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WO2009107322A1 - Composition pharmaceutique destinée au traitement du cancer - Google Patents

Composition pharmaceutique destinée au traitement du cancer Download PDF

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WO2009107322A1
WO2009107322A1 PCT/JP2009/000310 JP2009000310W WO2009107322A1 WO 2009107322 A1 WO2009107322 A1 WO 2009107322A1 JP 2009000310 W JP2009000310 W JP 2009000310W WO 2009107322 A1 WO2009107322 A1 WO 2009107322A1
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cancer
dfo
pharmaceutical composition
effect
deferoxamine
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Japanese (ja)
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坂井田功
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Yamaguchi University NUC
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Yamaguchi University NUC
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition that can be used as a therapeutic agent for cancer that requires iron ions for growth, and more specifically, has been used as a therapeutic agent for hyperchromatosis.
  • a pharmaceutical composition for the treatment of cancers that require iron ions for growth particularly a composition for the treatment of liver cancers such as hepatocellular carcinoma, comprising deferoxamine, an iron chelator, as an active ingredient It relates to things.
  • Liver cancer is a general term for cancer that occurs in the liver, and is classified into primary liver cancer that occurs when liver cells become cancerous and metastatic liver cancer that results from metastasis of cancer that occurs elsewhere.
  • Hepatocellular carcinoma (HCC) which occurs when hepatocytes become cancerous, accounts for 90% of primary liver cancer, and most hepatocellular cancers are known to occur from chronic hepatitis through cirrhosis. Yes. Onset is common among men in their 50s and 60s, and about 95% of hepatocellular carcinomas are characterized by infection with hepatitis B virus (HBV; 25%) or hepatitis C virus (HCV; 70%). It is.
  • Liver cancer is the fourth most common cancer in Japan and the third highest number of deaths (2004: National Cancer Center statistics). Efforts have been made.
  • the internal treatment is percutaneous ethanol injection (direct injection of pure ethanol into the liver and cancer tissue).
  • Necrosis percutaneous radiocautery therapy (necrosis of cancer tissue by direct irradiation of radio waves), hepatic artery embolization therapy (embedding the hepatic artery and cutting off blood supply to the cancer) Necrosis), chemotherapy by administration of various anticancer agents, and the like, and in fact, treatments combining these as necessary are performed.
  • liver cancer is recognized as an indication for liver cancer in 2007 (insurance coverage) anti-metabolites such as alkylating agents cyclophosphamide and 5-fluorouracil, doxorubicin, mitomycin C, etc.
  • antibiotics and platinum preparations such as cisplatin. Development was anxious.
  • Deferoxamine and some of its derivatives are drugs that have an iron chelating action and are known to be effective against hemochromatosis, a disease in which iron (iron ions) are present in excess in the body ( Patent Documents 1 and 2). Furthermore, a metal chelating agent containing deferoxamine is used for cancer treatment as an apoptosis-inducing compound (Patent Documents 3 and 4), a ribonucleotide reductase inhibitor (Patent Document 5), or an inhibitor of fibrous adhesions (Patent Document 6). The possibility of use is suggested.
  • Patent Document 7 as a result of examining the effects of a cytostatic and deferoxamine on a 6-week-old congenital acute leukemia patient in whom the effect of chemotherapy was not observed and a mouse transplanted with Lewis lung cancer cells, deferoxamine or cell proliferation was examined. When the inhibitor was administered alone, no effect was observed, but it was clarified that a synergistic antiproliferative effect was observed by administering deferoxamine in combination with a cell growth inhibitor.
  • Patent Document 8 several types of established tumor cells (breast cancer, colorectal cancer, erythroleukemia, sarcoma cancer, scaly cancer, testicular cancer, ovarian cancer, and bladder cancer-derived cell lines) are cultured in vitro.
  • an antigen fork preferably a bispecific antibody
  • deferoxamine or cisplatin a bispecific antibody
  • the effect of deferoxamine alone is to obtain an effect of stopping or delaying the growth of cultured cancer cells or an effect of reducing by about 10-20% (317G5-454A12 strain).
