellular matrix
  • MMP is also inhibited by tissue inhibitor of metalloproteinase (TIMP); however, metalloproteinase tissue inhibitors -2 (tissue inhibitor of metalloproteinase-2, TIMP-2) has the effect of inhibiting MMP, but there are also reports that TIMP-2 expression is positively correlated with cancer cell metastasis. Although cancer metastasis is the main cause of death in cancer patients, the current research on anti-cancer is still the main research direction to inhibit the growth of carcinoma in situ.
  • TIMP-2 tissue inhibitor of metalloproteinase-2
  • compositions containing a ferrous amino acid chelate compound for producing a medicament for preventing cancer metastasis which comprises a ferrous amino acid chelate.
  • Composition of the compound has inhibition The effect of cancer cell migration, inhibition of cancer cell invasion, inhibition of cancer cell MMP-related protein expression, or inhibition of cancer cell TIMP-related protein expression.
  • the technical means adopted by the present invention provides a use of a composition containing a ferrous amino acid chelate compound for the manufacture of a medicament for preventing cancer metastasis, wherein the medicament contains an effective dose of ferrous amino acid.
  • the "composition containing a ferrous amino acid chelate” is a composition containing a ferrous amino acid chelate prepared by mixing inorganic iron with an amino acid.
  • the ferrous metal chelate compound in the composition containing the ferrous amino acid chelate has a chelating ratio of ferrous iron to amino acid of between 1:1 and 1:4.
  • the ferrous metal chelate compound in the ferrous metal chelate-containing composition has a chelating ratio of ferrous iron to amino acid of between 1:1.5 and 1:2.5.
  • the effective amount of the ferrous amino acid chelate-containing composition is between mg/kg/day and mg/kg/day.
  • the effective amount of the ferrous amino acid chelate-containing composition is from 0.2 mg/kg/day to 200 mg/kg/day.
  • the effective amount of the ferrous amino acid chelate-containing composition is from 1 mg/kg/day to 100 mg/kg/day.
  • the effective dose is calculated by the concentration of the composition containing the ferrous amino acid chelate compound in the embodiment of the present specification from 1 ⁇ g/mL to 1000 ⁇ g/mL, and the blood volume in the body weight of 65 kg is about 1 of the body weight.
  • the relative blood concentration of /13 is obtained as a conversion; specifically, the effective dose is 0.2 mg/kg/day, that is, the concentration of the composition containing the ferrous amino acid chelate compound is 1 ⁇ g/mL times 13/65, In this way, the effective dose is 200 mg/kg/day, that is, the concentration of the composition containing the ferrous amino acid chelate compound is 1000 ⁇ g/mL times 13/65, so the concentration of the composition containing the ferrous amino acid chelate compound is obtained.
  • the effective dose in terms of 1 ⁇ g/mL to 1000 ⁇ g/mL is from 0.2 mg/kg/day to 200 mg/kg/day.
  • the composition containing a ferrous amino acid chelate is a composition containing a ferrous amino acid chelate compound prepared by mixing inorganic iron with an amino acid and heating at 60 ° C to 90 ° C for 8 hours to 48 hours.
  • the weight ratio of inorganic iron to amino acid is between 1:1.2 and 1:1.5.
  • the inorganic iron is ferrous sulfate, ferrous chloride, ferrous pyrophosphate or a combination thereof; the amino acid is glycine.
  • the ferrous metal chelate-containing composition is 95% to 100% by weight of a ferrous glycine chelate; still more preferably, 98% to 99.9% by weight of ferrous iron. Glycine chelate.
  • the ferrous metal chelate-containing composition includes a reducing agent including, but not limited to, ascorbic acid, citric acid, acetic acid, and propionic acid. (propionic acid), butyric acid, lactic acid, malic acid, sulfonic acid, succinic acid or a combination thereof.
  • a reducing agent including, but not limited to, ascorbic acid, citric acid, acetic acid, and propionic acid. (propionic acid), butyric acid, lactic acid, malic acid, sulfonic acid, succinic acid or a combination thereof.
  • preventing cancer metastasis means effectively controlling the transfer of cancer cells from the site where the original occurs to the growth of the organ tissues in the body, wherein prevention of cancer metastasis includes, but is not limited to, as exemplified by the present invention, preventing cancer metastasis means It inhibits cancer cell migration, inhibits cancer cell invasion, inhibits cancer cell MMP-related proteins, or inhibits the expression of cancer cell TIMP-related proteins.
  • the "effective dose” as used herein refers to an amount that achieves a desired slowing or prevention of cancer metastasis at a dose and for a desired period of time; according to the present invention, it refers to the administration of a specific range of amounts of ferrous amino acid-containing amino acids.
  • the composition of the chelate compound can reduce the cancer metastasis ability of lung cancer or breast cancer, or inhibit the migration of cancer cells, inhibit the invasion of cancer cells, inhibit the MMP-related proteins of cancer cells or inhibit the expression of TIMP-related proteins of cancer cells; The invention also refers to the effect of reducing the migration of cancer cells or reducing the invasion of cancer cells.
  • the "pharmaceutically acceptable carrier” of the present invention includes, but is not limited to, a solvent, an emulsifier, a suspending agent, a decomposer, a binding agent, and a formulation. Excipient, stabilizing agent, chelating agent, diluent, gelling agent, preservative, lubricant, surfactant (excipient) Surfactant, and other carriers similar or suitable for use in the present invention.
  • the "pharmaceutical” of the present invention may exist in various forms including, but not limited to, liquid, semi-solid, and solid pharmaceutical forms such as solutions, emulsions, suspensions, powders ( Powder), tablet, pill, lozenge, troche, chewing gum, slurry, liposome, Suppositories and other dosage forms similar or suitable for use in the present invention.
  • liquid, semi-solid, and solid pharmaceutical forms such as solutions, emulsions, suspensions, powders ( Powder), tablet, pill, lozenge, troche, chewing gum, slurry, liposome, Suppositories and other dosage forms similar or suitable for use in the present invention.
  • the pharmaceutical product is an enteral or parenteral dosage form.
