WO2010116550A1 - Procédé de test de sensibilité de tissu de tumeur - Google Patents

Procédé de test de sensibilité de tissu de tumeur Download PDF

Info

Publication number
WO2010116550A1
WO2010116550A1 PCT/JP2009/067444 JP2009067444W WO2010116550A1 WO 2010116550 A1 WO2010116550 A1 WO 2010116550A1 JP 2009067444 W JP2009067444 W JP 2009067444W WO 2010116550 A1 WO2010116550 A1 WO 2010116550A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituent
hydrogen atom
administration
alkyl group
Prior art date
Application number
PCT/JP2009/067444
Other languages
English (en)
Japanese (ja)
Inventor
船橋泰博
仙波太郎
Original Assignee
エーザイ・アール・アンド・ディー・マネジメント株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by エーザイ・アール・アンド・ディー・マネジメント株式会社 filed Critical エーザイ・アール・アンド・ディー・マネジメント株式会社
Publication of WO2010116550A1 publication Critical patent/WO2010116550A1/fr

Links

Images

Classifications

    • 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
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/403—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 carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging

Definitions

  • the present invention relates to a method for examining the sensitivity of tumor cells to a sulfonamide compound or an analog thereof by evaluating K trans or blood circulation in a tumor tissue when the sulfonamide compound or an analog thereof is allowed to act.
  • the present invention relates to a method for examining the antitumor effect of a compound.
  • a change in a biological marker closely related to the tumor growth inhibitory action as a surrogate marker.
  • the reactivity of a living body when an anti-cancer agent is administered largely depends on the sensitivity of tumor cells that are the target of the drug to the drug.
  • the sensitivity of this tumor cell to a drug varies greatly from tumor cell to tumor cell.
  • Such a difference in sensitivity is caused by a quantitative or qualitative difference in the target molecule of the drug or a factor related thereto, acquisition of drug resistance, or the like.
  • N- (3-chloro-1H-indol-7-yl) -1,4-benzenedisulfonamide hereinafter sometimes referred to as “E7070”
  • N- (3-cyano-4-methyl-1H -Indol-7-yl) -3-cyanobenzenesulfonamide hereinafter sometimes referred to as E7820
  • E7820 N-[[(4-chlorophenyl) amino] carbonyl] -2,3-dihydro-1H-indene-5 -Sulfonamide
  • LY186661 N-[[(3,4-dichlorophenyl) amino] carbonyl] -2,3-dihydrobenzofuran-5-sulfonamide
  • LY295501 N- (2,4-dichlorobenzoyl) -4-chlorophenylsulfonamide
  • An object of this invention is to provide the method of determining the sensitivity of the tumor by a sulfonamide compound.
  • the present inventor has determined whether or not the tumor tissue is sensitive to the sulfonamide compound using the K trans value by DCE-MRI analysis or the blood circulation by SPECT analysis as an index.
  • the present invention has been completed. (1) That is, the present invention examines the sensitivity of tumor tissue to a sulfonamide compound selected from the following formulas (I) to (V), or a pharmacologically acceptable salt thereof, or a solvate thereof.
  • the present invention provides a sulfonamide compound selected from the following formulas (I) to (V), or a pharmacologically thereof:
  • a method for examining the sensitivity of tumor tissue to an acceptable salt, or a solvate thereof comprising the following steps: (A) measuring K trans or blood circulation in the tumor tissue of the subject before and after administration of the sulfonamide compound to the subject; (B) Analyzing the measured values before and after the administration and classifying them into a low region, a middle region and a high region, (C) The method comprising the step of determining that the tumor tissue is sensitive to the sulfonamide compound when any one of the criteria of (c-1) and (c-2) is met.
  • the sulfonamide compound used in the present invention is as follows. ⁇ Sulfonamide compound> Formula (I): [Where: A ring represents a monocyclic or bicyclic aromatic ring optionally having a substituent, Ring B represents a 6-membered cyclic unsaturated hydrocarbon which may have a substituent or an unsaturated 6-membered heterocycle containing one nitrogen atom as a heteroatom, Ring C represents a 5-membered heterocycle containing 1 or 2 nitrogen atoms, which may have a substituent, W represents a single bond or —CH ⁇ CH—, X represents -N (R ⁇ 1 >)-or an oxygen atom, Y represents a carbon atom or a nitrogen atom, Z represents —N (R 2 ) — or a nitrogen atom,
  • R 1 and R 2 are independently the same or different and each represents a hydrogen atom or a lower alkyl group.
  • R 2b is a hydrogen atom, a halogen atom, a cyano group, —CF 3 , an optionally substituted C 1 -C 6 alkyl group, or an optionally substituted C 1 -C 4 alkoxycarbonyl.
  • R 3b represents a hydrogen atom or a C 1 -C 4 alkoxy group which may have a substituent
  • R 4b represents a hydrogen atom or an optionally substituted C 1 -C 6 alkyl group (provided that at least one of R 3b and R 4b is a hydrogen atom)
  • R 5b represents a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, —CF 3 or a nitro group
  • R 6b is a hydrogen atom, a halogen atom or an optionally substituted C 1 -C 6 alkyl group (provided that R 6b is an optionally substituted C 1 -C 6 alkyl group).
  • R 5b is a hydrogen atom and R 7b is a halogen atom
  • R 7b is a halogen atom, an optionally substituted C 1 -C 6 alkyl group or —CF 3 (wherein either R 5b or R 7b may have a substituent).
  • R 5b or R 6b Is a hydrogen atom.
  • the sulfonamide compound for example, 1) N- (3-cyano-4-methyl-1H-indol-7-yl) -3-cyanobenzenesulfonamide 2) N- (3-cyano-4-methyl-1H-indol-7-yl)- 6-chloro-3-pyridinesulfonamide 3) N- (3-bromo-5-methyl-1H-indol-7-yl) -4-sulfamoylbenzenesulfonamide 4) N- (5-bromo-3- Chloro-1H-indol-7-yl) -6-amino-3-pyridinesulfonamide 5) N- (3-Bromo-5-methyl-1H-indol-7-yl) -3-cyanobenzenesulfonamide 6) N- (4-Bromo-1H-indol-7-yl)
  • the sulfonamide compound As the sulfonamide compound, The thing chosen from the group which consists of can be illustrated. (7) In the present invention, the K trans value is measured by, for example, DCE-MRI, and the blood reflux value is measured by, for example, SPECT or PET. (8) The present invention further relates to a therapeutic agent for cancer comprising a sulfonamide compound selected from the above formulas (I) to (V), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • examples of the K trans value include those measured by DCE-MRI, and examples of the blood reflux value include those measured by SPECT or PET.
  • the sensitivity of a tumor to a sulfonamide compound can be evaluated. As a result, since it can be administered to cancer patients after judging whether or not the administration of the sulfonamide compound is effective, it is possible to determine whether or not the sulfonamide compound should be administered continuously thereafter, such as side effects. Risk can be reduced.
  • FIG. 1 is a graph showing the antitumor effect of E7820 in a rat model (in vivo) transplanted with a human renal cancer cell line.
  • FIG. 2A is a diagram showing an increase in the K trans of E7820 in a region of interest at the tumor margin when dynamic contrast magnetic resonance imaging analysis is performed in a rat model transplanted with a human renal cancer cell line (in vivo).
  • FIG. 2B is a diagram showing an increase in K trans of E7820 in a region of interest at the tumor margin when dynamic contrast magnetic resonance imaging analysis is performed in a rat model transplanted with a human renal cancer cell line (in vivo).
  • FIG. 2A is a diagram showing an increase in the K trans of E7820 in a region of interest at the tumor margin when dynamic contrast magnetic resonance imaging analysis is performed in a rat model transplanted with a human renal cancer cell line (in vivo).
  • FIG. 2A is a diagram showing an increase in the K trans of E7820 in a
  • FIG. 3A shows the effect of E7820 on the tumor blood circulation when analyzing the antitumor effect of E7820 and the uptake of Glucarate in the tumor by single photon emission computed tomography in a human colon cancer cell line HCT116 transplanted mouse model (in vivo).
  • FIG. 3B is a diagram showing a 3D image of an increasing effect on blood perfusion in a tumor when analyzing uptake of glucorate in the tumor by single photon emission computed tomography in a mouse model transplanted with human colon cancer cell line HCT116 (in vivo). It is.
  • FIG. 3A shows the effect of E7820 on the tumor blood circulation when analyzing the antitumor effect of E7820 and the uptake of Glucarate in the tumor by single photon emission computed tomography in a human colon cancer cell line HCT116 transplanted mouse model (in vivo). It is.
  • FIG. 3B is a diagram showing a 3D image of an increasing effect on blood perfusion in
  • FIG. 4A is a diagram showing an analysis result when K trans range analysis using dynamic contrast magnetic resonance imaging is performed in a human colon cancer cell line HCT116 transplanted rat model (in vivo).
  • FIG. 4B is a diagram showing analysis results when K trans range analysis using dynamic contrast-enhanced magnetic resonance imaging is performed in a human colon cancer cell line HCT116 transplanted rat model (in vivo).
  • FIG. 4C is a diagram showing analysis results when K trans range analysis using dynamic contrast-enhanced magnetic resonance imaging is performed in a human colon cancer cell line HCT116 transplanted rat model (in vivo).