  • the effect of deferoxamine is only to increase the effect of the antigen fork by using it together with the antigen fork. It was.
  • Non-patent Document 1 discloses that deferoxamine inhibits and reduces liver damage caused by acetaminophen and pre-tumor lesions in a rat diet model (Cholin-deficient L-amino acid defined diet) even in the rat body.
  • the present invention focuses on deferoxamine as a therapeutic agent for cancer (particularly liver cancer) that requires iron ions for growth, and includes deferoxamine, a derivative thereof, or a salt thereof as an active ingredient.
  • the purpose is to provide a pharmaceutical composition for the treatment of cancer.
  • the present inventor may progress from cirrhosis to liver cancer in patients with hemochromatosis, which is a disease in which iron is excessively deposited in the liver, without treatment. Focusing on the findings, he found that hepatocytes around carcinogenic lesions had excessive iron deposition, whereas hepatic cancer sites (inside liver cancer cells) no longer had excessive iron deposition. . In addition, it is hypothesized that iron is necessary for the growth of hepatoma cells, and deferoxamine, which has an iron chelating effect, is effective as an inhibitor of liver cancer. As a result, the present invention has been completed.
  • the present invention includes (1) deferoxamine (Deferoxamine), a derivative thereof, and a pharmacologically acceptable salt thereof as an active ingredient, and has an iron ion requirement for growth.
  • a pharmaceutical composition for treating cancer (2) a pharmaceutical composition according to (1) above, wherein the cancer requiring iron ion for growth is liver cancer, and (3) the liver
  • the pharmaceutical composition according to (1) or (2) above, which is a hepatocyte cancer, or (4) a pharmacologically acceptable salt is an organic acid salt
  • the pharmaceutical composition according to any one of (1) to (3) above, or (5) the organic acid salt is an organic acid salt having 2 or 1 carbon atoms, 4)
  • the present invention also provides (9) a method for treating cancer having an iron ion requirement for growth, comprising administering the pharmaceutical composition according to any one of (1) to (8) above, 10)
  • the method of the above-mentioned (9), wherein the cancer requiring iron ion for proliferation is liver cancer, or (11) the liver cancer is characterized by hepatocellular carcinoma.
  • the above (9) or (10) relates to the treatment method.
  • the present invention relates to (12) use of the pharmaceutical composition according to any one of (1) to (8) above in the manufacture of a medicament for treating cancer having an iron ion requirement for proliferation,
  • the use according to (12) above, wherein the cancer having an iron ion requirement for proliferation is liver cancer, or (14) the above, wherein the liver cancer is hepatocellular carcinoma ( The use according to 12) or (13).
  • Deferoxamine which is an active ingredient of the present invention, has already been established in safety, such as being used as a hemochromatosis therapeutic drug, and is expected to greatly shorten clinical trials, and far more than existing anticancer drugs. Therefore, it is possible to effectively proceed with treatment without lowering the quality of life (QOL) of the patient. Furthermore, combining with other cancer treatments other than chemotherapy is expected to increase the cancer treatment effect.
  • the effect of deferoxamine (DFO) on Huh-7 cells is shown.
  • the effect of DFO on HepG2 cells is shown.
  • the effect of DFO on HLF cells is shown.
  • the effect of 5-FU on Huh-7 cells is shown.
  • the effect of 5-FU on HepG2 cells is shown.
  • the effect of 5-FU on HLF cells is shown.
  • the effect of ADM on Huh-7 cells is shown.
  • the effect on Huh-7 cells by the combined use of DFO and 5-FU is shown.
  • the effect to HepG2 cell by combined use of DFO and 5-FU is shown.
  • the effect on HLF cells by the combined use of DFO and 5-FU is shown.
  • the effect on Huh-7 cells by the combined use of DFO and ADM is shown.
  • the time-dependent change of the expression level of the tumor marker by DFO processing is shown.
  • the CT image before the treatment in case 1 is shown.
  • the CT image after the treatment in case 1 is shown.