  • the enteral dosage form is an oral dosage form, the oral dosage form being a solution, emulsion, suspension, powder, lozenge, pill, buccal tablet, tablet, chewing gum or capsule.
  • the cancer includes, but is not limited to, melanoma, liver cancer, colon cancer, lung cancer, gastric cancer, esophageal cancer, breast cancer, prostate cancer ( Prostate cancer), leukemia, brain tumor, low-grade astrocytoma, high-grade astrocytoma, pituitary adenoma, Meningioma, central nervous lymphoma (CNS lymphoma), oligodendroglioma, craniopharyngioma, ependymoma, glial tumor (brain) Stem tumor), head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasopharyngeal tumor, salivary gland tumor, hypopharyngeal cancer ), thyroid cancer, oral cavity tumor, chest wall tumors, small cell lung cancer, non-small Non-small cell lung cancer (NSCLC), thymoma, mediastinal tumor, male breast cancer, abdomen-pelvis tumor, liver adeno
  • the cancer metastasis is breast cancer or lung cancer.
  • the medicament is for inhibiting migration of cancer cells, inhibiting invasion of cancer cells, inhibiting a matrix metalloproteinase-related protein or inhibiting a metalloproteinase tissue inhibitor.
  • the pharmaceutical is for inhibiting matrix metalloproteinase-1, matrix metalloproteinase-3 or metalloproteinase tissue inhibitor-2.
  • the ferrous metal chelate-containing composition of the present invention has an effect of inhibiting cancer metastasis, and the present invention demonstrates that treatment of a composition containing a ferrous amino acid chelate can effectively inhibit cancer cell migration, inhibit cancer cell invasion, and inhibit The expression of MMP-related proteins in cancer cells and the inhibition of TIMP-related proteins in cancer cells.
  • 1A is a breast cancer cell MDA-MB- after treatment of breast cancer cell MDA-MB-231 with composition A1 at a concentration of 0 ⁇ g/mL (control group), 5 ⁇ g/mL, 10 ⁇ g/mL, and 25 ⁇ g/mL, respectively. 231 Observed the migrated image at 40x magnification.
  • Figure 1B is a histogram (based on the control group) obtained after quantification of the migration image of the breast cancer cell MDA-MB-231 of Figure 1A.
  • 2A is a 40-fold treatment of non-small cell lung cancer cell A549 after treatment of A549 with composition A1 at a concentration of 0 ⁇ g/mL (control group), 100 ⁇ g/mL, 250 ⁇ g/mL, and 500 ⁇ g/mL, respectively. Magnified observation of the migrated image.
  • 2B is a histogram obtained by quantifying the migration image of the non-small cell lung cancer cell A549 of FIG. 2A (based on the control group).
  • 3A is a breast cancer cell MDA-MB- after treatment of breast cancer cell MDA-MB-231 with composition A1 at a concentration of 0 ⁇ g/mL (control group), 10 ⁇ g/mL, 25 ⁇ g/mL, and 50 ⁇ g/mL, respectively. 231 Invaded image observed at 40x magnification.
  • Figure 3B is a histogram of the breast cancer cell MDA-MB-231 invasion image of Figure 3A quantified (based on the control group).
  • 4A is a 40-fold treatment of non-small cell lung cancer cell A549 after treatment of A549 with composition A1 at a concentration of 0 ⁇ g/mL (control group), 100 ⁇ g/mL, 250 ⁇ g/mL, and 500 ⁇ g/mL, respectively. Magnification observed the image of the invasion.
  • Figure 4B is a histogram obtained from the invasive image of the non-small cell lung cancer cell A549 of Figure 4A (based on the control group).
  • 5A is a graph showing the expression of MMP-related protein secreted by breast cancer cell MDA-MB-231 after treatment of breast cancer cell MDA-MB-231 with composition A1 at a concentration of 0 ⁇ g/mL (control group) and 100 ⁇ g/mL, respectively.
  • the left column is the MMP-related protein of the control group and The expression of TIMP-related protein; the right column shows the MMP-related protein and TIMP-related protein expression in the breast cancer cell MDA-MB-231 experimental group.
  • 5B is a coordinate position of a MMP-related protein and a TIMP-related protein detected by the MMP antibody chip tested in FIG. 5A; Pos (ie, coordinates A1, A2, B1, B2, H3, and H4) are positive control groups, and Neg (ie, coordinates) C1, C2, D1, D2, G3 and G4) are negative control groups.
  • Pos ie, coordinates A1, A2, B1, B2, H3, and H4
  • Neg ie, coordinates C1, C2, D1, D2, G3 and G4 are negative control groups.
  • This example is a composition for preparing a ferrous amino acid chelate compound which is prepared in the following manner.
  • ferrous sulfate and glycine purity of 98% or more
  • ferrous sulfate and glycine purity of 98% or more
  • the ratio of ferrous and amino acid chelate of the ferrous amino acid chelate is between 1:1 and 1:4; and the obtained composition containing the ferrous amino acid chelate is prepared to have a concentration of 1 per ml.
  • Microgram ie 1 ⁇ g/mL
  • 5 ⁇ g/mL 5 ⁇ g/mL
  • 10 ⁇ g/mL 25 ⁇ g/mL
  • 30 ⁇ g/mL 50 ⁇ g/mL
  • 100 ⁇ g/mL 250 ⁇ g/mL
  • 500 ⁇ g/mL 500 ⁇ g/mL
  • 1000 ⁇ g/mL 1000 ⁇ g/mL
  • the breast cancer cell MDA-MB-231 was contained with 10% fetal bovine serum (FBS), 1% penicillin [100 units/ml (U/mL)]-streptomycin [100 ⁇ g/ml ( ⁇ g/ 500%] (penicillin-streptomycin) and 1% glutamine [200 mmol per liter (mM)] of the Roswell Park Memorial Institute medium (RPMI-1640) cultured at 37 In the incubator of °C and 5% carbon dioxide, subculture was carried out when the cells were attached for 7 to 8 minutes.
