WO2018021827A1 - Compositions for treating liver cancer comprising a vascular disrupting agent - Google Patents

Compositions for treating liver cancer comprising a vascular disrupting agent Download PDF

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WO2018021827A1
WO2018021827A1 PCT/KR2017/008053 KR2017008053W WO2018021827A1 WO 2018021827 A1 WO2018021827 A1 WO 2018021827A1 KR 2017008053 W KR2017008053 W KR 2017008053W WO 2018021827 A1 WO2018021827 A1 WO 2018021827A1
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pharmaceutically acceptable
acceptable salt
administered
sorafenib
liver cancer
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PCT/KR2017/008053
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English (en)
French (fr)
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Soo Jin Kim
Hosung Yu
Young Il Kim
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Chong Kun Dang Pharmaceutical Corp.
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Priority to SG11201809941VA priority Critical patent/SG11201809941VA/en
Priority to CN201780041299.7A priority patent/CN109475534A/zh
Priority to JP2018563047A priority patent/JP2019517506A/ja
Publication of WO2018021827A1 publication Critical patent/WO2018021827A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives 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
    • A61K31/70—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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • compositions for treating liver cancer which comprises a vascular disrupting agent (VDA), and a method for treating liver cancer using the same.
  • VDA vascular disrupting agent
  • Liver cancer is a malignant tumor with poor prognosis, which ranks second in Korea and third in the world, among the causes of death by cancer. Radical surgery is impossible in 70% or more of liver cancer patients, and even when liver cancer patients received radical dissection, the probability of recurrence of cancer in other areas within 5 years is 50% or more. Furthermore, the possibility for advanced liver cancer to respond to systemic anticancer therapy is very low (10% or less).
  • Vascular disrupting agents aim to rapidly and selectively disrupt established tumor blood vessels by selectively destroying microtubules in the cytoskeleton of vascular endothelial cells, and may induce ischemic necrosis in central area of tumors.
  • VDAs vascular disrupting agents
  • the compounds of formula I are tubulin polymerization inhibitors having double mechanisms: rapid disruption of already existing tumor blood vessels by microtubule instabilization; and apoptosis by cell cycle arrest.
  • VDAs vascular disrupting agents
  • the compounds of formula 1 are treated alone, there is a problem in that tumors may rapidly regrow from viable rims, thereby reducing the therapeutic availability of such agents.
  • the present inventors have conducted extensive studies to provide compositions and treatment methods capable of treating liver cancer, a malignant tumor, by solving the tumor regrowth problem while taking the advantage of a vascular disrupting agent as an anticancer agent.
  • VDA vascular disrupting agent
  • Another object of the present disclosure is to provide a combination for treatment of liver cancer, which comprises a vascular disrupting agent (VDA) and sorafenib.
  • VDA vascular disrupting agent
  • Still another object of the present disclosure is to provide a composition for chemoembolization, which comprises a vascular disrupting agent (VDA).
  • VDA vascular disrupting agent
  • compositions for treatment or adjuvant treatment of liver cancer which comprises a vascular disrupting agent (VDA).
  • VDA vascular disrupting agent
  • vascular disrupting agent is (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide represented by the following formula 1 or a pharmaceutically acceptable salt thereof:
  • the term "pharmaceutically acceptable salt” means salts that are generally used in the pharmaceutical field.
  • pharmaceutically acceptable salts include salts formed with inorganic ions such as calcium, potassium, sodium or magnesium; salts formed with inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid; salts formed with organic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid or vanillic acid; salts formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid,
  • a salt of (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide may be a hydrochloride salt.
  • the compositions of the present disclosure may be applied for treatment or adjuvant treatment of liver cancer.
  • the liver cancer includes all primary liver cancer or metastatic liver cancer, but the compositions of the present disclosure may be applied to primary liver cancer.
  • the liver cancer includes all hepatocellular carcinoma or cholagiocarcinoma, but the compositions of the present disclosure may be applied to hepatocellular carcinoma.
  • the liver cancer may be early-stage liver cancer, advanced liver cancer or end stage liver cancer, and the compositions of the present disclosure may be applied to advanced liver cancer.
  • compositions of the present disclosure may be prepared as single dosage forms or in multiple-dosage containers by formulating it with pharmaceutically acceptable carriers according to a method which can be readily carried out by a person skilled in the art.