  • the transition of the tumor marker after DFO administration in case 1 is shown.
  • the transition of the tumor marker after DFO administration in case 2 is shown.
  • the transition of the tumor marker after DFO administration in case 3 is shown.
  • the transition of the tumor marker after DFO re-administration in case 3 is shown.
  • the pharmaceutical composition for the treatment of cancer requiring iron ions for growth of the present invention includes at least one of deferoxamine, its derivatives, and pharmacologically acceptable salts as an active ingredient.
  • the deferoxamine is not particularly limited, and the deferoxamine is a deferoxamine-producing strain belonging to the genus Streptomyces, for example, Streptomyces 403 pilosus (stored as JCM4403 in RIKEN and ATCC 19797 in the United States). In addition to being obtained by culturing, it can also be synthesized by the method of Proleg et al. (Helv Chim Acta, 45, 31, 1962).
  • the deferoxamine derivative has any structure as long as it is a compound represented by the following chemical formula (I) and has an inhibitory effect on cancer, particularly liver cancer. There may be.
  • the substituent R1 may be hydrogen or other group, that is, sulfonyl group, oxy group, thio group, sulfinyl group, imino group, oxycarbonyl group, aromatic group, etc. Furthermore, an organic acid, a hydrocarbon chain, or the like may be bonded through these bonds.
  • X represents an adduct such as an organic acid adduct, and the adduct is preferably an organic acid adduct, more preferably an organic acid adduct having 1 or 2 carbon atoms. .
  • the salt of deferoxamine or a derivative thereof is not particularly limited as long as it is a conventional non-toxic acid addition salt that is pharmacologically acceptable, and specifically, an inorganic acid addition salt (for example, hydrochloride, odor) Hydrohalates, sulfates, phosphates, etc.), organic carboxylic acid addition salts or organic sulfonic acid addition salts (eg formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, Examples thereof include benzene sulfonate, p-toluene sulfonate, etc., salts with basic amino acids or acidic amino acids (eg arginine, aspartic acid, glutamic acid, etc.).
  • an inorganic acid addition salt for example, hydrochloride, odor
  • Hydrohalates for example, hydrochloride, odor
  • sulfates for example, hydrochloride, odor
  • sulfates for
  • Deferoxamine mesylate which is a particularly preferred example is shown as the salt of deferoxamine of the present invention in the following chemical formula (II). Deferoxamine mesylate is commercially available as a reagent or pharmaceutical.
  • Cancers that require iron ions for growth are not particularly limited as long as they require iron ions to grow or are affected by excessive deposition of iron or iron ions.
  • precancerous or cancerous for example, liver cancer (hepatocellular carcinoma, cholangiocellular carcinoma), melanoma (melanoma), fibrosarcoma, mucosal sarcoma, liposarcoma, chondrosarcoma, osteogen Sarcoma, chordoma, angiosarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial tumor, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, colon cancer, colon Cancer, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell cancer, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland
  • the pharmaceutical composition for the treatment of cancer requiring iron ions for proliferation of the present invention may further contain an anticancer agent or the like as a secondary component, and the anticancer agent includes an existing anticancer agent.
  • an anticancer agent developed in the future, for example, 5-Fluorouracil (5-FU), Adriamycin (ADM), Mitomycin, Cisplatin (Cisplatin), paclitaxel (Paclitaxel), docetaxel (Docetaxel), etoposide (Etoposide), lomustine (Melphalan), mercaptopurine (Mercaptopurine), etc.
  • 5-FU or ADM can be preferably mentioned.
  • deferoxamine mesylate when used in combination with 5-FU or ADM, it is 1/2 to 1/10 of the normal dose for 5-FU, and the normal dose for ADM. Since the effect was recognized even in an amount of 1/10 to 1/100, the effect was obtained by combining the anticancer agent as a secondary component with the main component deferoxamine having an effect as a single agent. It is possible to develop drugs for the treatment of cancer that have a synergistic effect with large side effects.