  • FIG. 4A is a diagram showing an analysis result when K trans range analysis using dynamic contrast magnetic resonance imaging is performed in a human colon cancer cell line HCT116 transplanted rat model (in vivo).
  • FIG. 4B is a diagram showing analysis results when K trans range analysis using dynamic contrast-enhanced magnetic resonance imaging is performed in a human colon cancer cell line HCT116 transplanted rat model
  • FIG. 5 is a diagram showing an increasing effect on intratumoral blood circulation by E7820 when K trans range analysis using dynamic contrast magnetic resonance imaging is performed in a rat model transplanted with a human renal cancer cell line (in vivo).
  • FIG. 6A is a view showing that E7820 has a tumor blood vessel normalizing action in a rat model of transplantation of human renal cancer cell lines (in vivo).
  • FIG. 6B is a view showing that E7820 has a tumor blood vessel normalizing action in a rat model of transplantation of human renal cancer cell lines (in vivo).
  • FIG. 6C is a diagram showing a significant increase result in the E7820 administration group of the pericellular coverage of tumor blood vessels, which is one of the indicators of normalization of tumor blood vessels.
  • FIG. 6A is a view showing that E7820 has a tumor blood vessel normalizing action in a rat model of transplantation of human renal cancer cell lines (in vivo).
  • FIG. 6B is a view showing that E78
  • FIG. 7A is a diagram showing an increase effect of intratumoral blood circulation when K trans range analysis using dynamic contrast-enhanced magnetic resonance imaging is performed in 5 human cancer cell line transplant rat models (in vivo).
  • FIG. 7B is a diagram showing an increase effect of intratumoral blood circulation when K trans range analysis using dynamic contrast-enhanced magnetic resonance imaging is performed in five human cancer cell line transplant rat models (in vivo).
  • FIG. 8 is a diagram showing the results of hierarchical clustering analysis of HCT116 cells.
  • FIG. 9 is a diagram showing a correlation coefficient in a DNA microarray.
  • FIG. 10 is a diagram showing a hierarchical clustering analysis result.
  • FIG. 11 is a diagram showing correlation coefficients in a DNA microarray.
  • FIG. 12 is a diagram showing a hierarchical clustering analysis result.
  • FIG. 13 is a diagram showing the results of an assay for measuring cytostatic activity.
  • FIG. 14 is a diagram showing the results of an assay for
  • DCE-MRI Dynamic Contrast Enhanced Magnetic Resonance Imaging
  • angiogenesis inhibitors such as VEGF inhibitors are effective through an inhibitory effect on vascular permeability.
  • trans It is known to lower the value.
  • K was determined by DCE-MRI analysis.
  • trans When the value was measured, a high state was observed in the peripheral region of the tumor tissue, and a low state was observed inside.
  • angiogenesis inhibitor E7820
  • KE was determined by DCE-MRI analysis.
  • trans When the value is measured, it is normal K trans A value distribution is observed, but in the specimen that showed an effect after administration, a high K was also observed inside the tumor.
  • K when it is considered sensitive to angiogenesis inhibitors trans The distribution can be detected by using the improvement in blood circulation inside the tumor, that is, the increase in blood circulation inside the tumor as an index, and blood circulation measurement by measuring the intratumoral concentration of contrast medium in SPECT may be substituted. It has been suggested that the increase in blood circulation can be used as an index to determine the effect of an angiogenesis inhibitor such as E7820.
  • the sensitivity of the tumor tissue to the sulfonamide compound is measured in the tumor tissue measured before administration of the sulfonamide compound.
  • sensitivity means an index indicating the ease of drug action.
  • K trans In the present invention, K trans As the value, a value measured from a cancer patient who has been administered the sulfonamide compound before and after the administration is used.
  • K trans is a numerical value indicating the change in the amount (concentration) of the contrast agent over time from plasma to the extravascular region in the tissue, and can be measured by DCE-MRI.
  • K trans May be displayed as” Ktrans ".
  • angiogenesis is induced by the tumor, but unlike the normal blood vessel, the induced blood vessel does not have sufficient functions such as few pericytes covering the blood vessel wall.
  • the blood vessel permeability is not enhanced in the normal blood vessels and the contrast medium does not leak out of the blood vessels, the transfer of the contrast medium in the normal tissue (that is, outside the blood vessels) is not enhanced. For this reason, it is not detected as a DCE-MRI image in normal tissues with few blood vessels.
  • abnormal blood vessels tumor blood vessels
  • tumor blood vessels abnormal blood vessels (tumor blood vessels) in tumor tissues where angiogenesis is fostering have increased vascular permeability, and the contrast medium can leak out of the blood vessels and migrate into the tumor tissues. It is detected as a DCE-MRI image in the tumor tissue.
  • the blood circulation in the tumor is poor because the blood vessels are not normal in the tumor.
  • the intratumoral pressure is high and the distribution of the contrast medium in the tumor tissue is poor. Only a part of the tumor tissue with a low pressure and good transfer of the contrast medium to the intratumoral tissue (that is, only the region with blood circulation) is detected as a DCE-MRI image.
  • the change in contrast agent concentration detected in this way in the target region of examination in the tumor tissue is represented by K trans
  • K trans The value is used as an index for determining the effect of the sulfonamide compound.
  • K trans Means the change in the concentration of the contrast agent over time as described above, and is a numerical value indicating the change in the amount (concentration) of the contrast agent over time (usually in minutes) from the plasma to the extravascular region in the tissue.
  • C is the concentration of the contrast agent in the tissue (mmol / L)
  • C p Is the concentration of the contrast agent in plasma (mmol / L).
  • V e Is the amount of extravascular area in tissue (% of tissue volume).
  • K ep Is a numerical value of the flow rate ratio of the contrast medium from the tissue to the plasma, and is represented by the following equation.
  • K ep K trans / V e Therefore, K as in the above formula ep Using K trans Can also be defined.
  • K trans Since the value is reflected as a change in the concentration of the contrast agent over time, depending on the region where the concentration change in the region of interest is high and low, K trans A distribution of values occurs. Therefore, in the present invention, K trans It is possible to set a value in a certain range and calculate the probability that the region exists within the range as a histogram. And K trans Classify the distribution of values into several regions trans The low value area is “low area”, K trans A high region is defined as a “high region”, and an intermediate region between a low region and a high region is defined as a “medium region”.
  • K trans The largest K of the values trans
  • the value is K trans Is divided into three or more areas as the upper limit for distribution conversion, and the lowest value of the divided areas is K trans It is defined as “low region”, “middle region”, “high region” in order from the region (FIG. 4), or the lowest K among the classified regions trans
  • the value can be defined as “low region”, and “middle region” and “high region” can be equally spaced from the remaining regions.
  • K trans When the value distribution range is set to 0.0 to 2.0, four boundaries are provided for every 0.4, and divided into five regions, 0.0 to 0.4 of the five regions are set.
  • a low region, 0.4 to 0.8 can be defined as a middle region, and 0.8 to 1.2 can be defined as a high region (FIG. 4).
  • the number of regions does not necessarily mean three. There may be a plurality of middle regions and high regions. For example, 1.2 or more can be defined as an “ultra-high region”.
  • the number of regions to be divided is 3 or more, preferably 3 or more and 5 or less. However, if it is 3 or more, there is no particular need to be particular and it can be appropriately set depending on the type of cancer, each cancer patient, and the like.
  • K trans The date or interval at which the measurement is performed is not particularly limited, and can be set as appropriate.
  • Blood circulation is a phenomenon in which blood circulates in blood vessels. As described above, since there are few normal blood vessels in the tumor tissue and the efficiency of blood circulation is low, the pressure in the tumor is high, and the contrast agent in the blood does not leak from the blood vessel, and the concentration of the contrast agent in the tissue is low. For this reason, in the tumor tissue, only an active region of blood circulation is detected as an image of the contrast agent.
  • a contrast agent labeled with a positron emitting nuclide or radioactive substance is administered before and after the sulfonamide compound is administered to the patient.
  • the intratumoral concentration of labeled contrast agent is used as a parameter for blood circulation.