  • the pharmaceutically acceptable carriers include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical compositions may further contain, in addition to the above-described components, lubricants, wetting agents, sweetening agents, flavoring agents, emulsifying agents, suspending agents, preservatives, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19 th ed., 1995).
  • the present disclosure provides a method for treatment of liver cancer, which comprises administering the pharmaceutical compositions of the present disclosure to a subject in need thereof.
  • the term "subject” is meant to include mammals, particularly humans.
  • the present disclosure provides a combination of a vascular disrupting agent and sorafenib.
  • the present disclosure provides a combination for treatment of liver cancer, which comprises: (1) (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide represented by the following formula 1 or a pharmaceutically acceptable salt thereof; and (2) sorafenib represented by the following formula 2 or a pharmaceutically acceptable salt thereof.
  • An antiangiogenic agent has the effect of inhibiting tumor angiogenesis, and thus has been widely used in anticancer strategies.
  • Sorafenib developed by Bayer is known to have two properties: direct anticancer effect, and angiogenic inhibition.
  • the anticancer effect of sorafenib is partially mediated by inhibition of B-RAF kinase, and appears to have the property of inhibiting angiogenesis by inhibiting VEGFR-2 and PDGFR- ⁇ .
  • an antiangiogenic agent such as sorafenib is administered alone, it inhibits only one aspect of angiogenesis, and thus the anticancer effect thereof is insufficient.
  • the combination of the present disclosure it was shown that when the compound of formula 1 (vascular disrupting agent) and sorafenib (antiangiogenic agent), which are anticancer agents having different treatment mechanisms, were administered in combination, they exhibited a very excellent liver cancer treatment activity due to their synergistic effect. Furthermore, the combination of the present disclosure can solve the tumor recurrence problem occurring when the compound of formula 1 or sorafenib is administered alone, because there remain little or no viable tumor cells as a result of administration of the combination of the present disclosure.
  • the pharmaceutically acceptable salt of sorafenib may be any salt that is generally used in the pharmaceutical field, and sorafenib p-toluenesulfonate salt may be used.
  • the combination of the present disclosure may comprise two separate formulations, and may also be composed of a single formulation.
  • the combination of the present disclosure may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) according to the intended use.
  • (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide or a pharmaceutically acceptable salt thereof may be administered orally or parenterally, preferably orally.
  • sorafenib or a pharmaceutically acceptable salt thereof may be administered orally.
  • the suitable doses of the active ingredients in the combination of the present disclosure may vary depending on the patient's body weight, age, sex, health conditions, diet, the time of administration, the mode of administration, excretion rate, the severity of the disease, and the like.
  • the daily dose of (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide represented or a pharmaceutically acceptable salt thereof is about 1.0 to 40.0 mg, preferably about 2.5 to 25.0 mg.
  • the daily dose of sorafenib or a pharmaceutically acceptable salt thereof is about 50 to 1500.0 mg, preferably about 100 to 1000 mg.
  • the frequency of administration of the active ingredients in the combination of the present disclosure may be determined depending on the dose thereof.
  • (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide or a pharmaceutically acceptable salt thereof may be administered at a frequency of once per day to once per week, and may also be administered 1 to 5 times per week depending on the route of administration.
  • sorafenib or a pharmaceutically acceptable salt thereof may be administered at a frequency of twice per day to once per week, and may also be administered 1 to 7 times per week or 1 to 2 times per day.
  • sorafenib or a pharmaceutically acceptable salt thereof may be administered at 20 minutes to 1 hour after oral administration of (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide or a pharmaceutically acceptable salt thereof.
  • the combination of the present disclosure has a very excellent liver cancer treatment activity, and when it is administered, there will remain little or no viable cancer cells, and thus the possibility of recurrence of cancer will be significantly low. Thus, the combination of the present disclosure may be effectively used for treatment of liver cancer.
  • the present disclosure provides a composition for chemoembolization, which comprises a vascular disrupting agent.
  • composition for chemoembolization which comprises: (1) (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide represented by the following formula 1 or a pharmaceutically acceptable salt thereof; (2) doxorubicin represented by the following formula 3 or a pharmaceutically acceptable salt thereof; and (3) lipiodol:
  • TACE transarterial chemoembolization
  • RFA radiofrequency ablation
  • the transarterial chemoembolization uses a strategy that maximizes a local anticancer effect against liver cancer by injecting an anticancer agent into the hepatic artery and obstructing the hepatic artery with an embolic agent.