  • the anticancer agent contained as an accessory component in the pharmaceutical composition for treating cancer that requires iron ions for growth of the present invention is an amount of 1/2 to 1/100 of the amount used as a single agent.
  • the dose of 5-fluorouracil is 600 mg / m 2 or less at a time, preferably 50-300 mg in total, more preferably 240-260 mg in total, and administration of adriamycin
  • the amount is 500 mg / m 2 or less per dose, preferably 50-450 mg / m 2 , more preferably 300-400 mg / m 2.
  • the dose of 5-fluorouracil is The total amount per patient is 600 mg or less, preferably 50-450 mg, more preferably 100-300 mg.
  • the dose of adriamycin is The amount 600 mg / m 2 or less, preferably 50-500 mg / m 2, more preferably 200-300 mg / m 2, the dose of mitomycin is total 60mg or less at a time, preferably 5-50 mg, more preferably It is 10-30 mg, and these anticancer agents are preferably included in combination, and more preferably all three types of anticancer agents are included.
  • the method for treating cancer having an iron ion requirement for growth according to the present invention is not particularly limited as long as it is a therapeutic method for administering the pharmaceutical composition of the present invention
  • the pharmaceutical composition of the present invention includes: Various pharmaceutical compounding ingredients such as usual pharmaceutically acceptable carriers, binders, stabilizers, excipients, diluents, pH buffers, disintegrants, solubilizers, solubilizers, isotonic agents, etc. Can be added and administered.
  • the dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it is a commonly used dosage form.
  • oral, rectal, intravaginal, parenteral, intramuscular, intraperitoneal, intraarterial can be appropriately selected from administration routes such as subarachnoid, intrabronchial, subcutaneous, intradermal, intravenous, intranasal, buccal, or sublingual. It is preferred to administer the product parenterally in the form of an injection.
  • the pharmaceutical composition for cancer treatment of the present invention may be systemic administration or local administration (local injection) to the affected area, but it may be local administration. preferable.
  • the topical administration means that the therapeutic agent is administered directly to the affected part, that is, the cancerous lesion part, and is not particularly limited to the route, but is preferably transhepatic arterial administration, more preferably transcutaneous.
  • Catheter administration can be mentioned as an example.
  • deferoxamine When using an injection used for systemic administration, deferoxamine is continuously used for 12-24 hours, more preferably 24 hours, depending on the administration route selected from any one of arterial injection, intravenous injection, and subcutaneous injection.
  • deferoxamine in an amount of 10 to 80 mg / kg suspended in 1 to 10 ml (10 ml or less) of an oily contrast medium at a time. months Once, or at appropriate dosing schedule depending on the condition, the form preferably administered by transhepatic arterial pathways.
  • the oil-based contrast agent in the above embodiment is used for the purpose of stagnating deferoxamine, which is the main component, in cancer cells by local administration, and is used in cancer treatment, particularly in embolization treatment of liver cancer.
  • the composition is not particularly limited as long as stagnation is observed, but iodinated poppy oil fatty acid ethyl ester is a suitable example as a commonly used oily contrast agent.
  • the pharmaceutical composition of the present invention can be used in the manufacture of a medicament for the treatment of cancer having an iron ion requirement for proliferation, and in particular, a medicament for the treatment of liver cancer such as hepatocellular carcinoma. It can be suitably used in production.
  • MTT [3- (4,5-Dimethylthiazol-2-yl) -2,5-Diphenylthetrazolium bromide] assay widely used in cultured cell survival experiments was used.
  • the principle of this assay is that MTT is specifically taken up into the mitochondria of living cells and measured by fluorescence at a wavelength of 570 nm.
  • Assay results are expressed as the average of two experiments. Figures 1 to 3 show the results of these experiments.
  • FIG. 1 is a graph showing the effect on Huh-7 cells.
  • the horizontal axis of the graph represents the time (hour) after addition of DFO, and the vertical axis represents the survival rate at each time when the control group is 100.
  • the survival rate decreased in the 5 ⁇ M DFO addition group (- ⁇ -), and further decreased in the 10 ⁇ M DFO addition group (- ⁇ -).