  • FBS fetal bovine serum
  • U/mL penicillin [100 units/ml
  • -streptomycin 100 ⁇ g/ml ( ⁇ g/ 500%]
  • glutamine 200 mmol per liter (mM)]
  • the breast cancer cell MDA-MB-231 was seeded in a 6-well plate at a cell density of 3 ⁇ 10 5 cells per well, and treated with a different concentration of the composition A1 prepared in Preparation Example 1 on each other day.
  • the concentration of the composition A1 was 0 ⁇ g/mL (as a control group), 5 ⁇ g/mL, 10 ⁇ g/mL, 25 ⁇ g/mL, and 50 ⁇ g/mL, respectively, and cultured in an incubator at 37 ° C, 5% carbon dioxide for 24 hours.
  • Non-small cell lung cancer cell A549 was cultured at 37 ° C with RPMI-1640 containing 10% fetal bovine serum, 1% penicillin (100 U/mL)-streptomycin (100 ⁇ g/mL), and 1% glutamic acid (200 mM). In a 5% carbon dioxide incubator, subculture is carried out when the cells are attached for 7 to 8 minutes.
  • the non-small cell lung cancer cells A549 were seeded in a 6-well plate at a cell density of 3 ⁇ 10 5 cells per well, and treated with the composition A1 prepared in Preparation Example 1, respectively, on the next day, wherein the composition A1 was The concentrations were 0 ⁇ g/mL (as control group), 100 ⁇ g/mL, 250 ⁇ g/mL, and 500 ⁇ g/mL, respectively, and cultured in an incubator at 37 ° C, 5% carbon dioxide for 24 hours.
  • the cell migration experiment of this example is a 24-well disk using a migration experiment (BD)
  • the lower orifice plate of the product No. 353047) contains a cell culture medium which is more nutritious to the cells, and causes the cells in the upper orifice plate to pass through the polycarbonate membrane at the bottom of the upper orifice plate and migrate to the culture solution of the lower orifice plate. Therefore, the number of cells passing through the polycarbonate membrane to the lower orifice plate reflects the migration ability of the cell strain.
  • the cell migration assay method is as follows:
  • cytosol breast cancer cells MDA-MB-231 containing 1 ⁇ 10 5 cells; non-small cell lung cancer cells A549 containing 1.5 ⁇ 10 5 cells
  • the upper orifice plate is placed in a lower orifice plate containing 600 ⁇ L of 10% FBS;
  • the 24-well plate of the migration experiment was cultured in an incubator at 37 ° C, 5% carbon dioxide for 8 hours to 16 hours (8 hours for breast cancer cells MDA-MB-231; 16 hours for non-small cell lung cancer cells A549) ), allowing cells to migrate;
  • the cell migration experiment of the non-small cell lung cancer cell A549 was treated with the composition A1 at a concentration of 100 ⁇ g/mL, 250 ⁇ g/mL, and 500 ⁇ g/mL, respectively.
  • the cell invasion assay of this example was similar to the cell migration assay of Example 1, with the difference that the device used was an invasion assay 24-well plate (BD). Item No. 354480), the top of the polycarbonate membrane at the bottom of the upper orifice plate is covered with a layer of matrigel, which is a basement membrane matrix extracted from mouse tumors. Matrigel can mimic the extracellular matrix in vivo. Therefore, the cells cannot penetrate at random, and the cells must secrete hydrolase to pass through the polycarbonate film coated with Matrigel. Therefore, the number of cells passing through the matrix gel coated polycarbonate film to the lower pore plate can reflect the species. Invasive ability of cell lines.
  • the cell invasion assay method is as follows:
  • the 24-well plate of the invasion experiment was cultured in an incubator at 37 ° C, 5% carbon dioxide for 20 hours to 24 hours (20 hours for breast cancer cells MDA-MB-231; 24 hours for non-small cell lung cancer cells A549) ), causing cells to invade;
  • Fig. 3A to Fig. 4B The results are shown in Fig. 3A to Fig. 4B.
  • the breast cancer cell MDA-MB-231 experimental group is compared with the control group of breast cancer cell MDA-MB-231 cells.
  • the concentration of 5 ⁇ g/mL, 10 ⁇ g/mL and 25 ⁇ g/mL of composition A1 After treatment with the concentration of 5 ⁇ g/mL, 10 ⁇ g/mL and 25 ⁇ g/mL of composition A1, the number of MDA-MB-231 invasion in breast cancer cells was significantly reduced, and the number of cell invasion in breast cancer cell MDA-MB-231 experimental group
  • the treatment concentration of the composition A1 is increased and decreased.
  • the cell invasion assay of non-small cell lung cancer cells A549 was treated with the compositions A1 at a concentration of 100 ⁇ g/mL, 250 ⁇ g/mL, and 500 ⁇ g/mL, respectively.
  • the number of A549 invasion of non-small cell lung cancer cells was significantly reduced compared with the control group, and the amount of cell invasion was inversely proportional to the treatment concentration of composition A1. Therefore, the results of Example 2 show that the composition A1 has an effect of inhibiting invasion of cancer cells.
  • the breast cancer cell MDA-MB-231 of Preparation Example 2 was seeded in a 6-well plate at a cell density of 3 ⁇ 105 cells per well, and treated with the composition A1 prepared in Preparation Example 1 every other day, wherein The breast cancer cells MDA-MB-231 were treated with a composition A1 concentration of 100 ⁇ g/mL, and cancer cells of the untreated composition A1 were used as a control group, and cultured in an incubator at 37 ° C, 5% carbon dioxide for 24 hours.
  • wash buffer 1 wash buffer 1
  • wash buffer 2 wash buffer 2
  • FIG. 5A and FIG. 5B The experimental results are shown in FIG. 5A and FIG. 5B.
  • the coordinate positions of the MMP-related protein and the TIMP-related protein represented in FIG. 5A are shown in the table of FIG. 5B, and the breast cancer cell MDA-MB- is treated with the composition A1 concentration of 100 ⁇ g/mL.
  • the MMP-1 expression in the E1 and E2 positions on the right is significantly higher than that in the control group (ie, E1 and E2 positions on the left).