  • These can be detected as signal values measured by each apparatus by using a nuclear medicine examination apparatus such as a PET apparatus or a SPECT apparatus. That is, by detecting the signal value in these nuclear medicine inspection devices, blood circulation in the tumor in the patient's body before and after administration of the sulfonamide compound can be measured as a change in the concentration of the contrast agent in the tumor.
  • PET a drug labeled with a radioisotope that emits positron is administered to a subject, and its distribution is imaged on a tomographic image with a PET camera, so that the local function of the organ is depicted in an image.
  • SPECT also injects drugs containing radioactive elements that emit radioactivity (gamma rays) intravenously, detects gamma rays emitted from radioactive isotopes administered into the body with a gamma camera, and computes the concentration distribution of the detected drugs.
  • Tomographic images or three-dimensional images Like PET, it is used for the purpose of observing biological functions and is effective for early detection of cerebrovascular disorders, heart disease, and cancer.
  • the concentration change in the tumor can be quantitatively evaluated using a value called SUV (Standardized Uptake Value).
  • Tumor, brain, muscle, etc. are set as the region of interest, and the SUV maximum value and average SUV in the region of interest are calculated and compared with the accumulated SUV, the standard SUV for each organ, or the surrounding normal region average SUV Measure blood flow in the tumor as a change in contrast medium.
  • the date or interval for measuring the SUV is not particularly limited and can be set as appropriate. For example, it may be set as 1st to 20th day, 1st week, 2nd week, 4th week after administration of the sulfonamide compound. 3.
  • Sulfonamide compounds in the present invention, the sulfonamide compound includes a compound represented by the following general formula (I).
  • a ring represents a monocyclic or bicyclic aromatic ring optionally having a substituent
  • Ring B represents a 6-membered cyclic unsaturated hydrocarbon which may have a substituent, or an unsaturated 6-membered heterocycle containing one nitrogen atom as a heteroatom
  • Ring C represents a 5-membered heterocycle containing 1 or 2 nitrogen atoms, which may have a substituent
  • W represents a single bond or —CH ⁇ CH—
  • X is -N (R 1 )-Or oxygen atom
  • Y represents a carbon atom or a nitrogen atom
  • Z is -N (R 2 )-Or a nitrogen atom.
  • R 1 And R 2 are each independently the same or different and each represents a hydrogen atom or a lower alkyl group.
  • the compound of the general formula (I) includes a compound in which X is an oxygen atom. This compound is included in the “sulfonamide compound” in the present invention as an analog of the sulfonamide compound.
  • the “monocyclic or bicyclic aromatic ring which may have a substituent” in the ring A means an aromatic hydrocarbon, or a nitrogen atom, an oxygen atom and sulfur.
  • Examples of the main aromatic ring contained in the A ring include pyrrole, pyrazole, imidazole, thiophene, furan, thiazole, oxazole, benzene, pyridine, pyrimidine, pyrazine, pyridazine, naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline , Cinnoline, indole, isoindole, indolizine, indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole, benzopyrazole, benzothiazole, etc., but the aromatic ring contained in A ring is not limited to these .
  • the aromatic ring may have 1 to 3 substituents, and when there are a plurality of substituents, they may be the same or different.
  • substituents include an amino group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a mercapto group, a cyano group, a lower alkylthio group, and a halogen atom, which may be substituted with a lower alkyl group or a lower cycloalkyl group.
  • a is a single bond,-(CH 2 ) k -, -O- (CH 2 ) k -, -S- (CH 2 ) k -Or -N (R 3 )-(CH 2 ) k -, K is an integer from 1 to 5, R 3 Is a hydrogen atom or a lower alkyl group, b is -CH 2 -D (wherein d represents an amino group, a halogen atom, a hydroxyl group, a lower alkylthio group, a cyano group or a lower alkoxy group which may be substituted with a lower alkyl group), a group represented by the formula: -A-ef [wherein, a is as defined above, and e is -S (O)-or -S (O)] 2 -, F is an amino group optionally substituted with a lower alkyl group or a lower alkoxy group, a lower alkyl
  • these alkyl groups may be bonded to form a 5- or 6-membered ring.
  • the A ring is a nitrogen-containing heterocycle having a hydroxyl group or a mercapto group, these groups may take the form of an oxo group or a thioxo group by taking a resonance structure.
  • the meaning of the ring B “optionally substituted 6-membered cyclic unsaturated hydrocarbon or unsaturated 6-membered heterocycle containing one nitrogen atom as a hetero atom”
  • a part of the unsaturated bond is benzene or pyridine, which may be hydrogenated, may have one or more substituents on the ring, and there are two or more substituents Are the same or different.
  • the C ring “optionally substituted 5-membered heterocycle containing 1 or 2 nitrogen atoms” means pyrrole or pyrazole in which a part of the unsaturated bond may be hydrogenated Imidazole, which may have 1 or 2 substituents on the ring, and when there are 2 substituents, it may be the same or different.
  • Examples of the substituent that the B ring and the C ring may have include, for example, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, an oxo group, a formula —C (O) -r ( r represents a hydrogen atom, an amino group optionally substituted with a lower alkyl group, a lower alkyl group, a lower alkoxy group or a hydroxyl group), an amino group optionally substituted with a lower alkyl group, a trifluoromethyl group, etc. It can be mentioned, but is not limited to these.
  • R 1 And R 2 And the “lower alkyl group” in the definition of the substituent that the A ring, the B ring and the C ring may have means a linear or branched alkyl group having 1 to 6 carbon atoms, , But not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group (amyl group) ), Isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group 3-methylpentyl group, 1-ethylpropyl group, 1,1-dimethyl
  • preferred groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. More preferred groups include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and the most preferred group is a methyl group.
  • the “lower cycloalkyl group” in the definition of the substituent that the ring A may have means a cycloalkyl group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group. , Cycloheptyl group, cyclooctyl group and the like, but are not limited thereto.
  • the “lower alkylthio group” means an alkylthio group derived from the above lower alkyl group.
  • a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group examples thereof include, but are not limited to, a sec-butylthio group and a tert-butylthio group.
  • the “lower alkoxy group” in the definition of the substituent that the A ring, the B ring and the C ring may have is not limited to these, but includes, for example, a methoxy group, an ethoxy group, an n-propoxy group.
  • halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the compound represented by the general formula (I) of the present invention can be produced by a known method. For example, WO95 / 07276 pamphlet (WO95 / 07276) and / or JP-A-7-165708 (JP7-). 165708).
  • a preferred compound is a compound represented by the following formula XI.
  • the A ring represents benzene, pyridine, thiophene or pyrimidine
  • M is -SO 2 NH 2 Represents a cyano group, a halogen atom or an amino group
  • N is C 1-4 Represents an alkyl group, a hydrogen atom or a halogen atom
  • L represents a cyano group, a halogen atom or a hydrogen atom.
  • preferred compounds are 1) N- (3-Cyano-4-methyl-1H-indol-7-yl) -3-cyanobenzenesulfonamide (E7820) 2) N- (3-Cyano-4-methyl-1H-indol-7-yl) -6-chloro-3-pyridinesulfonamide 3) N- (3-Bromo-5-methyl-1H-indol-7-yl) -4-sulfamoylbenzenesulfonamide 4) N- (5-Bromo-3-chloro-1H-indol-7-yl) -6-amino-3-pyridinesulfonamide 5) N- (3-Bromo-5-methyl-1H-indol-7-yl) -3-cyanobenzenesulfonamide 6) N- (4-Bromo-1H-indol-7-yl) -4-cyanobenzenesulfonamide 7) N- (4-Chloro
  • E7070 can also be referred to as N- (3-chloro-1H-indol-7-yl) -4-sulfamoylbenzenesulfonamide
  • E7820 can be referred to as 3-cyano-N- (3-cyano-4.
  • -Methyl-1H-indol-7-yl) benzenesulfonamide are particularly preferred compounds.
  • the sulfonamide compound includes a compound represented by the following general formula (II).
  • E is -O-, -N (CH 3 )-, -CH 2 -, -CH 2 CH 2 -Or -CH 2 O-
  • D is -CH 2 -Or -O-
  • R 1a Represents a hydrogen atom or a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom)
  • R 2a Means a halogen atom or a trifluoromethyl group, respectively.
  • the compound represented by the general formula (II) of the present invention can be produced by a known method, for example, by the method described in European Patent Application Publication No. 0222475A1 (EP0222475A1).
  • LY186664 refers to N-[[(4-chlorophenyl) amino] carbonyl] -2,3-dihydro-1H-indene-5-sulfonamide, the structural formula of which is shown in the following formula (VIII).
  • LY186664 can be manufactured by a known method, for example, by the method described in European Patent Application Publication No. 0222475A1 (EP022475A1).
  • LY295501 refers to N-[[(3,4-dichlorophenyl) amino] carbonyl] -2,3-dihydrobenzofuran-5-sulfonamide, and the structural formula is shown in the following formula (IX).
  • LY295501 can be produced by a known method, for example, by the method described in European Patent Application Publication No. 0222475A1 (EP0222475A1) and / or European Patent Application Publication No. 0555036A2 (EP0555036A2).