  • the transarterial chemoembolization is used as palliative therapy.
  • Normal liver tissue receives 70% or more of blood via the portal vein, but liver cancer tissue receives 90% or more of blood through the hepatic artery.
  • the anticancer agent when an anticancer agent is injected through the hepatic artery in transarterial chemoembolization (TACE), the anticancer agent can be administered to liver cancer tissue at a relatively high concentration compared to normal liver tissue.
  • this direct injection through the hepatic artery can increase the amount of anticancer agent accumulated in liver cancer tissue by about 100-fold compared to systemic injection.
  • growth of new blood vessels around liver cancer tissue due to a response to hypoxia induced by chemoembolization is one of the major causes of recurrence.
  • composition for chemoembolization when the compound of formula 1 (vascular disrupting agent) and doxorubicin are administered in combination topically to liver cancer cells, they will exhibit a very high liver cancer treatment activity due to their synergistic effect. In addition, there will remain little or no viable tumor cells as a result of administration of the composition of the present disclosure, and thus the composition of the present disclosure makes it possible to solve the tumor recurrence problem occurring when the compound of formula 1 or doxorubicin is administered alone.
  • Lipiodol in the composition for chemoembolization performs various functions. Specifically, lipiodol functions to deliver the anticancer agents in the composition for chemoembolization to liver cancer cells. Furthermore, lipiodol also functions as a contrast medium. In addition, lipiodol functions to embolize the hepatic artery, and thus can enhance the embolic effect of an embolic agent such as gelatin.
  • lipiodol in the composition for chemoembolization functions to deliver the anticancer agents in the composition to liver cancer cells, functions as a contrast medium to make it possible to perform chemoembolization, and also exhibits an embolic effect to assist in treatment of liver cancer.
  • composition for chemoembolization according to the present disclosure may further contain an aqueous contrast medium.
  • Doxorubicin is a hydrophilic substance that is difficult to dissolve in lipiodol.
  • the composition of the present disclosure preferably further contains an aqueous contrast medium.
  • (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide or a pharmaceutically acceptable salt thereof and doxorubicin or a pharmaceutically acceptable salt thereof in the composition of the present disclosure may be present at a weight of 5:1 to 1:5, preferably 2:1 to 1:2.
  • (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide or a pharmaceutically acceptable salt thereof in the composition of the present disclosure is preferably contained in an amount of 5.0 to 30.0 mg per mL of lipiodol.
  • doxorubicin or a pharmaceutically acceptable salt thereof in the composition of the present disclosure is preferably contained in an amount of 5.0 to 50.0 mg per mL of the aqueous contrast medium.
  • composition for chemoembolization according to the present disclosure may be applied to various chemoembolization therapies.
  • the composition for chemoembolization according to the present disclosure may be administered topically to an area to be embolized. Most preferably, it is administered topically to the liver via transarterial chemoembolization (TACE).
  • TACE transarterial chemoembolization
  • the composition for chemoembolization according to the present disclosure has a very excellent liver cancer treatment activity, and when it is administered, there will little or no viable cancer cells, and thus the possibility of recurrence of cancer will be significantly low. Accordingly, the composition for chemoembolization according to the present disclosure can be effectively used for treatment of liver cancer.
  • an embolic agent may be injected to embolize a desired area.
  • the embolic agent is preferably a gelatin-like substance.
  • the preferred doses of (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide or a pharmaceutically acceptable salt thereof and doxorubicin or a pharmaceutically acceptable salt thereof may vary depending on various factors, including the patient's body weight, age, sex, health conditions, diet, the time of administration, the mode of administration, excretion rate, the severity of the disease, and the like.
  • the daily dose of (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide or a pharmaceutically acceptable salt thereof in the composition for chemoembolization according to the present disclosure is about 1.0 to 40.0 mg/kg, preferably 2.5 to 25.0 mg/kg.
  • the daily dose of doxorubicin or a pharmaceutically acceptable salt thereof in the composition for chemoembolization according to the present disclosure is about 10.0 to 1000.0 mg/kg, preferably 20.0 to 800.0 mg/kg.
  • compositions of the present disclosure exhibit excellent liver cancer treatment activity, and act such that the possibility of recurrence of cancer is low.