  • the performance was reduced; and compared with the control group, MMP-3 (ie, G1 and G2 positions in the right image) and TIMP-2 (ie, E3 and E4 positions in the right image) of the breast cancer cell MDA-MB-231 experimental group
  • the amount was also slightly reduced, indicating that the composition A1 described in the present invention can inhibit the expression of MMP-1, MMP-3 and TIMP-2 of cancer cells, and suggests that the composition A1 may inhibit the expression of MMP-related proteins or TIMP-related proteins. And reduce the ability of cancer cells to invade.

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Abstract

一种含有亚铁氨基酸螯合物的组合物用于制造防止癌症转移的医药品的用途，其中医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及药学上可接受的载体。所述含有亚铁氨基酸螯合物的组合物制造而得的医药品具有防止癌症转移的效果。

Description

含有亚铁氨基酸螯合物的组合物用于制造防止癌症转移的医药品的用途 技术领域
本发明是关于含有亚铁氨基酸螯合物的组合物的用途，特别是其用于制造防止癌症转移的医药品的用途。
背景技术
癌症转移(cancer metastasis)，也称恶性转移，其是癌症无法治愈的主要原因。癌症转移是指癌细胞自原始发生的位置转移至体内他处器官组织继续生长，使得癌症治疗更为困难，通常已无法根除，仅能进行放射线治疗或化疗抑制癌细胞继续增生以延长患者生命。
癌症转移是极为复杂的过程，目前有研究指出癌细胞可以转移至其他器官组织的主要原因为癌细胞具有侵袭(invasion)的能力，癌细胞异常活化并大量分泌基质金属蛋白水解酶(matrix metalloproteinase，MMP)，基质金属蛋白水解酶可分解细胞外基质(extracellular matrix，ECM)，得以让癌细胞侵袭周围组织并转移至其他器官，其中MMP-1与MMP-3已被证实与癌细胞转移息息相关。有研究指出，发炎性细胞激素(inflammatory cytokines)会刺激MMP的合成，此外，MMP亦会受到金属蛋白水解酶组织抑制因子(tissue inhibitor of metalloproteinase，TIMP)抑制；然而如金属蛋白水解酶组织抑制因子-2(tissue inhibitor of metalloproteinase-2，TIMP-2)虽具有抑制MMP的作用，却还有文献指出TIMP-2的表现量与癌细胞转移成正相关。尽管癌症转移是造成癌症患者死亡的主要原因，然而目前的抗癌相关研究依旧是以抑制原位癌生长为主要研究方向。
发明内容
鉴于此，由于癌症患者具有对于抑制癌症转移的需求，本发明的目的在于提供一种含有亚铁氨基酸螯合物的组合物用于制造防止癌症转移的医药品的用途，其中含有亚铁氨基酸螯合物的组合物具有抑制 癌细胞迁移、抑制癌细胞侵袭、抑制癌细胞MMP相关蛋白质表现或抑制癌细胞TIMP相关蛋白质表现的功效。
为达到上述的发明目的，本发明所采用的技术手段为提供一种含有亚铁氨基酸螯合物的组合物用于制造防止癌症转移的医药品的用途，其中医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及其药学上可接受的载体。
依据本发明，“含有亚铁氨基酸螯合物的组合物”是由无机铁与氨基酸混合所制得的含有亚铁氨基酸螯合物(ferrous amino acid chelate)的组合物。
优选地，所述含有亚铁氨基酸螯合物的组合物中的亚铁氨基酸螯合物的亚铁与氨基酸的螯合比例介于1：1至1：4之间。
优选地，所述含有亚铁氨基酸螯合物的组合物中的亚铁氨基酸螯合物的亚铁与氨基酸的螯合比例介于1：1.5至1：2.5之间。
优选地，所述含有亚铁氨基酸螯合物的组合物的有效剂量介于mg/kg/日至mg/kg/日。
优选地，所述含有亚铁氨基酸螯合物的组合物的有效剂量介于0.2mg/kg/日至200mg/kg/日。
优选地，所述含有亚铁氨基酸螯合物的组合物的有效剂量介于1mg/kg/日至100mg/kg/日。
依据本发明，有效剂量的计算方式是以本说明书的实施方式的含有亚铁氨基酸螯合物的组合物的浓度1μg/mL至1000μg/mL，以65公斤人体体重中血液量约占体重的1/13的相对血液浓度作为换算而得；具体而言，有效剂量为0.2mg/kg/日即是以含有亚铁氨基酸螯合物的组合物的浓度1μg/mL乘13/65而得，以此类推，有效剂量为200mg/kg/日即是以含有亚铁氨基酸螯合物的组合物的浓度1000μg/mL乘13/65而得，故由含有亚铁氨基酸螯合物的组合物的浓度1μg/mL至1000μg/mL换算的有效剂量为0.2mg/kg/日至200mg/kg/日。
更优选地，所述含有亚铁氨基酸螯合物的组合物是由无机铁与氨基酸混合并历经60℃至90℃加热8小时至48小时所制得的含有亚铁氨基酸螯合物的组合物，其中无机铁与氨基酸的重量比例介于1：1.2至1：1.5之间。