  • the survival rate after 96 hours of the 10 ⁇ M DFO addition group was 24% of the control. Even when 100 ⁇ M (...,%), 500 ⁇ M (...,%), Or 1000 ⁇ M (...,...) DFO was added, the same effect as the addition of 10 ⁇ M was observed. That is, DFO showed an antitumor effect on cultured hepatoma cells in a time-dependent and concentration-dependent manner.
  • FIG. 2 is a diagram showing the effect of DFO on HepG2, the horizontal axis of the graph shows the time after the start of culture (hour), and the vertical axis shows the survival rate at each time when the control group is 100.
  • the survival rate decreased in the 5 ⁇ M DFO addition group (- ⁇ -), and further decreased in the 10 ⁇ M DFO addition group (- ⁇ -).
  • the survival rate after 96 hours in the 100 ⁇ M DFO addition group was 28% of the control.
  • DFO showed a time-dependent and concentration-dependent antitumor effect.
  • FIG. 3 is a diagram showing the effect of DFO on HLF, where the horizontal axis of the graph shows the time after the start of culture (hour), and the vertical axis shows the survival of each time when the control group is 100.
  • the survival rate decreased in the 5 ⁇ M DFO addition group (- ⁇ -), and further decreased in the 10 ⁇ M DFO addition group (- ⁇ -).
  • the survival rate after 96 hours in the 100 ⁇ M DFO addition group was 36% of the control.
  • DFO exhibited a time-dependent and concentration-dependent antitumor effect.
  • FIG. 4 shows the effect of 5-FU on Huh-7 cells.
  • the horizontal axis of the graph is the time after addition of 5-FU, and the vertical axis is relative to the control group (no drug added) as 100.
  • a good survival rate Compared with the control group (- ⁇ -), when 5-FU was added to a concentration of 0.1 ⁇ g / ml (- ⁇ -), almost no effect was seen, and 0.5 ⁇ g / ml (- (2) The effect was small even at 1.0 ⁇ g / ml (... ⁇ ).
  • the survival rate at the addition of 1.0 ⁇ g / ml was 75% of the control.
  • FIG. 5 shows the effect of 5-FU on HepG2 cells.
  • the horizontal axis of the graph shows the time after addition of 5-FU, and the vertical axis shows the relative survival rate when the control group is 100.
  • the control group - ⁇ -
  • the effect was small, and the survival rate after 96 hours was 81 times that of the control.
  • %Met A certain antitumor effect was observed at 0.5 ⁇ g / ml (- ⁇ -) and 1.0 ⁇ g / ml (... ⁇ ).
  • the survival rate at the addition of 1.0 ⁇ g / ml was 43% of the control.
  • FIG. 6 shows the effect of 5-FU on HLF cells.
  • the horizontal axis of the graph shows the time after addition of 5-FU, and the vertical axis shows the relative survival rate when the control group is 100.
  • the control group - ⁇ -
  • the survival rate after 96 hours was 95% of the control.
  • the survival rate after 96 hours is as high as 83% and 79%. From these results, it is widely used as an anticancer agent.
  • 5-FU is not expected to be very effective for hepatocellular carcinoma, and there are cell types with little effect, whereas deferoxamine provided by the present invention can be used as a single agent. It showed excellent antitumor effect exceeding 5-FU, and it was shown that the effect does not vary so much depending on the cell type.
  • FIG. 7 shows the effect of ADM on Huh-7 cells.
  • the horizontal axis of the graph shows the time after addition of ADM, and the vertical axis shows relative survival when the control group is 100.
  • the control group (- ⁇ -)
  • the effect increased, and the survival rate after 96 hours was 40% of the control.
  • 10 ⁇ M a more prominent effect was observed, and the survival rate after 96 hours was 9% of the control.
  • ADM is known as an anticancer agent having a very strong side effect such as myocardial injury and equivalent to 10 ⁇ M. Is a numerical value that should be used as a reference value because it is a clinically impractical number.