  • the sulfonamide compound includes a compound represented by the following general formula (III).
  • J represents —O— or —NH—
  • R 1b May have a hydrogen atom, a halogen atom or a substituent.
  • 1 -C 6 C which may have an alkyl group or a substituent 1 -C 4 Alkoxy group, optionally substituted C 1 -C 4 Alkylthio group, -CF 3 , -OCF 3 , -SCF 3 , C which may have a substituent 1 -C 4 Alkoxycarbonyl group, nitro group, azide group, -O (SO 2 ) CH 3 , -N (CH 3 ) 2
  • 2b Is a hydrogen atom, a halogen atom, a cyano group, -CF 3
  • R 6b May have a hydrogen atom, a halogen atom or a substituent.
  • 1 -C 6 Alkyl group (however, R 6b C may have a substituent 1 -C 6 When alkyl, R 5b Is a hydrogen atom and R 7b Is a halogen atom), R 7b May have a halogen atom or a substituent.
  • 1 -C 6 Alkyl group or -CF 3 However, R 5b Or R 7b Either of which may have a substituent 1 -C 6 An alkyl group or R 7b May have a halogen atom or a substituent.
  • the “halogen atom” is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1 -C 6 The “alkyl group” has the same meaning as the above-mentioned “lower alkyl group” and is not particularly limited, but is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group.
  • C 1 -C 4 “Alkoxy group” means an alkoxy group having 1 to 4 carbon atoms in the above-mentioned “lower alkoxy group”, and is not particularly limited, but is preferably a methoxy group, an ethoxy group, or an n-propoxy group. , Isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group and the like.
  • alkyl group is not particularly limited, and examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • “C 1 -C 4 Examples of the “alkoxycarbonyl group” include, but are not limited to, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec- A butoxycarbonyl group, a tert-butoxycarbonyl group, etc. can be mentioned.
  • the substituent to be introduced is not particularly limited.
  • Alkyl group for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, etc.
  • C 1 -C 4 An alkoxy group for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, etc.
  • amino group for example, hydroxyl group, halogen atom (for example, And a substituent such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom) or a silyl group.
  • the compound represented by the general formula (III) of the present invention can be produced by a known method, for example, by the method described in International Publication No. 02/098848 (WO02 / 098848).
  • a preferred compound is LY-ASAP.
  • LY-ASAP refers to N- (2,4-dichlorobenzoyl) -4-chlorophenylsulfonamide, and its structural formula is shown in the following formula (X).
  • LY-ASAP can be produced by a known method, for example, by the method described in International Publication No. 02/098848 (WO02 / 098848).
  • examples of the sulfonamide compound include LY573636.
  • LY573636 means N- (2,4-dichlorobenzoyl) -5-bromothiophene-2-sulfonamide, and its structural formula is shown in the following formula (IV).
  • LY573636 is preferably a sodium salt.
  • LY573636 can be produced by a known method. For example, in the same manner as described in WO 02/098848 (WO02 / 098848), commercially available 5-bromothiophene-2-sulfonyl chloride and 2,4- It can be produced from dichlorobenzoic acid.
  • LY57363636 can be produced by the method described in Example 63 in International Publication No. 2003/035629 (WO2003 / 035629).
  • examples of the sulfonamide compound include CQS.
  • CQS refers to 2-sulfanilamide-5-chloroquinoxaline, and the structural formula is shown in the following formula (V).
  • CQS can be manufactured by a well-known method, for example, can be manufactured by the method of (J.Am.Chem.Soc., 1947,71,6-10).
  • Sulfonamide compounds may form pharmacologically acceptable salts with acids or bases.
  • the sulfonamide compound in the present invention includes these pharmacologically acceptable salts.
  • Examples of the salt with an acid include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, formic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, tartaric acid, and benzoic acid.
  • examples thereof include salts with acids, organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid.
  • Examples of the salt with a base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N′- Examples thereof include salts with organic bases such as dibenzylethylenediamine, arginine and lysine (organic amine salts) and ammonium salts.
  • the sulfonamide compound may be an anhydride or may form a solvate such as a hydrate.
  • the solvate may be either a hydrate or a non-hydrate, but a hydrate is preferred.
  • the sulfonamide compound in the present invention includes those solvates and / or optical isomers.
  • the sulfonamide compound in the present invention also includes a sulfonamide compound that undergoes metabolism such as oxidation, reduction, hydrolysis, and conjugation in vivo.
  • the sulfonamide compound in the present invention also includes a compound that generates a sulfonamide compound by undergoing metabolism such as oxidation, reduction, and hydrolysis in vivo.
  • the sulfonamide compound is any compound selected from the group consisting of general formula (I), general formula (II), general formula (III), formula (IV) and formula (V), Preferably, it is at least one compound selected from the group consisting of E7070, E7820, LY186411, LY295501, LY-ASAP, LY573636 and CQS, more preferably at least one selected from the group consisting of E7070, E7820, LY295501 and LY573636.
  • the present invention is a method for examining the sensitivity of tumor tissue to the sulfonamide compound, or a pharmacologically acceptable salt thereof, or a solvate thereof, and includes the following steps.
  • a step of administering a contrast agent or a sulfonamide compound to the subject may be added to the above step.
  • the present invention A method for examining the sensitivity of tumor tissue to the sulfonamide compound, or a pharmacologically acceptable salt thereof, or a solvate thereof, which may include the following steps.
  • a contrast agent is administered to the subject
  • C administering the sulfonamide compound to the subject
  • D administering a contrast agent to the subject
  • E K in the tumor tissue of the subject after the sulfonamide compound was administered to the subject trans Or measure blood circulation
  • F Compare the measured values in (b) and (e)
  • G) When the measured value after the administration is increased compared to the measured value before the administration, the tumor tissue is judged to be sensitive to the sulfonamide compound.
  • K trans And / or blood circulation is a numerical value indicating a change in the amount (concentration) of the contrast agent and / or the amount (concentration) of the contrast agent over time. Therefore, the measured value is expressed as a value at a specific time (referred to as a predetermined time) in a partial region (referred to as a predetermined part) in the region of interest.
  • the measured value includes an integrated value of a value of the predetermined region between times T1 and T2, an integrated value of a value of the predetermined region at a predetermined time (that is, a value at a predetermined time of the entire region of interest), and further, the entire region of interest It can also be expressed as an integral value of the values between the times T1 and T2.
  • Sensitivity can be determined by comparing the value thus obtained as the difference or ratio between the “measured value before administration of the sulfonamide compound” and the “measured value after administration of the sulfonamide compound”. .
  • the measurement value after administration is the measurement value before administration. It can be judged that the tumor tissue is sensitive to the sulfonamide compound.
  • the method of the present invention is a method for examining the sensitivity of a tumor tissue to a sulfonamide compound, a pharmacologically acceptable salt thereof, or a solvate thereof, and includes the following steps.
  • a step of administering a contrast agent or a sulfonamide compound to the subject may be added to the above step.
  • the present invention A method for examining the sensitivity of a tumor tissue to a sulfonamide compound, or a pharmacologically acceptable salt thereof, or a solvate thereof, comprising the following steps: (A) A contrast agent is administered to the subject, (B) K in the tumor tissue of the subject before administration of the sulfonamide compound to the subject trans Or measure blood circulation, (C) administering the sulfonamide compound to the subject, (D) administering a contrast agent to the subject, (E) K in the tumor tissue of the subject after the sulfonamide compound was administered to the subject trans Or measure blood circulation, (F) Analyzing the measured values in (b) and (e) above and classifying them into low, medium and high regions, (G) The step of judging that the tumor tissue is sensitive to the sulfonamide compound when any one of the following criteria (c-1) and (c-2) is met.
  • the above-described method including: ⁇ Judgment criteria> (C-1)
  • the ratio of the low area after the administration is reduced as compared with the ratio of the low area before the administration, or the ratio of the middle area or the high area after the administration is the middle area or the high area before the administration.