  • compositions of the present disclosure may be used for treatment or adjuvant treatment of liver cancer.
  • FIG. 1 shows the results of bioluminescence imaging (BLI) of a control group and each test groups (administered parenterally) in Hep3B xenograft mouse models.
  • FIG. 2 is a graph comparing the relative BLI signal intensity between a control group and each test groups (administered parenterally) in Hep3B xenograft mouse models.
  • FIG. 3 shows H&E staining and TUNEL staining images of a control group and each test groups (administered parenterally).
  • FIG. 4 is a graph comparing apoptosis rate between a control group and each test groups (administered parenterally).
  • FIG. 5 shows CD31 staining images of a control group and each test group (administered parenterally).
  • FIG. 6 is a graph comparing microvessel density (MVD) between a control group and each test groups (administered parenterally).
  • FIG. 7 shows the results of bioluminescence imaging (BLI) of a control group and each test groups (administered orally) in Hep3B xenograft mouse models.
  • FIG. 8 is a graph comparing the relative BLI signal intensity between a control group and each test groups (administered orally) in Hep3B xenograft mouse models.
  • FIG. 9 is a graph comparing apoptosis rate between a control group and each test groups (administered orally).
  • FIG. 10 shows CD31 staining images of a control group and each test groups (administered orally).
  • FIG. 11 is a graph comparing the microvessel area (MVA) between a CD31-stained control group and each CD31-stained test groups (administered orally).
  • FIG. 12 shows images of a meca-32-staiend control group and each meca-32-stained test groups (administered orally).
  • FIG. 13 is a graph comparing the microvessel area (MVA) between a meca-32-stained control group and each meca-32-stained test groups (administered orally).
  • FIG. 14 is a graph comparing the viable tumor portion between test groups after injecting test substances into rabbit VX2 liver cancer models via transarterial chemoembolization (TACE) (A: group administered with lipiodol; B: group administered with lipiodol + VDA; C: group administered with lipiodol + doxorubicin; D: group administered with lipiodol + VDA + doxorubicin).
  • TACE transarterial chemoembolization
  • Hep3B cells Human hepatocellular carcinoma Hep3B cells were purchased from the Korean Cell Line Bank (Seoul, Korea). Hep3B cells were infected with lentivirus containing firefly luciferase reporter gene, and a clone strongly expressing the reporter was isolated in order to establish a Hep3B+luc cell line.
  • luciferase Stable expression of luciferase was confirmed by bioluminescence imaging (BLI) (PerkinElmer, Waltham, MA, USA).
  • the Hep3B+luc cell line was maintained with Dulbecco's modified Eagle medium (DMEM, WelgeneInc, Seoul, Korea) containing 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA) and 1% antibiotics (Gibco, USA).
  • DMEM Dulbecco's modified Eagle medium
  • FBS Gibco, Grand Island, NY, USA
  • antibiotics Gibco, Grand Island, NY, USA
  • mice Male Balb/c nude mice (6-week-old) were purchased from Orientbio (Seoul, Korea).
  • Hep3B+luc cells were inoculated into the right flank of each animal through a 27-gauge needle syringe. When the tumor diameter exceeded 5 mm on about 14 days after inoculation, the animals were used in the test.
  • the compound of formula 1 (VDA) was prepared by the preparation method disclosed in International Patent Publication No. WO 2009-119980, and was dissolved in 0.9% saline.
  • Sorafenib p-toluenesulfonate salt (LC laboratories, Woburn, MA, USA) was dissolved in CremophorEL/ethanol (50:50; Sigma CremophorEL, 95% ethyl alcohol) at 4-fold, and then diluted with water on the day of use.
  • Bioluminescence imaging was performed before drug administration (day 0) and day 2, day 6, day 10 and day 14 after drug administration. Mice were anesthetized, and then imaged with an IVIS spectrum system (PerkinElmer, Waltham, MA, USA). D-luciferin (0.375 mg/ml; Promega, Madison, WI, USA) in phosphate buffered saline (PBS) was injected intraperitoneally into the mice. Bioluminescence was recorded as sum of measured photons per sec in the region of interest (ROI). For measurement of in vivo bioluminescence, ROIs having the same size and shape, which includes the tumor of each animal, were used. Quantification of BLI data was performed using Living Image software (version 2.50.1, Perkin Elmer, Waltham, MA, USA).