更优选地，所述无机铁是硫酸亚铁、氯化亚铁、焦磷酸亚铁或其组合；该氨基酸是甘氨酸。
更优选地，所述含有亚铁氨基酸螯合物的组合物是含有重量百分比为95％至100％的亚铁甘氨酸螯合物；又更优选地，重量百分比为98％至99.9％的亚铁甘氨酸螯合物。
更优选地，所述含有亚铁氨基酸螯合物的组合物中包括还原剂，该还原剂包括，但不限于抗坏血酸(ascorbic acid)、柠檬酸(citric acid)、乙酸(acetic acid)、丙酸(propionic acid)、丁酸(butyric acid)、乳酸(lactic acid)、羟琥珀酸(malic acid)、磺酸(sulfonic acid)、丁二酸(succinic acid)或其组合。
本发明所述“防止癌症转移”是指有效控制癌细胞自原始发生的部位转移至体内他处器官组织继续生长，其中防止癌症转移包括但不限于如本发明所例示者，防止癌症转移是指抑制癌细胞迁移(migration)、抑制癌细胞侵袭(invasion)、抑制癌细胞MMP相关蛋白质、或抑制癌细胞TIMP相关蛋白质的表现量。
本发明所述“有效剂量”是指在剂量上及对于所需要的时间段而言对达成所要减缓或防止癌症转移的量；依据本发明，是指透过施用特定范围量的含有亚铁氨基酸螯合物的组合物，能够使得肺癌或乳腺癌的癌症转移能力下降，或是抑制癌细胞迁移、抑制癌细胞侵袭、抑制癌细胞MMP相关蛋白质或抑制癌细胞TIMP相关蛋白质的表现量；依据本发明，另指能减少癌细胞迁移或减少癌细胞侵袭的功效。
本发明所述“医药学上可接受的载体”包含，但不限于溶剂(solvent)、乳化剂(emulsifier)、悬浮剂(suspending agent)、分解剂(decomposer)、黏结剂(binding agent)、赋形剂(excipient)、稳定剂(stabilizing agent)、螯合剂(chelating agent)、稀释剂(diluent)、胶凝剂(gelling agent)、防腐剂(preservative)、润滑剂(lubricant)、表面活性剂(surfactant)，及其他类似或适用本发明的载体。
本发明所述“医药品”可以多种形式存在，该等形式包含，但不限于液体、半固体及固体药剂形式，诸如溶液(solution)、乳剂(emulsion)、悬浮液(suspension)、粉末(powder)、锭剂(tablet)、丸剂(pill)、口含锭(lozenge)、片剂(troche)、口嚼胶(chewing gum)、胶囊(slurry)、脂质体、 栓剂以及其他类似或适用本发明的剂型。
优选地，所述医药品是经肠道的或非经肠道的剂型。
更优选地，所述该经肠道的剂型是口服剂型，其口服剂型是溶液、乳剂、悬浮液、粉末、锭剂、丸剂、口含锭、片剂、口嚼胶或胶囊。
优选地，所述癌症包括，但不限于黑色素瘤(melanoma)、肝癌、结肠癌(colon cancer)、肺癌、胃癌(gastric cancer)、食道癌(esophageal cancer)、乳癌(breast cancer)、前列腺癌(prostate cancer)、血癌(leukemia)、脑部肿瘤(brain tumor)、低度星状细胞瘤(low-grade astrocytoma)、高度星状细胞瘤(high-grade astrocytoma)、垂体腺瘤(pituitary adenoma)、脑脊髓膜瘤(meningioma)、中枢神经淋巴瘤(CNS lymphoma)、寡树突神经胶细胞瘤(oligodendroglioma)、颅咽管瘤(craniopharyngioma)、室管膜瘤(ependymoma)、胶质细胞肿瘤(brain stem tumor)、头颈瘤(head and neck tumor)、喉癌(laryngeal cancer)、口咽癌(oropharyngeal cancer)、鼻咽癌(nasopharyngeal tumor)、唾液腺肿瘤(salivary gland tumor)、下咽癌(hypopharyngeal cancer)、甲状腺癌(thyroid cancer)、口腔肿瘤(oral cavity tumor)、胸廓肿瘤(chest wall tumors)、小细胞肺癌(small cell lung cancer)、非小细胞肺癌(non-small cell lung cancer,NSCLC)、胸腺瘤(thymoma)、纵隔肿瘤(mediastinal tumor)、男性乳癌(male breast cancer)、腹骨盆(abdomen-pelvis tumor)、肝腺癌(liver adenocarcinoma)、肝细胞癌(hepatoma)、胆囊癌(gallbladder cancer)、胆道癌(biliary tract cancer)、胰脏癌(pancreatic cancer)、小肠肿瘤(small intestinal tumor)、大肠肿瘤(large intestinal tumor)、肛门癌(anal cancer)、膀胱癌(bladder cancer)、肾细胞癌(renal cell carcinoma)、子宫颈癌(cervix cancer)、子宫内膜癌(endometrial cancer)、卵巢癌(ovarian cancer)、子宫肉瘤(uterine sarcoma)或皮肤癌(skin cancer)。
更优选地，所述癌症转移是乳腺癌或肺癌。
优选地，所述医药品是用于抑制癌细胞迁移、抑制癌细胞侵袭、抑制基质金属蛋白水解酶相关蛋白质或抑制金属蛋白水解酶组织抑制因子。
更优选地，所述医药品是用于抑制基质金属蛋白水解酶-1、基质金属蛋白水解酶-3或金属蛋白水解酶组织抑制因子-2。