  • C-2 The ratio of the low area after administration is reduced as compared with the ratio of the low area before administration, and the ratio of the middle area or high area after administration is the middle area or high area before administration.
  • K defined as above trans
  • this fluctuation is used as an indicator of whether the subject's tumor tissue is sensitive to sulfonamide compounds. be able to.
  • the above fluctuation can be expressed as a difference or a ratio of a probability or a numerical value before and after the administration of the sulfonamide compound.
  • Graphs can be graphed to analyze curve fluctuations.
  • the proportion of the low region after the administration is Or the percentage of the middle or high area after administration is reduced compared to the percentage of the middle or high area before administration, It can be determined that the tumor tissue is sensitive to the sulfonamide compound. Judgment of whether a tumor tissue is sensitive to sulfonamide compounds may be based only on the probability distribution of the low region, or only the probability distribution of the middle region or the high region, or a combination of both. Good.
  • the sulfonamide compound when it is determined that the tumor cells are sensitive to the sulfonamide compound, the sulfonamide compound may be determined to have a more antitumor effect on a cancer patient having the tumor cell. it can.
  • the sulfonamide compound When having a higher antitumor effect, for example, when an antitumor effect higher than the average antitumor effect in patients with similar symptoms can be expected, the higher antitumor effect than other patients suffering from the same cancer type Can be expected, or a higher antitumor effect can be expected than patients suffering from other cancer types.
  • the sulfonamide compound can be used for administration to patients determined to be sensitive by the method of the present invention.
  • the sulfonamide compound may be for use in the method of the present invention.
  • the sulfonamide compound may be used as it is or may be a pharmaceutical composition containing other components.
  • the pharmaceutical composition is not particularly limited as long as it is a pharmaceutical composition containing the sulfonamide compound.
  • Examples of the pharmaceutical composition include tablets, powders, granules, fine granules, capsules, syrups, troches, inhalants and other oral preparations, suppositories, ointments, eye ointments, tapes, eye drops And external preparations such as nasal preparations, nasal drops, ear drops, poultices, and lotions, and injections.
  • the dosage of the sulfonamide compound varies depending on the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, properties of pharmaceutical preparation, preparation, type, type of active ingredient, etc.
  • tumor include, for example, brain tumor, cervical cancer, esophageal cancer, tongue cancer, lung cancer, breast cancer, pancreatic cancer, gastric cancer, cancer of the small intestine or duodenum, colon cancer (colon cancer, rectal cancer), bladder cancer, renal cancer, liver cancer, Prostate cancer, uterine cancer, ovarian cancer, thyroid cancer, gallbladder cancer, pharyngeal cancer, sarcoma (eg, osteosarcoma, chondrosarcoma, Kaposi sarcoma, myoma, angiosarcoma, fibrosarcoma, etc.), leukemia (eg, chronic myelogenous leukemia) (CML), acute myeloid leukemia (AML), chronic lymphocy
  • CML chronic myelogenous leukemia
  • AML acute myeloid leukemia
  • the present invention provides a test kit containing a contrast agent for use in a method for examining the sensitivity of tumor cells to a sulfonamide compound and / or a method for examining the antitumor effect of a sulfonamide compound.
  • the kit of the present invention may contain components commonly used in general measurement in addition to the above contrast agent.
  • the test kit of the present invention is provided with K trans Even if it contains an instruction manual, a package insert, etc. that describe using the value as an index for a method of diagnosing the sensitivity of a tumor tissue to a sulfonamide compound and / or a method of examining the antitumor effect of a sulfonamide compound Good.
  • the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
  • Human renal cancer cell line Caki-1 (purchased from ATCC) was cultured in RPMI 1640 (containing 10% FBS) in a 5% carbon dioxide incubator. After the culture, each cell was recovered by trypsin-EDTA according to a conventional method. The cells were suspended in RPMI 1640, and a suspension was prepared at 2 ⁇ 10 7 cells / 200 ⁇ l. 0.2 mL of the cell suspension was transplanted subcutaneously on the body side into nude rats (purchased from Charles River) that had been gamma-irradiated (7 Gy, cobalt 60, INRA, Dijion, France) 24 hours before transplantation.
  • E7820 3.13 mg / kg and 6.25 mg / kg, twice a day for 2 weeks, oral administration
  • E7820 was manufactured based on the description of the international publication 01/56607 pamphlet (WO01 / 56607).
  • the tumor major axis and minor axis were measured with a Digimatic caliper, and the tumor volume and the specific tumor volume were calculated by the following equations.
  • Tumor volume (TV) tumor major axis (mm) ⁇ tumor minor axis 2 (mm 2 ) / 2 The results are shown in FIG. As shown in FIG.
  • E7820 shows a significant difference in the antitumor effect in the 6.25 mg / kg administration group compared to the non-administration group in the nude rat subcutaneous transplantation model of human renal cancer cell line Caki-1, and the antitumor effect depends on the dose. It became clear that there was a difference.
  • a standard object (phantom) for Gd-DTPA having a prescribed T1 value for adjustment is placed in the contrast field of view, and nine images are taken from a rotation angle of 10 degrees to 90 degrees (in 10 degree increments).
  • Tumor volume was calculated by overlaying the number of voxels of the region of interest for each slice. Analysis of dynamic contrast magnetic resonance images was performed with three slices per sample, and a region of interest (contrast medium distribution region) was manually created for each slice. The average T1 value in the tumor before contrast medium administration was calculated from the T1-weighted image of the tumor imaged for adjustment. Next, the concentration of the contrast agent in the region of interest was calculated based on the following calculation formula.
  • C (t) 1 / r 1 (1 / T 1 (t) ⁇ 1 / T 10 )
  • T 1 (t) Average T1 value in the region of interest at time t
  • T 10 Average T1 value in the region of interest before administration
  • concentration of the contrast agent in plasma was calculated based on the following calculation formula.
  • Cp (t) D (a 1 e -m1t + a 2 e -m2t)
  • C (t) concentration of drug in plasma at time t (mmol / L)
  • D Gd-DTPA amount administered (mmol / kg) a1, a2, -m1, -m2: Factors related to the disappearance curve of Gd-DTPA, and the contrast agent uptake curve was determined to reproduce results consistent with the kinetic model developed by Tofts et al.
  • the kinetic model of Tofts et al. Is widely used to analyze the kinetic factors in dynamic contrast-enhanced magnetic resonance imaging [Toft PS, J Magn Reson Imaging, 1999, 10, p223; Padhani AR, Br J Radiol.
  • HCT116 Human colon cancer cells
  • Strain HCT-116 was cultured in RPMI 1640 (containing 10% FBS) in a 5% carbon dioxide incubator. After the culture, each cell was recovered by trypsin-EDTA according to a conventional method. The cells were suspended in RPMI 1640, and a suspension was prepared at 5 ⁇ 10 6 cells / 100 ⁇ l. Nude mice (purchased from Taconic) were transplanted 0.1 mL of the cell suspension subcutaneously on the body side.
  • test substance E7820 (100 and 200 mg / kg, once daily for 11 days, oral administration) was started.
  • the 99mTc label Glucarate was prepared as follows. That is, a 30 mCi 0.3 ml sodium technesate solution was added to a vial containing 12.5 mg Glucarate to prepare 99mTc-labeled Glucarate, and the final concentration was adjusted with physiological saline and used.
  • the labeling efficiency was developed with 99mTc-labeled Glucarate after thin-layer chromatography, and then the radioactivity was scanned (Bioscan) to confirm that 90% or more of the radioactivity was labeled, and the experiment was conducted. It was. The average labeling efficiency was 97.24 ⁇ 3.02%.
  • Imaging was performed by injecting about 1 mCi of 99mTc-labeled Glucarate solution from the tail vein and using nanoSPECT / CT TM (Bioscan, DC, USA) after 20 minutes (single photon emission computed tomography; 24 Min imaging, computed tomography; 4 min half imaging).
  • Quantitative analysis of tumor uptake and brain uptake of 99mTc-labeled Glucarate was done by setting the region of interest using three-dimensional reconstructed anatomical computed tomography and single photon emission computed tomography images.
  • Tumor volume was determined using the following formula.
  • Tumor volume (TV) tumor major axis (mm) ⁇ tumor minor axis 2 (mm 2 ) / 2
  • the relative tumor volume was determined using the following formula.
  • Relative tumor volume tumor volume before administration (mm 3 ) / tumor volume after administration (mm 3 ) The results are shown in FIG. FIG.
  • FIG. 3A is a graph showing the measurement of blood circulation in a tumor using an E7820 human colon cancer cell line HCT116-transplanted mouse model (in vivo). It is the result of examining by tomography. The figure shows the anti-tumor effect and the effect on intratumoral Glucarate concentration (kBq / mm 3 ) due to intratumoral Glucarate uptake.