  • Control group vehicle (saline, administered intraperitoneally);
  • sorafenib (30 mg/kg, administered orally 6 times per week (once per day for day 1 to day 6));
  • Tumor volume (length ⁇ width 2 ) / 2
  • mice were sacrificed for tissue processing, immunohistochemical staining and histological analysis.
  • test animals were anesthetized deeply, transcardially perfused with saline by a ventricular catheter, and then treated with 10% paraformaldehyde (PFA) by gravity flow for 10 minutes.
  • PFA paraformaldehyde
  • the tumor tissue was collected, fixed in formalin, and embedded in paraffin. The largest portion of the tumor was sectioned to a thickness of 4 ⁇ m.
  • TUNEL terminal deoxynucleotidyl transferase dUTP nick-end labeling
  • Measurement of immunostained areas was based on the Weidner method. Using a Leica microscope (model DM2500, leica, Germany), three areas were observed at low magnifications (40x and 100x). The number of microvessels in each area was measured in a 200x field (20x objective lens, 10x ocular lens). Image analysis for the number of blood vessels was performed using software (Image analysis, Leica, Germany). In this software, one cell in stained lumen was calculated as one point. The average number of microvessels in all the measured areas was determined as microvessel density (MVD).
  • MMD microvessel density
  • Quantitative data were expressed as mean ⁇ standard deviation. The statistical significance of difference in tumor volume, bioluminescence imaging, percent apoptosis and microvessel density between the groups was analyzed using Mann-Whitney's U-test. p ⁇ 0.05 was considered significant. All data were calculated using commercial software (SPSS, version 21.0 for Windows, SPSS, Chicago, IL, USA).
  • xenograft mice were administered with the compound of formula 1 (VDA), and the body weight of the mice and tumor growth in the mice were observed during the test period. Mice that become weakened during the test period were not observed.
  • the tumor growth inhibitory effect of the group administered with the combination of VDA and sorafenib was similar to that of the group administered with sorafenib alone. This suggests that the tumor growth inhibitory effect of administration of the compound of formula 1 (VDA) alone is not significant.
  • the relative BLI signal of the control group continued to increase. This suggests that Hep3B-luc tumors actively grew.
  • the BLI signal decreased gradually for 6 days and was significantly restored after day 6.
  • the relative BLI signal decreased after administration of the compound of formula 1 (day 1 and day 8), and this decreased signal was continued for 2 days and significantly restored after 2 days. This suggests that the compound of formula 1 exhibits a rapid shut down effect and a cytotoxic effect in the initial stage after administration.
  • the relative BLI signal significantly decreased in the initial stage, and the combination showed a tumor inhibitory effect for 10 days after the start of administration (see FIG. 1).
  • tumor microvessel density (MVD) was obtained on day 14 after single administration of each of the drugs.
  • tumor blood vessels were large and distributed throughout the tumor.
  • blood vessel images different from that observed in the control group appeared.
  • blood vessels had a short length and were distributed at the margin of the tumor. Comparison between the test groups was based on the density of blood vessels (see FIG. 5).
  • Bioluminescence imaging was performed before drug administration (day 0) and day 2, day 4, day 8, day 11, day 15, day 18 and day 20 after drug administration. Mice were anesthetized, and then imaged with an IVIS spectrum system (PerkinElmer, Waltham, MA, USA). D-luciferin (0.375 mg/ml; Promega, Madison, WI, USA) in phosphate buffered saline (PBS) was injected intraperitoneally into the mice. Bioluminescence was recorded as sum of measured photons per sec in the region of interest (ROI). For measurement of in vivo bioluminescence, ROIs having the same size and shape, which includes the tumor of each animal, were used. Quantification of BLI data was performed using Living Image software (version 2.50.1, Perkin Elmer, Waltham, MA, USA).
  • Vehicle saline, administered orally
  • sorafenib 15 mg/kg, administered orally 7 times per week
  • Oral administration was performed at 2 pm each day, and in the group administered with the combination, sorafenib was administered at 30 minutes after administration of the compound of formula 1.
  • Tumor volume (length ⁇ width 2 ) / 2
  • mice were sacrificed for tissue processing, immunohistochemical staining and histological analysis.