本发明所述含有亚铁氨基酸螯合物的组合物具有抑制癌症转移的效果，且本发明证实处理含有亚铁氨基酸螯合物的组合物中可以有效抑制癌细胞迁移、抑制癌细胞侵袭、抑制癌细胞MMP相关蛋白质及抑制癌细胞TIMP相关蛋白质的表现量。
附图说明
以下附图仅旨在对本发明做示意性说明和解释，并不限定本发明的范围。其中：
图1A是本发明分别以浓度为0μg/mL(控制组)、5μg/mL、10μg/mL及25μg/mL的组合物A1处理乳腺癌细胞MDA-MB-231后，乳腺癌细胞MDA-MB-231以40倍放大倍率观察迁移的影像。
图1B是图1A的乳腺癌细胞MDA-MB-231迁移影像经量化后所得的柱状图(以控制组为基准)。
图2A是本发明分别以浓度为0μg/mL(控制组)、100μg/mL、250μg/mL及500μg/mL的组合物A1处理非小细胞肺癌细胞A549后，非小细胞肺癌细胞A549以40倍放大倍率观察的迁移的影像。
图2B是图2A的非小细胞肺癌细胞A549迁移影像经量化后所得的柱状图(以控制组为基准)。
图3A是本发明分别以浓度为0μg/mL(控制组)、10μg/mL、25μg/mL及50μg/mL的组合物A1处理乳腺癌细胞MDA-MB-231后，乳腺癌细胞MDA-MB-231以40倍放大倍率观察的侵袭的影像。
图3B是图3A的乳腺癌细胞MDA-MB-231侵袭影像经量化后所得的柱状图(以控制组为基准)。
图4A是本发明分别以浓度为0μg/mL(控制组)、100μg/mL、250μg/mL及500μg/mL的组合物A1处理非小细胞肺癌细胞A549后，非小细胞肺癌细胞A549以40倍放大倍率观察的侵袭的影像。
图4B是图4A的非小细胞肺癌细胞A549侵袭影像经量化后所得的柱状图(以控制组为基准)。
图5A是本发明分别以浓度为0μg/mL(控制组)、100μg/mL的组合物A1处理乳腺癌细胞MDA-MB-231后，乳腺癌细胞MDA-MB-231分泌的MMP相关蛋白质表现量；左栏为控制组的MMP相关蛋白质及 TIMP相关蛋白质表现量；右栏为乳腺癌细胞MDA-MB-231实验组的MMP相关蛋白质及TIMP相关蛋白质表现量。
图5B是图5A所实验的MMP抗体芯片所探测的MMP相关蛋白质及TIMP相关蛋白质的坐标位置；Pos(即坐标A1、A2、B1、B2、H3及H4)为正对照组，Neg(即坐标C1、C2、D1、D2、G3及G4)为负对照组，当Pos的位置为均匀表现蛋白质(黑点)，Neg的位置为空白，通过Pos、Neg作为该MMP抗体芯片的MMP相关蛋白质及TIMP相关蛋白质的表现量的对照。
具体实施方式
以下配合附图及本发明的优选实施例，进一步阐述本发明为达成预定发明目的所采取的技术手段。
制备例1 制备含有亚铁氨基酸螯合物的组合物
本实施例是用以制备含有亚铁氨基酸螯合物的组合物，其是以下述方式制备。首先，将硫酸亚铁与甘氨酸(纯度98％以上)以重量比1:1.3混合并历经60℃至90℃加热8小时至48小时，以获得该含有亚铁氨基酸螯合物的组合物，其中亚铁氨基酸螯合物的亚铁与氨基酸螯合比例是介于1：1至1：4之间；再将所获得的含有亚铁氨基酸螯合物的组合物调制成浓度为每毫升含有1微克(即1μg/mL)、5μg/mL、10μg/mL、25μg/mL、30μg/mL、50μg/mL、100μg/mL、250μg/mL、500μg/mL以及1000μg/mL，并以A1代称该组合物。
制备例2 培养乳腺癌细胞MDA-MB-231
将乳腺癌细胞MDA-MB-231以含有10％胎牛血清(fetal bovine serum,FBS)、1％青霉素[100单位/毫升(U/mL)]-链霉素[100微克/毫升(μg/mL)](penicillin-streptomycin)以及1％麸酰胺酸(glutamine)[200毫摩尔每升(mM)]的洛斯维帕克纪念研究所培养基(Roswell Park Memorial Institute medium,RPMI-1640)培养于37℃、5％二氧化碳的培养箱中，待细胞贴附7至8分满时，再进行继代培养。
制备例3 以组合物A1处理乳腺癌细胞MDA-MB-231
将乳腺癌细胞MDA-MB-231以每孔3×105个细胞的细胞密度种于6孔盘中，并于隔日分别加入不同浓度的由制备例1所制得的组合物A1进行处理，其中组合物A1的浓度分别为0μg/mL(作为控制组)、5μg/mL、10μg/mL、25μg/mL及50μg/mL，并于37℃、5％二氧化碳的培养箱中培养24小时。
制备例4 培养非小细胞肺癌细胞A549
将非小细胞肺癌细胞A549以含有10％胎牛血清、1％青霉素(100U/mL)-链霉素(100μg/mL)以及1％麸酰胺酸(200mM)的RPMI-1640培养于37℃、5％二氧化碳的培养箱中，待细胞贴附7至8分满时，再进行继代培养。
制备例5 以组合物A1处理肺癌细胞A549
将非小细胞肺癌细胞A549以每孔3×105个细胞的细胞密度种于6孔盘中，并于隔日分别加入由制备例1所制得的组合物A1进行处理，其中组合物A1的浓度分别为0μg/mL(作为控制组)、100μg/mL、250μg/mL及500μg/mL，并于37℃、5％二氧化碳的培养箱中培养24小时。
实施例1 组合物A1对于癌细胞迁移(cell migration)的影响
本实施例的细胞迁移实验是利用迁移实验24孔盘(BD
Figure PCTCN2016108366-appb-000001
货品编号353047)的下层孔盘盛装对于细胞较为营养的细胞培养液，趋使上层孔盘内的细胞穿过上层孔盘底部的聚碳酸酯膜，迁移到下层孔盘的培养液。因此，通过聚碳酸酯膜至下层孔盘的细胞数量可反映出该种细胞株的迁移能力。细胞迁移实验方法如下所述：
(1)以制备例3的乳腺癌细胞MDA-MB-231及制备例4的非小细胞肺癌细胞A549分别以组合物A1处理24小时后，各别收集每孔的细胞并以PBS润洗2次，将细胞打散悬浮于1mL不含有或含有相同处理剂量组合物A1的无血清的RPMI-1640细胞培养液中进行细胞饥饿(cell starvation)2小时；
(2)各取300μL细胞液(乳腺癌细胞MDA-MB-231含有1×105个细 胞；非小细胞肺癌细胞A549含有1.5×105个细胞)各别加入迁移实验24孔盘的上层孔盘中，而后将上层孔盘放入含有600μL的10％FBS的下层孔盘中；
(3)将该迁移实验24孔盘置于37℃、5％二氧化碳的培养箱中培养8小时至16小时(乳腺癌细胞MDA-MB-231为8小时；非小细胞肺癌细胞A549为16小时)，使细胞进行迁移；
(4)取出上层孔盘并将培养液抽干并将上层孔盘放入甲醇(methanol)中8分钟进行细胞固定，再将上层孔盘取出风干；
(5)以10倍稀释浓度的吉姆萨染液(Giemsa solution)将上层孔盘的细胞进行染色1小时，再使用棉花棒将上层孔盘底部内的细胞擦拭干净；
(6)量化统计自上层孔盘穿过聚碳酸酯膜并黏附于聚碳酸酯膜下方的细胞数量。
结果请参阅图1A至图2B所示，请先参阅图1A及图1B，与控制组的乳腺癌细胞MDA-MB-231细胞数量为基准相比，乳腺癌细胞MDA-MB-231实验组分别以浓度5μg/mL、10μg/mL及25μg/mL的组合物A1处理后，乳腺癌细胞MDA-MB-231迁移的数量均显著减少，且乳腺癌细胞MDA-MB-231实验组细胞迁移数量随着组合物A1的处理浓度增加而减少；请参阅图2A及图2B，分别以浓度100μg/mL、250μg/mL及500μg/mL的组合物A1处理非小细胞肺癌细胞A549后，其细胞迁移实验结果与乳腺癌细胞MDA-MB-231实验组相同，非小细胞肺癌细胞A549迁移的数量相较于其控制组均显著减少，且细胞迁移数量与组合物A1的处理浓度呈反比。由此可知，组合物A1具有抑制癌细胞迁移的效果。
实施例2 组合物A1对于癌细胞侵袭(cell invasion)的影响
本实施例的细胞侵袭实验类似于实施例1的细胞迁移实验，其差别在于所使用的器材为侵袭实验24孔盘(BD
Figure PCTCN2016108366-appb-000002
货品编号354480)，其上层孔盘底部的聚碳酸酯膜上方多覆盖了一层基质胶(matrigel)，该基质胶是由小鼠肿瘤所提取的基底膜基质，基质胶可模拟体内细胞外基质，使得细胞无法随意穿透，细胞必须分泌水解酶才 能穿过覆有基质胶的聚碳酸酯膜，因此，通过覆有基质胶的聚碳酸酯膜至下层孔盘的细胞数量可反映出该种细胞株的侵袭能力。细胞侵袭实验方法如下所述：
(1)以制备例3的乳腺癌细胞MDA-MB-231以组合物A1处理24小时后，将各别收集每孔的细胞并以PBS润洗两次后，将细胞打散悬浮于1mL不含有或含有相同处理剂量组合物A1的无血清的RPMI中进行细胞饥饿(cell starvation)2小时；
(2)加入500μL无血清的RPMI-1640培养液于侵袭实验24孔盘的上层孔盘中，并放置于培养箱培养2小时使得上层孔盘底部的基质胶浸润；
(3)各取300μL细胞液(乳腺癌细胞MDA-MB-231含有6×104个细胞；非小细胞肺癌细胞A549含有3×105个细胞)各别加入上层孔盘中，而后将上层孔盘放入含有600μL的10％FBS的下层孔盘中；
(4)将该侵袭实验24孔盘置于37℃、5％二氧化碳的培养箱中培养20小时至24小时(乳腺癌细胞MDA-MB-231为20小时；非小细胞肺癌细胞A549为24小时)，使细胞进行侵袭；
(5)取出上层孔盘并将培养液抽干并将上层孔盘放入甲醇(methanol)中8分钟进行细胞固定，再将上层孔盘取出风干；
(6)以10倍稀释的吉姆萨染液(Giemsa solution)将上层孔盘的细胞进行染色1小时，再使用棉花棒将上层孔盘底部内的基质胶及细胞擦拭干净；
(7)量化统计自上层孔盘穿过覆有基质胶的聚碳酸酯膜并黏附于聚碳酸酯膜下方的细胞数量。
结果如图3A至图4B所示，首先由图3A及图3B可看出与控制组的乳腺癌细胞MDA-MB-231细胞数量为基准相比，乳腺癌细胞MDA-MB-231实验组分别以浓度5μg/mL、10μg/mL及25μg/mL组合物A1处理后，乳腺癌细胞MDA-MB-231侵袭的数量均显著减少，且乳腺癌细胞MDA-MB-231实验组细胞侵袭数量随着组合物A1的处理浓度增加而减少。
请参阅图4A及图4B，分别以浓度100μg/mL、250μg/mL及500μg/mL组合物A1处理非小细胞肺癌细胞A549后，其细胞侵袭实验结 果与乳腺癌细胞MDA-MB-231实验组相同，非小细胞肺癌细胞A549侵袭的数量相较于其控制组均显著减少，且细胞侵袭数量与组合物A1的处理浓度呈反比。因此，实施例2的结果显示组合物A1具有抑制癌细胞侵袭的效果。
实施例3 组合物A1对于癌细胞分泌MMP相关蛋白质及TIMP相关蛋白质的影响
将制备例2的乳腺癌细胞MDA-MB-231以每孔3×105个细胞的细胞密度种于6孔盘中，并于隔日加入由制备例1所制得的组合物A1进行处理，其中乳腺癌细胞MDA-MB-231以组合物A1浓度100μg/mL处理，并以未处理组合物A1的癌细胞作为控制组，并于37℃、5％二氧化碳的培养箱中培养24小时。经24小时处理后，分别收集各孔的细胞培养液并加入1倍苯甲基磺酰氟(Phenylmethanesulfonyl fluoride，PMSP)后，离心5分钟移除细胞并取用细胞培养液为待测检体，以MMP抗体芯片(购自于abcam公司；货品编号ab134004)进行实验，本实施例的操作方法是采用试剂组所提供的步骤进行，操作方法如下所述：