  • FIG. 3B is a single photon emission computed tomography and computed tomography image with three-dimensional reconstruction of E7820 intratumoral Glucarate uptake. As shown in FIG.
  • a K trans histogram of the dynamic contrast magnetic resonance image was created as follows. The value of K trans was divided into 125 regions in increments of 0.016 from 0.0 to 2.0, and the number of voxels belonging to each region was determined. Three slices per tumor were analyzed, and the average value for each region was taken as the value of one tumor.
  • K trans range analysis of dynamic contrast-enhanced magnetic resonance images was performed as follows.
  • the value of K trans was divided into a range of 5 in increments of 0.4 from 0.0 to 2.0, and used as an index of the degree of blood circulation (0.0-0.4; low blood circulation, 0.4- 0.8; medium blood circulation, 0.8-1.2; high blood circulation, 1.2-1.6; ultrahigh blood circulation).
  • FIG. 4A is a representative image of daily changes in intratumoral blood circulation (K trans distribution) accompanying proliferation of HCT116.
  • FIG. 4B is a diagram showing qualitative evaluation of intratumoral blood circulation (K trans distribution) using a K trans histogram.
  • FIG. 4C is a diagram showing quantitative evaluation of intratumoral blood circulation (K trans distribution) using K trans range analysis.
  • Example 4 K trans range analysis Since quantitative analysis of changes in tumor blood circulation was possible, in this example, it was examined whether the same results as in Example 4 could be verified even during drug administration.
  • the human renal cancer cell line Caki-1 was transplanted into nude rats. After transplantation, administration of test substance E7820 (3.13 mg / kg, 6.25 mg / kg, twice a day for 2 weeks, oral administration) was started from the time when the tumor volume became about 1000 mm 3 .
  • Magnetic resonance image analysis was performed on the day before the start of administration and on the second, seventh, thirteen, and twenty days after the start of administration, and T2-weighted images, T1-weighted images, and dynamic contrast images were obtained.
  • Blood circulation (K trans ) was examined, the effect of E7820 on blood circulation throughout the Caki-1 tumor was analyzed using a K trans histogram, and quantitatively evaluated by K trans range analysis. All experiments of magnetic resonance image analysis were performed in the same manner as in Example 2.
  • the creation of the K trans histogram of the dynamic contrast magnetic resonance image was performed in the same manner as in Example 4 except that the value of K trans was set as follows. 0.0-0.4; Low blood circulation, 0.4-0.8; Medium blood circulation, 0.8-1.2; High blood circulation The results are shown in FIG. FIG.
  • E7820 significantly improves the intratumoral blood circulation (distribution of K trans ) in a rat model transplanted with a human renal cancer cell line (in vivo). It is possible to inspect by K trans range analysis using resonance imaging. E7820 significantly decreased the region of low blood circulation (K trans range; 0.0-0.4) from the second post-administration in a nude rat subcutaneous transplantation model of human renal cancer cell line Caki-1 region (K trans range; 0.0-0.4) after 7 days and 13 days significantly low blood perfusion in reduces, region (K trans range of high blood perfusion; 0.8-1.2 ). These effects were not observed on the 20th day, 7 days after the end of administration. Therefore, compared to the case where K trans is analyzed without dividing it into ranges, the effect can be measured more quantitatively when divided into ranges.
  • Tumor blood vessel normalization effect of E7820 in human renal cancer cell line transplant rat model In the same manner as in Example 1, human renal cancer cell line Caki-1 was transplanted into nude rats. Administration of test substance E7820 (6.25 mg / kg, twice a day, 2 weeks, oral administration) was started from the time when the tumor volume reached about 300 mm 3 after transplantation. Two methods were used to evaluate E7820 for tumor vessel normalization. One was an effect on the diffusion of a fluorescent dye Hoechst 33342 (Bisbenzimidine) bound to DNA into the tumor, and the other was an effect on the pericyte coverage of blood vessels in the tumor.
  • Hoechst 33342 Bisbenzimidine
  • the Hoechst 33342 solution adjusted to 2 mg / ml with physiological saline was administered at a dose of 20 mg / kg from the tail vein on the 7th day after the start of administration, and 1 minute after administration, the tumor After removal, the tumor was embedded in tissue-TEK OCT compound (Takara, Torrance, CA, USA) and frozen using liquid nitrogen.
  • the diffusion of Hoechst 33342 was performed using a frozen section (using 2 sections per tumor) under a fluorescence microscope equipped with a fluorescence light source. Evaluation was performed by quantifying the area ( ⁇ m 2 ) of the labeled cell surface.
  • Quantification was performed on a gray scale (0-16383), the background fluorescent region (0-870) was not diffused, and the brighter region (870-16383) was diffused region.
  • the effect on the pericyte coverage of blood vessels in the tumor it was killed by blood sampling under anesthesia on the 14th day after the start of administration, and the removed tumor was embedded in an OCT compound and frozen using liquid nitrogen. Was used as a sample. Immunofluorescence staining of tumor blood vessels was performed using frozen sections (2 sections per tumor were used). After fixing the sample with acetone, it was treated with 3% bovine serum albumin and 5% sheep serum prepared with PBS for 20 minutes at room temperature to suppress nonspecific binding.
  • mouse anti-rat ⁇ -smoothmuscle actin ( ⁇ -SMA) antibody (A5228, Sigma) was used as a primary antibody and treated at room temperature for 1 hour.
  • ⁇ -SMA ⁇ -smoothmuscle actin
  • a mouse IgG1 antibody (Dakocytomation) that does not cross the rat was used.
  • a sheep antibody (Ref A11061, Invitrogen) against anti-mouse antibody conjugated with Alexa Fluor (registered trademark) 568 was used.
  • Alexa Fluor registered trademark
  • Pericellular coverage of intratumoral blood vessels is selected as 5 spots per slice of hot spots with the highest blood vessel density, and stained in green covered with red cells surrounding the number of microvessels stained green under a microscope. The ratio of the number of pericyte-coated blood vessels was calculated.
  • FIG. 6A is a representative image of the diffusion of the fluorescent dye Hoechst 33342 into the tumor increased by E7820.
  • FIG. 6B is a diagram showing a quantitative analysis result of diffusion of the fluorescent dye Hoechst 33342 into the tumor increased by E7820.
  • FIG. 6C is a diagram showing a significant increase result in the E7820 administration group of the pericellular coverage of tumor blood vessels, which is one of the indicators of normalization of tumor blood vessels.
  • E7820 promoted the diffusion of the fluorescent dye Hoechst33342 into the tumor on the 7th day after administration in a nude rat subcutaneous transplantation model of the human renal cancer cell line Caki-1 (FIGS. 6A and B). On the 14th day after administration, the pericyte coverage was significantly increased in the E7820 administration group (FIG. 6C). From these results, it was shown that E7820 normalizes tumor blood vessels in the human renal cancer cell line Caki-1.
  • the human breast cancer cell line MDA-MB-231 was excised once when the tumor volume reached about 600 mm 3 , about 20-30 mg of a tumor piece was prepared, and replanted subcutaneously on the nude rat side.
  • the tumor volume is about 300 mm 3 (Caki-1), about 600 mm 3 (HCT-116), about 500 mm 3 (MDA-MB-231), about 800 mm 3 (LoVo), about 600 mm 3 (H460).
  • Administration of test substance E7820 (6.25 mg / kg, twice a day, 2 weeks, oral administration) was started from this point.
  • the tumor volume was determined by measuring the major axis and minor axis of the tumor with a digital caliper, and the tumor volume and the specific tumor volume were calculated according to the following equations.
  • Tumor volume (TV) tumor major axis (mm) ⁇ tumor minor axis 2 (mm 2 ) / 2
  • the antitumor effect was calculated by the following formula using the tumor volume.
  • FIG. 7A is a diagram showing the excellent antitumor effect of E7820 in 3 of the 5 models studied.
  • FIG. 7B shows that the superior antitumor effect of E7820 correlates with the improvement effect of K trans distribution (significant increase in low blood circulation region and significant decrease in middle blood circulation region) by K trans range analysis. It is a table.
  • E7820 showed a significant growth inhibitory effect in all models compared to the control, but complete inhibition of tumor growth or tumor shrinkage was observed with MDA-MB-231, Caki-1 and HCT-. Only 116 of 3 models were observed (FIG. 7A).
  • E7820 showed a significant decrease in the low blood circulation region (K trans range; 0.0-0.4) in the K trans range analysis.
  • DNA microarray analysis 1) Cell culture, compound treatment, and RNA extraction
  • human colon cancer-derived cell line HCT116 American Type Culture Collection, Manassas, VA, U S.A.
  • human leukemia cell line MOLT-4 American Type Culture Collection, Manassas, VA, USA
  • 10% fetal bovine serum 100 units / ml penicillin, 100 ⁇ g / ml
  • RPMI-1640 medium supplemented with a large amount of streptomycin.
  • the culture and the compound treatment were performed in an incubator adjusted to 5% CO 2 and 37 ° C.