  • TUNEL terminal deoxynucleotidyl transferase dUTP nick-end labeling
  • Microvessel areas were determined by immunochemical staining of CD31 and meca-32. Using a Leica microscope (model DM2500, leica, Germany), three areas were observed at low magnifications (40x and 100x). The number of microvessels in each area was measured in a 200x field (20x objective lens, 10x ocular lens). Image analysis for the number of blood vessels was performed using software (Image analysis, Leica, Germany).
  • Quantitative data were expressed as mean ⁇ standard deviation.
  • the tumor volume and bioluminescence imaging of each group was evaluated using RMANOVA test, and the statistical significance of difference in percent apoptosis and microvessel area between the groups was analyzed using one-way ANOVA test. p ⁇ 0.05 was considered significant. All data were calculated using commercial software (SPSS, version 21.0 for Windows, SPSS, Chicago, IL, USA).
  • anti-CD31-stained histological samples (FIG. 10) and quantification of the tumor MVA therein (FIG. 11), and meca-32-stained histological samples (FIG. 12) and quantification of the tumor MVA therein (FIG. 13) were obtained on day 21 after the start of each drug.
  • MVA analysis performed using CD31 indicated that the control group, the group administered with the compound of formula 1 alone, and the group administered with sorafenib alone, showed tumor MOVs of 16339 ⁇ 3614, 14452 ⁇ 2709, and 14934 ⁇ 3154, respectively, whereas the group administered with the combination showed a tumor MVA of 7161 ⁇ 4522, which was significantly lower than those of the other groups (see FIG. 11).
  • VX2 carcinoma liver tumor models established as representative animal models of liver cancer were used. The abdomens of male New Zealand White rabbits (weighing 3 kg) were incised, and the left lobe of the liver was exposed. Then, a VX2 carcinoma tumor chip prepared to have a size of 1 mm 3 was implanted into the surface of the liver by a syringe needle. At 2 to 3 weeks after tumor implantation, non-contrast computed tomography (CT) and perfusion MR imaging were performed to determine whether or not a tumor would be produced.
  • CT non-contrast computed tomography
  • perfusion MR imaging were performed to determine whether or not a tumor would be produced.
  • Test group A a group administered with lipiodol (0.2 mL of lipiodol + 0.05 mL of contrast medium [GE Healthcare Visipaque 270]);
  • Test group B a group administered with lipiodol and the compound of formula 1 (VDA) (0.2 mL of lipiodol + 1.26 mg of the compound of formula 1 (VDA) + 0.05 mL of contrast medium [GE Healthcare Visipaque 270]);
  • Test group C a group administered with lipiodol and doxorubicin (0.2 mL of lipiodol + 0.05 mL of contrast media [GE Healthcare Visipaque 270] and 1 mg of doxorubicin);
  • Test group D a group administered with lipiodol, the compound of formula 1 (VDA) and doxorubicin (0.2 mL of lipiodol + 1.26 mg of the compound of formula 1 (VDA) + 0.05 mL of contrast medium [GE healthcare Visipaque 270] + 1 mg of doxorubicin).
  • a microcatheter was passed through the rabbit auricular artery and celiac trunk and advanced into the left hepatic artery, and then drugs corresponding to test groups A to D were carefully injected into the left hepatic artery.
  • non-enhanced CT was performed to determine the presence or absence of tumors, and after TACE, lipiodol deposited in tumors was evaluated.
  • liver tissue was extracted to make pathological slides. H&E staining and TUNEL staining were performed to determine necrotic tumor areas. The necrotic tumor area was calculated using the Image J program, and the viable tumor portion was expressed as percentages. The results are shown in Table 1 below and FIG. 14.
  • test group D administered with a combination of lipiodol, the compound of formula 1 (VDA) and doxorubicin, the viable tumor portion was 0.66%, indicating that most tumors were removed.
  • VDA the compound of formula 1
  • doxorubicin the compound of formula 1 (VDA) and doxorubicin
  • test groups A and C had a standard deviation of 10% or more, indicating that the reproducibility of the tumor treatment effect of the drugs was poor.
  • results for test group D had a standard deviation of only about 1%, indicating that the drugs administered to test group D reproducibly treated liver cancer.
  • test group D As a result, it was shown that the degree of acute liver injury in test group D was the highest, but was restored to levels similar to those in the other test groups after 7 days. In addition, no rabbit death was observed in test group, indicating that liver injury in test group D was acceptable.

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