  • FIG. 8 is a graph showing the combined effect of DFO and 5-FU on Huh-7 cells.
  • the horizontal axis of the graph represents the time after the addition of each drug (hour), and the vertical axis represents the relative value when the control group is 100.
  • the black bar graph is the control
  • the dark gray is the one with the addition of 5 ⁇ M DFO alone
  • the light gray is the one with the addition of 0.1 ⁇ g / ml 5-FU
  • the white bar graph is the addition of DFO and 5-FU at the same time Is the result of things.
  • the survival after 96 hours was 61% of the control.
  • FIG. 9 is a graph showing the combined effect of DFO and 5-FU on HepG2 cells.
  • the horizontal axis of the graph is the time after the addition of each drug (hour), and the vertical axis is the relative survival when the control group is 100. Indicates the rate.
  • the black bar graph is the control, the dark gray is the one added with 5 ⁇ M DFO alone, the light gray is the one added with 5-FUg0.1 ⁇ g / ml alone, the white bar graph is the one added with DFO and 5-FU at the same time It is a result.
  • the effect similar to Huh-7 cell was seen also in HepG2 cell, and the survival rate after 96 hours was 68% of control.
  • FIG. 10 is a graph showing the combined effect of DFO and 5-FU on HLF cells.
  • the horizontal axis of the graph is the time after the addition of each drug (hour), and the vertical axis is the relative survival when the control group is 100. Indicates the rate.
  • the black bar graph is the control, the dark gray is the one added with 5 ⁇ M DFO alone, the light gray is the one added with 5-FUg0.1 ⁇ g / ml alone, the white bar graph is the one added with DFO and 5-FU at the same time It is a result. HLF cells were less effective than Huh-7 and HepG2 cells, and survival after 96 hours was 79% of controls.
  • FIG. 11 is a graph showing the combined effect of DFO and ADM on Huh-7 cells, where the horizontal axis of the graph is the time after the addition of each drug (hour), and the vertical axis is the relative survival when the control group is 100. Indicates the rate.
  • Black bar graph is a control, dark gray is ADM 10 nM added alone, white is DFO 5 ⁇ M added alone, light gray is DFO 5 ⁇ M and ADM 0.1 nM added simultaneously, lighter
  • the gray color is the result of adding DFO 5 ⁇ M and ADM 1 nM at the same time, and the light gray color is the result of adding DFO 5 ⁇ M and ADM 10 nM at the same time.
  • Huh-7 cells and HepG2 cells cultured by the above method are washed with ice-cooled Phosphate-buffered saline (PBS) and put into a Cell lysis buffer containing 1 mM Phenylmethanesulfonyl fluoride (manufactured by Cell Signaling Technology). Suspended. The cell membrane was crushed with an ultrasonic crusher, and the membrane components were removed by centrifugation to obtain a whole cell protein sample. Mitochondrial protein and cytoplasmic protein were each separated and purified by Mitochondria / cytosol fractionation kit (manufactured by Biovision), and the expression levels of each tumor marker were compared by Western blotting.
  • PBS Phosphate-buffered saline
  • FIG. 12 shows the results of comparison of tumor marker protein expression.
  • the left lane in the figure represents the expression level of each marker in Huh-7 cells (the marker name is shown at the left end), and the right lane represents the expression level of each marker in HepG2 cells.
  • Huh-7 cells there was no change in the expression level of ⁇ -actin as a control, whereas the expression of Cyclin D1, Cyclin D3, cdk4, and p-Rb decreased, whereas the amount of Cytochrome c protein increased. did.
  • Cyclin D1, Cyclin D3, and cdk are proteins related to the cell cycle, and the expression level of these proteins is reduced by the addition of DFO, so DFO suppresses cell growth of cultured hepatoma cells. It was shown that.
  • Cytochrome c is known to increase in cell death, and this result showed that DFO also induced cell death of hepatoma cells. Since p-Rb also decreased with time, it was shown that DFO stopped the cell cycle at the G0 / G1 phase. In HepG2 cells, the expression of CyclinD1, Cyclin D3, cdk4, and p-Rb decreased and Cytochrome c tended to increase in the same manner as Huh-7 cells, supporting the results in Huh-7 cells.