  • HCT116 cells and MOLT-4 cells were seeded at a rate of 2.0 ⁇ 10 6 cells in a 10 cm-diameter cell culture dish, and the following compound treatment was performed after culturing for 24 hours.
  • E7820 0.8 ⁇ M
  • E7070 0.8 ⁇ M
  • LY295501 (30 ⁇ M)
  • CQS 8 ⁇ M
  • adriamicin 0.2 ⁇ M
  • daunomycin 0.2 ⁇ M
  • ICRF154 80 ⁇ M
  • ICRF159 Twelve compounds were evaluated: 80 ⁇ M), kenpaulone (10 ⁇ M), alsterpululone (10 ⁇ M), trichostatin A (0.1 ⁇ M), and rapamycin (80 ⁇ M).
  • E7070 (0.8 ⁇ M) was evaluated for MOLT-4 cells.
  • adriamycin and daunomycin are DNA topoisomerase II inhibitors that intercalate with DNA
  • ICRF154 and ICRF159 are catalytic type DNA topoisomerase II inhibitors
  • kenpululone and aldosterpine kenpululone and aldosterpine
  • Trichostatin A is a histone deacetylase inhibitor
  • rapamycin is a known compound as an mTOR / FRAP inhibitor.
  • the compound treatment concentration was set as a concentration 3 to 5 times higher than the 50% growth inhibitory concentration of each compound on HCT116 cells (based on the 3-day cell growth inhibitory activity using WST-8).
  • DEPC diethylpyrocarbonate
  • T7-d (T) 24 primer 5 ⁇ M T7-d (T) 24 primer, 1 ⁇ First strand buffer, 10 mM DTT, 500 ⁇ M dNTP mix, and 20 units / ⁇ l SuperScript II Reverse Transcriptase were added to 10 ⁇ g RNA at 42 ° C. for 1 hour. Single-stranded DNA was synthesized. Subsequently, 1 ⁇ Second strand buffer, 200 ⁇ M dNTP mix, 67 U / ml DNA ligase, 270 U / ml DNA polymerase I, and 13 U / ml RNase H were added, and the mixture was reacted at 16 ° C. for 2 hours to obtain double-stranded cDNA. Synthesized.
  • 67 U / ml T4 DNA polymerase I was added and reacted at 16 ° C. for 5 minutes, and then 10 ⁇ l of 0.5 M EDTA was added to stop the reaction.
  • the obtained cDNA was purified with phenol / chloroform and labeled with biotinylated UTP and CTP using RNA Transscript Labeling Kit (Enzo Diagnostics) according to the attached operation method.
  • the reaction product was purified by an RNeasy column, and then cRNA was fragmented by heating at 94 ° C. for 35 minutes in 200 mM trisacetic acid pH 8.1, 150 mM magnesium acetate, 50 mM potassium acetate.
  • GeneChip (Affymetrix) Human Focus array in 100 mM MES, 1 M sodium salt, 20 mM EDTA, 0.01% Tween 20, for 16 hours at 45 ° C. After hybridization, GeneChip was washed and stained according to the protocol Midi_euk2 attached to the Affymetrix fluidics station. For staining, streptavidin-phycoerythrin and biotinylated anti-streptavidin goat antibody were used. The stained GeneChip was scanned using a HP argon ion laser confocal microscope (Hewlett Packard), and the fluorescence intensity was measured.
  • HP argon ion laser confocal microscope Hewlett Packard
  • HCT116 cells were used, and E7820 (0.16 ⁇ M), E7070 (0.26 ⁇ M), LY186664 (59 ⁇ M), LY295501 (24 ⁇ M), LY573636 (9.6 ⁇ M), CQS (4.0 ⁇ M) , MST16 (100 ⁇ M), ethoside (3.6 ⁇ M), ethoxolamide (410 ⁇ M), capsaicin (280 ⁇ M), trichostatin A (0.16 ⁇ M) and kenpaulone (7.1 ⁇ M) were examined for changes in gene expression. It was.
  • MST16 the DNA topoisomerase II inhibitors catalytic type
  • etoposide is DNA topoisomerase II inhibitor that induces formation of cleavable complex
  • ethoxzolamide is carbonic anhydrase inhibitor
  • capsaicin is tumor-specific plasmamembrane NADH oxidase inhibitor
  • trichostatin A is A histone deacetylase inhibitor
  • kenpaulone are known compounds as cyclin-dependent kinases (CDKs) inhibitors, respectively.
  • the compound treatment concentration was set to a concentration twice that of the 50% growth inhibitory concentration of each compound on HCT116 cells (based on the 3-day cytostatic activity using MTT).
  • LY1 is LY186664, “LY2” LY295501, “LY5” is LY573636, “CAI” is ethoxazolide, “Cap” is capsaicin, “MST” is MST16, “Etop” “Represents ethoside,” TSA “represents trichostatin A, and” Kenp “represents kenpaulone.
  • “de hclust ( * ,“ average ”)” is a command for performing statistical analysis, and indicates that clustering analysis by R was performed using the average value of duplicate experimental data. Show.
  • Cancer cell line panel experiment Using 36 human cancer cell panels, the correlation of cell growth inhibitory activity of E7820, E7070, CQS, LY186661, and LY295501 was examined.
  • the cancer cell lines used were DLD-1, HCT15, HCT116, HT29, SW480, SW620, WiDr (above, human colon cancer cell line), A427, A549, LX-1, NCI-H460, NCI-H522, PC-.
  • PC-10 above, human lung cancer cell line
  • GT3TKB HGC27, MKN1, MKN7, MKN28, MKN74 (above, human gastric cancer cell line), AsPC-1, KP-1, KP-4, MiaPaCaII, PANC- 1, SUIT-2 (above, human pancreatic cancer cell line), BSY-1, HBC5, MCF-7, MAD-MB-231, MDA-MB-435, MDA-MB-468 (above, human breast cancer cell line) , CCRF-CEM, HL60, K562, MOLT-4 (above, human leukemia cell line) 10% fetal bovine serum, and cultured in 5% CO 2 under 37 ° C.
  • Table 1 shows the types of human cancer cell lines, the number of squeezed cells and the doubling time in the human cancer cell line panel.
  • Cells were plated in a 96-well microplate (flat bottom) with the number of cells listed in Table 1 (50 ⁇ l / well), and after 24 hours, 3-fold dilution series of compounds were added (50 ⁇ l / well). After 72 hours, WST-8 (10 ⁇ l / well) was added, and the absorbance at 450 nm was measured.
  • the 50% growth inhibitory inhibitory concentration for all 36 cancer cells was determined by the least square method, and the patterns were compared among the compounds.
  • Pearson's correlation coefficients was used (Paul, K. D. et al. Display and analysis of patterns of differential activity of drugs in augmentation. Natl.Cancer Inst.1989, 81, 1088-1092; Monks, A. et al.Feasibility of a high-flux anticancer drug using a diverse panel of culture. l lines.J.Natl.Cancer Inst.1991,83,757-766.).
  • E7070, E7820, LY186411, LY295501 and CQS showed high correlation coefficients in the growth inhibitory activity against each cancer cell line (Table 2). Therefore, this analysis strongly suggests that E7070, E7820, LY186664, LY295501 and CQS have the same or similar mechanism of action, resulting in the same or similar genetic changes and effects.
  • Table 2 shows the correlation coefficients between compounds (E7070, E7820, CQS, LY186661 and LY295501) in the human cancer cell line panel.
  • HCT116-C9 is a sub-strain isolated from human colorectal cancer-derived HCT116 (American Type Culture Collection, Manassas, VA, USA). This HCT116-C9 was cultured in the presence of E7070, and the E7070 concentration was increased. The E7070 resistant substrains obtained by gradual elevation are HCT116-C9-C1 and HCT116-C9-C4 (Molecular Cancer Therapeutics, 2002, 1,275-286).
  • HCT116-C9 Three cell lines of HCT116-C9, HCT116-C9-C1, and HCT116-C9-C4 were spread on a 96-well microplate (flat bottom) at 3000 cells / well (50 ⁇ l / well), and after 3 hours, a 3-fold dilution series of compounds was added. Added (50 ⁇ l / well). Furthermore, cell growth inhibitory activity was evaluated 72 hours later by the MTT method (Mossmann T., J. Immunol. Methods, 1983, 65, 55-63). The 50% growth inhibitory inhibitory concentration for each cancer cell was determined by the least square method. As a result, the cell growth inhibitory activity of E7070 was 0.127 ⁇ M for HCT116-C9 (C9).
  • HCT116-C9-C1 C9C1
  • HCT116-C9-C4 C9C4
  • IC50 31.9 ⁇ M and 26.9 ⁇ M
  • the cell growth inhibitory activity of E7070 against C9C1 and C9C4 is remarkable. It was confirmed that it decreased (FIG. 13).
  • the cytostatic activity of LY573636 was evaluated simultaneously with E7070 using the E7070 resistant strain in the same manner as in Example 11.
  • LY573636 was considered to have the same or similar mechanism of action as E7070, and was strongly suggested to produce the same or similar genetic changes and effects.
  • E7820 shows antitumor activity from the results of Example 1, and it is clear from the results of Example 6 that it has a blood vessel normalizing action.
  • E7820 was found to test the anti-tumor effect of a sulfonamide compound K trans or PET or SPECT.
  • a sulfonamide compound preferably E7070, LY186411, LY295501, LY-ASAP, LY573636 or CQS or a combination thereof, can be examined using K trans or PET or SPECT as an index.
  • the sensitivity of a tumor to a sulfonamide compound can be evaluated. As a result, it can be administered to cancer patients after judging whether or not the administration of the sulamide compound is effective.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Physics & Mathematics (AREA)
  • Urology & Nephrology (AREA)
  • Microbiology (AREA)
  • Optics & Photonics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Toxicology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Food Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur un procédé de test de la sensibilité d'un tissu de tumeur vis-à-vis d'un composé de sulfonamide. De façon spécifique, l'invention porte sur un procédé de test de la sensibilité d'un tissu de tumeur à un composé de sulfonamide, lequel procédé comprend les étapes consistant à mesurer des valeurs Ktarns dans un tissu de tumeur collecté à partir d'un sujet avant et après que le composé sulfonamide ou un analogue de celui-ci ait été administré au sujet et à analyser la répartition des valeurs Ktarns avant et après l'administration.
PCT/JP2009/067444 2009-03-30 2009-09-30 Procédé de test de sensibilité de tissu de tumeur WO2010116550A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009083275A JP2012136435A (ja) 2009-03-30 2009-03-30 腫瘍組織の感受性を検査する方法
JP2009-083275 2009-03-30