(1)将芯片各别放入8孔盘中，加入2mL的阻隔缓冲液(blocking buffer)，于室温下震荡30分钟；
(2)移除阻隔缓冲液，而后各别加入1mL的待测检体(各组细胞培养液)，于室温下震荡反应2小时；
(3)待反应完毕后，移除孔盘中的细胞培养液；
(4)加入2mL的润洗缓冲液1(wash buffer 1)，于室温下震荡清洗芯片5分钟后，移除润洗缓冲液1，此步骤重复2次；
(5)加入2mL的润洗缓冲液2(wash buffer 2)，于室温下震荡清洗芯片5分钟后，移除润洗缓冲液1，此步骤重复1次；
(6)加入1mL的一级抗体：生物素连结抗-细胞激素(biotin-conjugated anti-cytokines)，于室温震荡2小时；
(7)移除一级抗体，再重复步骤(4)及步骤(5)以清洗芯片。
(8)加入2mL的二级抗体：辣根过氧化酶连结亲合素(HRP-conjugated streptavidin)，于室温震荡2小时；
(9)移除二级抗体，再重复步骤(4)及步骤(5)以清洗芯片。
(10)将各芯片自8孔盘内取出，移除芯片上多余液体后，于芯片表面上淋上500μL的显影剂，静置2分钟后以X-ray底片呈色。
实验结果如图5A及图5B所示，图5A所表现的MMP相关蛋白质及TIMP相关蛋白质的坐标位置请参阅图5B表格所示，以组合物A1浓度100μg/mL处理乳腺癌细胞MDA-MB-231后，如图5A右图的乳腺癌细胞MDA-MB-231实验组，其中右图E1及E2位置的MMP-1的表现量明显比控制组的MMP-1(即左图E1及E2位置)表现量降低；且相较于控制组，乳腺癌细胞MDA-MB-231实验组的MMP-3(即右图G1及G2位置)及TIMP-2(即右图E3及E4位置)的表现量也有些许减少，表示本案所述组合物A1可抑制癌细胞的MMP-1、MMP-3及TIMP-2的表现，并且暗示组合物A1可能是通过抑制MMP相关蛋白或TIMP相关蛋白质的表现量而降低癌细胞侵袭的能力。
以上所述仅是本发明的优选实施例而已，并非对本发明做任何形式上的限制，虽然本发明已以优选实施例公开如上，然而并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明技术方案的范围内，当可利用上述公开的技术内容作出些许改动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。

Claims (14)

  1. 一种含有亚铁氨基酸螯合物的组合物用于制造防止癌症转移的医药品的用途，其中医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及其药学上可接受的载体。
  2. 根据权利要求1所述的用途，其特征在于，所述含有亚铁氨基酸螯合物的组合物中的亚铁氨基酸螯合物的亚铁与氨基酸的螯合比例介于1：1至1：4之间。
  3. 根据权利要求1所述的用途，其特征在于，所述含有亚铁氨基酸螯合物的组合物中的亚铁氨基酸螯合物的亚铁与氨基酸的螯合比例介于1：1.5至1：2.5之间。
  4. 根据权利要求1所述的用途，其特征在于，所述含有亚铁氨基酸螯合物的组合物的有效剂量介于0.2mg/kg/日至200mg/kg/日。
  5. 根据权利要求1所述的用途，其特征在于，所述含有亚铁氨基酸螯合物的组合物的有效剂量介于1mg/kg/日至100mg/kg/日。
  6. 根据权利要求1至5中任一项所述的用途，其特征在于，所述含有亚铁氨基酸螯合物的组合物是由无机铁与氨基酸混合并历经60℃至90℃加热8小时至48小时所制得的含有亚铁氨基酸螯合物的组合物，其中无机铁与氨基酸的重量比例介于1：1.2至1：1.5之间。
  7. 根据权利要求6所述的用途，其特征在于，所述无机铁是硫酸亚铁、氯化亚铁、焦磷酸亚铁或其组合；该氨基酸是甘氨酸。
  8. 根据权利要求6所述的用途，其特征在于，所述含有亚铁氨基酸螯合物的组合物中包括还原剂，该还原剂是抗坏血酸、柠檬酸、乙酸、丙酸、丁酸、乳酸、羟琥珀酸、磺酸、丁二酸或其组合。
  9. 根据权利要求1所述的用途，其特征在于，所述医药品是经肠道的或非经肠道的剂型。
  10. 根据权利要求9所述的用途，其特征在于，所述经肠道的剂型是口服剂型，其口服剂型是溶液、乳剂、悬浮液、粉末、锭剂、丸剂、口含锭、片剂、口嚼胶或胶囊。
  11. 根据权利要求1所述的用途，其特征在于，所述癌症转移是黑色素瘤、肝癌、结肠癌、肺癌、胃癌、食道癌、乳癌、前列腺癌、血癌、脑部肿瘤、低度星状细胞瘤、高度星状细胞瘤、垂体腺瘤、脑脊髓膜瘤、中枢神经淋巴瘤、寡树突神经胶细胞瘤、颅咽管瘤、室管膜瘤、胶质细胞肿瘤、头颈瘤、喉癌、口咽癌、鼻咽癌、唾液腺肿瘤、下咽癌、甲状腺癌、口腔肿瘤、胸廓肿瘤、小细胞肺癌、非小细胞肺癌、胸腺瘤、纵隔肿瘤、男性乳癌、腹骨盆、肝腺癌、肝细胞癌、胆囊癌、胆道癌、胰脏癌、小肠肿瘤、大肠肿瘤、肛门癌、膀胱癌、肾细胞癌、子宫颈癌、子宫内膜癌、卵巢癌、子宫肉瘤或皮肤癌。
  12. 根据权利要求1所述的用途，其特征在于，所述癌症转移是乳腺癌或肺癌。
  13. 根据权利要求1所述的用途，其特征在于，所述医药品是用于抑制癌细胞迁移、抑制癌细胞侵袭、抑制基质金属蛋白水解酶相关蛋白质或抑制金属蛋白水解酶抑制因子相关蛋白质。
  14. 根据权利要求13所述的用途，其特征在于，所述医药品是抑制基质金属蛋白水解酶-1、基质金属蛋白水解酶-3或金属蛋白水解酶抑制因子-2。
PCT/CN2016/108366 2016-12-02 2016-12-02 含有亚铁氨基酸螯合物的组合物用于制造防止癌症转移的医药品的用途 WO2018098804A1 (zh)

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