  • HCC hepatocellular carcinoma frequently occurring in the liver
  • TACE transarterial chemoembolization
  • Blood data at the start of treatment were as follows: TP 7.8 g / dl, Alb 2.5 g / dl, FBS 144 mg / dl, BUN 9 mg / dl, Cre 0.64 mg / dl, T.P. Bil 1.3 mg / dl, D.I.
  • the tumor marker data at the start of treatment were as follows: AFP (L3) 36.4 ng / ml (L3 is 0.5% or less normal), PIVKA2 603 AU (normal 40 AU or less) Background liver cirrhosis (B Type) and Child-Pug B (7 points).
  • the administration schedule of the weekly DFO intraarterial administration therapy is as follows: One administration is 24 hours and administration is 1 to 5 administrations per week. 2 weeks is 1 course, and at least 2 courses are repeated, and this course is repeated as appropriate for the cases where the effect can be expected. Effectiveness is determined by tumor markers or diagnostic imaging. Specifically, chemotherapy is performed from a gripper needle punctured in the reservoir port. DFO (deferoxamine mesylate; trade name Desferral; manufactured by Novartis; common in clinical trials) 80 mg / kg or less is adjusted to a total volume of 240 ml with physiological saline and administered with an infusion pump for 24 hours. After completion, heparin Na 5000 units / A is injected to finish.
  • DFO deferoxamine mesylate
  • Desferral manufactured by Novartis; common in clinical trials
  • FIG. 13 is a CT image before treatment.
  • an intrahepatic tumor is observed in the part indicated by the white circle and the black arrow, and in the simple CT images of B and C, the part indicated by the white arrow in the figure. Lung metastases were confirmed.
  • FIG. 14 is a CT image after 3 months from the start of treatment.
  • the tumor marker data at the start of treatment were as follows: AFP (L3) 1.6 ng / ml (L3 is normal at 5% or less), PIVKA2 4942 AU (normal 40 AU or less) Background liver is cirrhosis (C type) And Child-Pugh C (11 points).
  • DFO 50 mg / kg / day 4 times (once 24 hours continuous administration) / week was started.
  • mild appetite decline and mild renal dysfunction were observed without major side effects.
  • the tumor marker PIVKA2 rapidly decreased and normalized after 2 weeks in the second half after a 1-week withdrawal.
  • the transition of the tumor marker is shown in FIG.
  • the horizontal axis of the graph shows the time elapsed from the start of treatment, the vertical axis shows the marker value, and the DFO administration schedule is shown on the graph.
  • the PIVKA2 marker was rapidly decreased by DFO administration. He later died in February 2007 due to a sudden rupture of esophageal varices when he was not treated with DFO.
  • Blood data at the start of treatment were as follows: TP 7.2 g / dl, Alb 3.1 g / dl, BUN 15 mg / dl, Cre 1.05 mg / dl, T.P. Bil 2.0 mg / dl, D.D.
  • FIG. 17 shows the transition of the tumor marker.
  • the horizontal axis of the graph represents the time elapsed from the start of treatment, and the vertical axis represents the marker value.
  • the timing of DFO administration is shown in the upper part of the graph. As shown in the graph, it was clarified that the marker rapidly decreased by administration of DFO.
  • FIG. 18 shows the transition of the tumor marker at the time of DFO re-administration.
  • the horizontal axis of the graph represents the time elapsed from the start of treatment, the vertical axis represents the marker value, and the timing of DFO administration is shown at the top of the graph.
  • the tumor marker rapidly increased when DFO administration was stopped at home temporarily, the number of metastases in the lung increased, the tumor in the liver also increased, and the treatment resumed, but died at the end of April 2007. Survived 1 year and 1 month after DFO administration. Compared to the usual course of no treatment, both hepatic and pulmonary metastases did not increase rapidly, and the growth was slow. Case.
  • liver cancer particularly hepatocellular carcinoma
  • Deferoxamine has already been established as a safe drug for iron overload, which leads to the development of a highly effective liver cancer drug with few side effects.

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Abstract

La présente invention concerne une composition pharmaceutique qui est efficace en tant qu'agent thérapeutique pour le cancer qui nécessite un ion de fer pour son expansion, particulièrement un cancer du foie. L'invention concerne spécifiquement une composition pharmaceutique qui renferme, en tant que principe actif, de la déféroxamine qui est l'un des agents chélateurs du fer qui ont été utilisés en tant qu'agents thérapeutiques pour l'hémochromatose. La composition pharmaceutique est efficace en tant qu'agent thérapeutique pour le cancer du foie.
PCT/JP2009/000310 2008-02-25 2009-01-27 Composition pharmaceutique destinée au traitement du cancer Ceased WO2009107322A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011115062A1 (fr) * 2010-03-15 2011-09-22 国立大学法人 岡山大学 Adjuvant présentant un effet antitumoral
JP2013508448A (ja) * 2009-10-26 2013-03-07 ザ ユニバーシティ オブ バーミンガム アルギン酸塩を含む抗癌組成物
CN113456622A (zh) * 2021-06-17 2021-10-01 新乡医学院 甲磺酸去铁胺在制备抗肿瘤药物中的应用

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Publication number Priority date Publication date Assignee Title
JP6179904B2 (ja) * 2012-11-05 2017-08-16 国立大学法人山口大学 ソラフェニブの副作用低減剤
JP7103745B2 (ja) * 2015-10-05 2022-07-20 国立大学法人 岡山大学 癌幹細胞抑制剤、癌の転移又は再発の抑制剤並びに癌細胞の未分化マーカー発現抑制剤
JP2018188419A (ja) * 2017-05-11 2018-11-29 株式会社ダステック 抗腫瘍活性、抗菌活性、および／または抗ウイルス活性を有し、副作用が低減された鉄キレート剤を含む医薬組成物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62223130A (ja) * 1985-11-25 1987-10-01 ザ　ホスピタル　フオ−　シツク　チルドレン 複合治療剤，その製造方法及び製剤又は製剤パツク
JP2006511490A (ja) * 2002-05-13 2006-04-06 メタバシス・セラピューティクス・インコーポレイテッド Ｐｍｅａおよびそのアナログの新規ホスホン酸系プロドラッグ

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62223130A (ja) * 1985-11-25 1987-10-01 ザ　ホスピタル　フオ−　シツク　チルドレン 複合治療剤，その製造方法及び製剤又は製剤パツク
JP2006511490A (ja) * 2002-05-13 2006-04-06 メタバシス・セラピューティクス・インコーポレイテッド Ｐｍｅａおよびそのアナログの新規ホスホン酸系プロドラッグ

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HANN, HIE WON L. ET AL.: "Antitumor effect of deferoxamine on human hepatocellular carcinoma growing in athymic nude mice", CANCER, vol. 70, no. 8, 1992, NEW YORK, NY, UNITED STATES, pages 2051 - 2056 *
HANN, HIE WON L. ET AL.: "Effect of iron and desferoxamine on cell growth and in vitro ferritin synthesis in human hepatoma cell lines", HEPATOLOGY, vol. 11, no. 4, 1990, PHILADELPHIA, PA, UNITED STATES, pages 566 - 569 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013508448A (ja) * 2009-10-26 2013-03-07 ザ ユニバーシティ オブ バーミンガム アルギン酸塩を含む抗癌組成物
US9421220B2 (en) 2009-10-26 2016-08-23 The University Of Birmingham Edgbaston Anti-cancer composition comprising alginate
WO2011115062A1 (fr) * 2010-03-15 2011-09-22 国立大学法人 岡山大学 Adjuvant présentant un effet antitumoral
CN113456622A (zh) * 2021-06-17 2021-10-01 新乡医学院 甲磺酸去铁胺在制备抗肿瘤药物中的应用

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