Publications (1)

Publication Number Publication Date
WO2010116550A1 true WO2010116550A1 (fr) 2010-10-14

Family

ID=42935853

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/067444 WO2010116550A1 (fr) 2009-03-30 2009-09-30 Procédé de test de sensibilité de tissu de tumeur

Country Status (2)

Country Link
JP (1) JP2012136435A (fr)
WO (1) WO2010116550A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115252603A (zh) * 2022-07-08 2022-11-01 深圳市第二人民医院(深圳市转化医学研究院) indisulam在制备治疗膀胱癌的药物中的应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6296459A (ja) * 1985-09-23 1987-05-02 イ−ライ・リリ−・アンド・カンパニ− 抗腫瘍化合物
WO2000050395A1 (fr) * 1999-02-26 2000-08-31 Eisai Co., Ltd. Composes indoles contenant un sulfonamide
WO2002042493A1 (fr) * 2000-11-24 2002-05-30 Eisai C0. Ltd. Procede d'essai de la sensibilite aux agents anticancereux de cellules tumorales
JP2004530709A (ja) * 2001-06-06 2004-10-07 イーライ・リリー・アンド・カンパニー 抗腫瘍剤としての使用のためのベンゾイルスルホンアミドおよびスルホニルベンズアミジン
WO2006036025A1 (fr) * 2004-09-30 2006-04-06 Eisai R & D Management Co., Ltd. Procédé pour évaluer la sensibilité d’une cellule tumorale à un composé contenant un sulfonamide
WO2007123274A1 (fr) * 2006-04-20 2007-11-01 Eisai R & D Management Co., Ltd. Nouveau marqueur CONTRE la SENSIBILITÉ À un COMPOSÉ de sulfonamide

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6296459A (ja) * 1985-09-23 1987-05-02 イ−ライ・リリ−・アンド・カンパニ− 抗腫瘍化合物
WO2000050395A1 (fr) * 1999-02-26 2000-08-31 Eisai Co., Ltd. Composes indoles contenant un sulfonamide
WO2002042493A1 (fr) * 2000-11-24 2002-05-30 Eisai C0. Ltd. Procede d'essai de la sensibilite aux agents anticancereux de cellules tumorales
JP2004530709A (ja) * 2001-06-06 2004-10-07 イーライ・リリー・アンド・カンパニー 抗腫瘍剤としての使用のためのベンゾイルスルホンアミドおよびスルホニルベンズアミジン
WO2006036025A1 (fr) * 2004-09-30 2006-04-06 Eisai R & D Management Co., Ltd. Procédé pour évaluer la sensibilité d’une cellule tumorale à un composé contenant un sulfonamide
WO2007123274A1 (fr) * 2006-04-20 2007-11-01 Eisai R & D Management Co., Ltd. Nouveau marqueur CONTRE la SENSIBILITÉ À un COMPOSÉ de sulfonamide

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FERRIER, MC ET AL.: "VALIDATION OF DYNAMIC CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING- DERIVED VASCULAR PERMEABILITY MEASUREMENTS USING QUANTITATIVE AUTORADIOGRAPHY IN THE RG2 RAT BRAIN TUMOR MODEL.", NEOPLASIA, vol. 9, no. 7, 2007, pages 546 - 555 *
MORGAN, B. ET AL.: "A SIMPLE, REPRODUCIBLE METHOD FOR MONITORING THE TREATMENT OF TUMOURS USING DYNAMIC CONTRAST-ENHANCED MR IMAGING.", BR. J .CANCER, vol. 94, no. 10, 2006, pages 1420 - 1427 *
O'CONNOR, JP ET AL.: "DCE-MRI BIOMARKERS IN THE CLINICAL EVALUATION OF ANTIANGIOGENIC AND VASCULAR DISRUPTING AGENTS.", BR. J. CANCER, vol. 96, no. 2, 2007, pages 189 - 195 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115252603A (zh) * 2022-07-08 2022-11-01 深圳市第二人民医院(深圳市转化医学研究院) indisulam在制备治疗膀胱癌的药物中的应用

Also Published As

Publication number Publication date
JP2012136435A (ja) 2012-07-19

Similar Documents

Publication Publication Date Title
Avril et al. Monitoring response to treatment in patients utilizing PET
Stroobants et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec®)
Ravnan et al. Vemurafenib in patients with BRAF V600E mutation–positive advanced melanoma
Vilgrain et al. Insights into the diagnosis of hepatocellular carcinomas with hepatobiliary MRI
AU2019264073B2 (en) 2-amino-2-(1,2,3-triazole-4-yl)propane-1,3-diol derivative of novel compound for directly inhibiting ASM activity, and use thereof
JP2022082565A (ja) がんを処置するための方法
Jacobson et al. Interrogating tumor metabolism and tumor microenvironments using molecular positron emission tomography imaging. Theranostic approaches to improve therapeutics
Honer et al. Anti-angiogenic/vascular effects of the mTOR inhibitor everolimus are not detectable by FDG/FLT-PET
Zhuang et al. Time‐intensity curve parameters in colorectal tumours measured using double contrast‐enhanced ultrasound: correlations with tumour angiogenesis
WO2015160868A1 (fr) Méthodes de traitement du cancer à l'aide d'une polythérapie avec des inhibiteurs de la kinase tor
JP2021113819A (ja) 皮膚におけるｃ−Ｊｕｎ Ｎ末端キナーゼの阻害の測定方法
BR112021005518A2 (pt) métodos para tratar distúrbios mieloproliferativos
KR20200126388A (ko) Chk1 저해제를 포함하는 암의 치료 방법
JP2022501432A (ja) ヒト疾患の治療のためのｆｌ１１８プラットフォーム位置７および９由来の類似体の組成、合成、処方および適用の問題
Shiozawa et al. Evaluation of sorafenib for advanced hepatocellular carcinoma with low α-fetoprotein in arrival time parametric imaging using contrast-enhanced ultrasonography
WO2010116550A1 (fr) Procédé de test de sensibilité de tissu de tumeur
Kudo Recent trends in the management of hepatocellular carcinoma with special emphasis on treatment with regorafenib and immune checkpoint inhibitors
Saito et al. Hepatocellular Carcinoma in Keio Affiliated Hospitals—Diagnosis, Treatment, and Prognosis of this Disease—
Yu et al. Evaluation of the relationship between [18F] FDG and P-glycoprotein expression: an experimental study
Luo et al. Role of diffusional kurtosis imaging in evaluating the efficacy of transcatheter arterial chemoembolization in patients with liver cancer
Kostakoglu Radionuclide response assessment of breast cancer
WO2018226971A1 (fr) Compositions peptidiques pour imagerie moléculaire d'immuno-oncologie et administration ciblée de médicaments
JP7419572B2 (ja) 小児がん治療用医薬組成物
Benson et al. Inhibition of Tumor Angiogenesis in GIST Therapy
Boonsirikamchai et al. Imaging of gastrointestinal stromal tumors and assessment of benefit from systemic therapy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09843056

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09843056

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP