JP5280603B2 - 転移阻害のための方法 - Google Patents
転移阻害のための方法 Download PDFInfo
- Publication number
- JP5280603B2 JP5280603B2 JP2003531978A JP2003531978A JP5280603B2 JP 5280603 B2 JP5280603 B2 JP 5280603B2 JP 2003531978 A JP2003531978 A JP 2003531978A JP 2003531978 A JP2003531978 A JP 2003531978A JP 5280603 B2 JP5280603 B2 JP 5280603B2
- Authority
- JP
- Japan
- Prior art keywords
- taurolidine
- tumor
- liver
- cells
- use according
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
- 206010027476 Metastases Diseases 0.000 title claims description 29
- 230000009401 metastasis Effects 0.000 title claims description 25
- 238000000034 method Methods 0.000 title description 22
- 230000005764 inhibitory process Effects 0.000 title description 6
- AJKIRUJIDFJUKJ-UHFFFAOYSA-N taurolidine Chemical compound C1NS(=O)(=O)CCN1CN1CNS(=O)(=O)CC1 AJKIRUJIDFJUKJ-UHFFFAOYSA-N 0.000 claims description 126
- 229960004267 taurolidine Drugs 0.000 claims description 126
- 206010028980 Neoplasm Diseases 0.000 claims description 68
- 210000004185 liver Anatomy 0.000 claims description 60
- 230000000694 effects Effects 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 102000011727 Caspases Human genes 0.000 claims description 14
- 108010076667 Caspases Proteins 0.000 claims description 14
- 208000029742 colonic neoplasm Diseases 0.000 claims description 14
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 14
- 230000010412 perfusion Effects 0.000 claims description 14
- 210000005228 liver tissue Anatomy 0.000 claims description 13
- 230000001394 metastastic effect Effects 0.000 claims description 13
- 208000014018 liver neoplasm Diseases 0.000 claims description 12
- 206010019695 Hepatic neoplasm Diseases 0.000 claims description 9
- 210000000056 organ Anatomy 0.000 claims description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- 230000017531 blood circulation Effects 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 5
- 239000008280 blood Substances 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 230000001839 systemic circulation Effects 0.000 claims description 4
- 230000004087 circulation Effects 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 210000003200 peritoneal cavity Anatomy 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 2
- 238000012084 abdominal surgery Methods 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 208000037841 lung tumor Diseases 0.000 claims description 2
- 208000025402 neoplasm of esophagus Diseases 0.000 claims description 2
- 208000025189 neoplasm of testis Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 201000003120 testicular cancer Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 102
- 238000011282 treatment Methods 0.000 description 41
- 241001465754 Metazoa Species 0.000 description 21
- 102000012406 Carcinoembryonic Antigen Human genes 0.000 description 19
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 19
- 238000002347 injection Methods 0.000 description 19
- 239000007924 injection Substances 0.000 description 19
- 206010009944 Colon cancer Diseases 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 210000000952 spleen Anatomy 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 230000006907 apoptotic process Effects 0.000 description 13
- 230000021164 cell adhesion Effects 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 238000003556 assay Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 230000009467 reduction Effects 0.000 description 12
- 230000009885 systemic effect Effects 0.000 description 12
- 230000001464 adherent effect Effects 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- 108090000397 Caspase 3 Proteins 0.000 description 10
- 102000003952 Caspase 3 Human genes 0.000 description 10
- 231100000135 cytotoxicity Toxicity 0.000 description 10
- 230000003013 cytotoxicity Effects 0.000 description 10
- 210000003240 portal vein Anatomy 0.000 description 10
- 206010027457 Metastases to liver Diseases 0.000 description 9
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 8
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- 230000003247 decreasing effect Effects 0.000 description 8
- 238000001356 surgical procedure Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 238000000684 flow cytometry Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229940127089 cytotoxic agent Drugs 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000002271 resection Methods 0.000 description 5
- 229940123169 Caspase inhibitor Drugs 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 231100000002 MTT assay Toxicity 0.000 description 4
- 238000000134 MTT assay Methods 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000000118 anti-neoplastic effect Effects 0.000 description 4
- 210000000709 aorta Anatomy 0.000 description 4
- 108010078837 aspartyl-glutamyl-valyl-aspartyl-p-nitroanilide Proteins 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 230000003833 cell viability Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 210000002767 hepatic artery Anatomy 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000012752 Hepatectomy Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 229920004890 Triton X-100 Polymers 0.000 description 3
- 239000013504 Triton X-100 Substances 0.000 description 3
- 230000025164 anoikis Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000019423 liver disease Diseases 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 3
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 2
- 206010057248 Cell death Diseases 0.000 description 2
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 2
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 102000006382 Ribonucleases Human genes 0.000 description 2
- 108010083644 Ribonucleases Proteins 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 238000002784 cytotoxicity assay Methods 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012317 liver biopsy Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FBFNMTGUOBUGFQ-UHFFFAOYSA-M 2-(2,5-diphenyltetrazol-1-ium-1-yl)-4,5-dimethyl-1,3-thiazole;bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=C(C=2C=CC=CC=2)N=NN1C1=CC=CC=C1 FBFNMTGUOBUGFQ-UHFFFAOYSA-M 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 238000000035 BCA protein assay Methods 0.000 description 1
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102100029855 Caspase-3 Human genes 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 101000793880 Homo sapiens Caspase-3 Proteins 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000009857 Microaneurysm Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 238000010162 Tukey test Methods 0.000 description 1
- MIFGOLAMNLSLGH-QOKNQOGYSA-N Z-Val-Ala-Asp(OMe)-CH2F Chemical compound COC(=O)C[C@@H](C(=O)CF)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)OCC1=CC=CC=C1 MIFGOLAMNLSLGH-QOKNQOGYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229950004398 broxuridine Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000008619 cell matrix interaction Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000012707 chemical precursor Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000062 effect on obesity Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 201000001037 lung lymphoma Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- INAAIJLSXJJHOZ-UHFFFAOYSA-N pibenzimol Chemical compound C1CN(C)CCN1C1=CC=C(N=C(N2)C=3C=C4NC(=NC4=CC=3)C=3C=CC(O)=CC=3)C2=C1 INAAIJLSXJJHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000011581 secondary neoplasm Diseases 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000010304 tumor cell viability Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000007332 vesicle formation Effects 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US32628801P | 2001-10-01 | 2001-10-01 | |
| US60/326,288 | 2001-10-01 | ||
| PCT/US2002/031079 WO2003028642A2 (en) | 2001-10-01 | 2002-10-01 | Methods of inhibiting metastases |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010107880A Division JP2010209101A (ja) | 2001-10-01 | 2010-05-10 | 転移阻害のための方法 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2005504814A JP2005504814A (ja) | 2005-02-17 |
| JP2005504814A5 JP2005504814A5 (enExample) | 2006-01-05 |
| JP5280603B2 true JP5280603B2 (ja) | 2013-09-04 |
Family
ID=23271590
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003531978A Expired - Fee Related JP5280603B2 (ja) | 2001-10-01 | 2002-10-01 | 転移阻害のための方法 |
| JP2010107880A Pending JP2010209101A (ja) | 2001-10-01 | 2010-05-10 | 転移阻害のための方法 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010107880A Pending JP2010209101A (ja) | 2001-10-01 | 2010-05-10 | 転移阻害のための方法 |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US6753328B2 (enExample) |
| EP (1) | EP1450814B1 (enExample) |
| JP (2) | JP5280603B2 (enExample) |
| AU (1) | AU2002362459B2 (enExample) |
| CA (1) | CA2462564C (enExample) |
| WO (1) | WO2003028642A2 (enExample) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6753328B2 (en) * | 2001-10-01 | 2004-06-22 | Rhode Island Hospital | Methods of inhibiting metastases |
| WO2004094823A2 (en) | 2003-04-23 | 2004-11-04 | Biovalve Technologies, Inc. | Hydraulically actuated pump for long duration medicament administration |
| US9089636B2 (en) | 2004-07-02 | 2015-07-28 | Valeritas, Inc. | Methods and devices for delivering GLP-1 and uses thereof |
| JP2009532117A (ja) | 2006-03-30 | 2009-09-10 | ヴァレリタス，エルエルシー | マルチカートリッジ式流体投与装置 |
| CN101528195B (zh) * | 2006-09-07 | 2012-03-28 | 埃德盖斯特利希索恩化学工业股份公司 | 羟甲基转移剂在制备治疗骨癌的药物中的用途 |
| DE102008060549A1 (de) | 2008-12-04 | 2010-06-10 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Wirkstoff-Peptid-Konstrukt zur extrazellulären Anreicherung |
| WO2011011688A2 (en) | 2009-07-24 | 2011-01-27 | Rhode Island Hospital | DENDRITIC CELL VACCINES FOR ASPARAGINYL- β - HYDROXYLASE EXPRESSING TUMORS |
| US11738120B1 (en) | 2022-04-14 | 2023-08-29 | Cormedix Inc. | Synthesis of taurolidine, purity profiles and polymorphs |
Family Cites Families (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1124285A (en) | 1964-10-06 | 1968-08-21 | Geistlich Soehne Ag | Novel perhydro-1,2,4-thiadiazine dioxides-(1,1), their preparation and compositionscontaining them |
| GB1408010A (en) | 1972-11-20 | 1975-10-01 | Geistlich Soehne Ag | Sulphamoylphenyl-imidazolidinones |
| GB1557163A (en) | 1975-06-24 | 1979-12-05 | Geistlich Soehne Ag | Dental care preparations |
| US4107305A (en) | 1975-08-04 | 1978-08-15 | Ed. Geistlich Sohne A.G. Fur Chemische Industrie | Treatment of endotoxaemia |
| GB1588110A (en) | 1978-05-31 | 1981-04-15 | Geistlich Soehne Ag | Pharmaceutical compositions for the treatment of scars |
| US4337251A (en) | 1979-05-09 | 1982-06-29 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Method of avoiding and removing adhesions |
| CA1190855A (en) | 1980-09-03 | 1985-07-23 | Rolf W. Pfirrmann | Treatment of osteitis |
| GB8328073D0 (en) | 1983-10-20 | 1983-11-23 | Geistlich Soehne Ag | Chemical compounds |
| GB8328111D0 (en) | 1983-10-20 | 1983-11-23 | Geistlich Soehne Ag | Chemical compounds |
| GB8328074D0 (en) | 1983-10-20 | 1983-11-23 | Geistlich Soehne Ag | Chemical compositions |
| US5210083A (en) | 1986-07-17 | 1993-05-11 | Ed. Geistlich Sohne A.G. Fur Chemische Industrie | Pharmaceutical compositions |
| GB8617482D0 (en) | 1986-07-17 | 1986-08-28 | Geistlich Soehne Ag | Pharmaceutical composition |
| US5573771A (en) | 1988-08-19 | 1996-11-12 | Osteomedical Limited | Medicinal bone mineral products |
| US5069662A (en) * | 1988-10-21 | 1991-12-03 | Delcath Systems, Inc. | Cancer treatment |
| US5819748A (en) | 1988-11-30 | 1998-10-13 | Ed Geistlich Sohne Ag Fur Chemische Industrie | Implant for use in bone surgery |
| GB8827986D0 (en) | 1988-11-30 | 1989-01-05 | Geistlich Soehne Ag | Chemical product |
| GB9005856D0 (en) | 1990-03-15 | 1990-05-09 | Geistlich Soehne Ag | Compositions |
| GB9015108D0 (en) | 1990-07-09 | 1990-08-29 | Geistlich Soehne Ag | Chemical compositions |
| US5635532A (en) | 1991-10-21 | 1997-06-03 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Compositions and methods for therapy and prevention of pathologies including cancer, AIDS and anemia |
| GB9216155D0 (en) | 1992-07-30 | 1992-09-09 | Geistlich Soehne Ag | Treatment of dentoalveolar infections |
| US5954687A (en) | 1995-04-28 | 1999-09-21 | Medtronic, Inc. | Burr hole ring with catheter for use as an injection port |
| US5976822A (en) | 1995-05-18 | 1999-11-02 | Coulter International Corp. | Method and reagent for monitoring apoptosis and distinguishing apoptosis from necrosis |
| GB9600426D0 (en) | 1996-01-10 | 1996-03-13 | Ed Geistlich Sohne A G | Compositions |
| AU734460B2 (en) | 1997-05-22 | 2001-06-14 | Oklahoma Medical Research Foundation | Use of taurolidine for treatment of leukemias |
| US6479481B1 (en) | 1999-06-04 | 2002-11-12 | Ed. Geistlich Soehne Ag Fur Chemische Industrie | Methods and compositions for treating primary and secondary tumors of the central nervous system (CNS) |
| US7151099B2 (en) | 1998-07-31 | 2006-12-19 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Use of taurolidine and/or taurultam for treatment of abdominal cancer and/or for the prevention of metastases |
| GB9716219D0 (en) * | 1997-07-31 | 1997-10-08 | Geistlich Soehne Ag | Prevention of metastases |
| US6011030A (en) | 1997-09-22 | 2000-01-04 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Method of treating symptoms of microbial infection or sepsis |
| US5972933A (en) | 1998-01-08 | 1999-10-26 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Method of treating microbial infections |
| US6117868A (en) | 1998-09-16 | 2000-09-12 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Treatment of gastrointestinal ulcers or gastritis caused by microbial infection |
| US20020098164A1 (en) * | 2000-10-27 | 2002-07-25 | Redmond H. Paul | Treatment of tumor metastases and cancer |
| SE516215C2 (sv) * | 1999-07-10 | 2001-12-03 | Argmed Kb | Perfusionssystem samt pumpanordning och styrsystem för användning i perfusionssystemet |
| CA2393252A1 (en) | 1999-12-06 | 2001-06-07 | Paul Calabresi | Use of methylol-containing compounds to treat tumors |
| CA2363973C (en) * | 2000-11-28 | 2009-03-10 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Enhancement of effectiveness of 5-fluorouracil in treatment of tumor metastases and cancer |
| US6753328B2 (en) * | 2001-10-01 | 2004-06-22 | Rhode Island Hospital | Methods of inhibiting metastases |
-
2002
- 2002-10-01 US US10/262,778 patent/US6753328B2/en not_active Expired - Lifetime
- 2002-10-01 CA CA2462564A patent/CA2462564C/en not_active Expired - Fee Related
- 2002-10-01 JP JP2003531978A patent/JP5280603B2/ja not_active Expired - Fee Related
- 2002-10-01 WO PCT/US2002/031079 patent/WO2003028642A2/en not_active Ceased
- 2002-10-01 EP EP02800392.9A patent/EP1450814B1/en not_active Expired - Lifetime
- 2002-10-01 AU AU2002362459A patent/AU2002362459B2/en not_active Ceased
-
2004
- 2004-06-21 US US10/873,802 patent/US7122541B2/en not_active Expired - Lifetime
-
2010
- 2010-05-10 JP JP2010107880A patent/JP2010209101A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003028642A2 (en) | 2003-04-10 |
| US20050032785A1 (en) | 2005-02-10 |
| US6753328B2 (en) | 2004-06-22 |
| EP1450814A2 (en) | 2004-09-01 |
| CA2462564C (en) | 2012-07-10 |
| JP2010209101A (ja) | 2010-09-24 |
| JP2005504814A (ja) | 2005-02-17 |
| WO2003028642A3 (en) | 2003-12-04 |
| US20030069229A1 (en) | 2003-04-10 |
| CA2462564A1 (en) | 2003-04-10 |
| WO2003028642A9 (en) | 2004-03-04 |
| US7122541B2 (en) | 2006-10-17 |
| EP1450814B1 (en) | 2016-11-30 |
| AU2002362459B2 (en) | 2007-08-02 |
| EP1450814A4 (en) | 2008-02-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10245240B2 (en) | Treatment of prostate carcinoma | |
| JP2010209101A (ja) | 転移阻害のための方法 | |
| Flaig et al. | A study of high‐dose oral silybin‐phytosome followed by prostatectomy in patients with localized prostate cancer | |
| Das et al. | Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFκB | |
| CA2689717C (en) | Non-toxic anti-cancer drug combining ascorbate, magnesium and a naphthoquinone | |
| AU2002362459A1 (en) | Methods of inhibiting metastases | |
| Fakih et al. | Inhibition of prostate cancer growth by estramustine and colchicine | |
| Cheng et al. | Cryptotanshinone enhances the efficacy of Bcr-Abl tyrosine kinase inhibitors via inhibiting STAT3 and eIF4E signalling pathways in chronic myeloid leukaemia | |
| JP2020132625A (ja) | 肝臓癌に対するサフラナールとソラフェニブの併用療法 | |
| Garnick | Advanced renal cell cancer | |
| Karaca et al. | COMPARISON OF THE EFFECTS OF DOCETAXEL and AMYGDALIN TREATMENT ON CELL DEATH, INTEGRIN-α and INTEGRIN-β EXPRESSIONS IN DU145 PROSTATE CANCER CELL LINE | |
| Yu et al. | Harmine exerts anticancer effects through the ROS/p38 axis to induce autophagy and apoptosis in osteosarcoma | |
| Lobianco | Targeting Redox Metabolism for Liver Cancer Therapy | |
| JP4522261B2 (ja) | ブドウ膜黒色腫の処置 | |
| JP2005247807A (ja) | Ｎｓａｉｄを利用した癌治療用組成物 | |
| US20090054507A1 (en) | Control of malignant cells by kinase inhibition | |
| WO2023041978A1 (es) | COMPOSICIONES SINÉRGICAS DE COMPUESTOS CONTRA EL COMPLEJO HETERODIMÉRICO K-RAS4B/PDE6δ PARA EL TRATAMIENTO DE CÁNCER DE PÁNCREAS | |
| WO2009032213A1 (en) | Control of malignant cells by kinase inhibition | |
| Rodríguez-Fragoso | Gallic acid produces hepatoprotection by modulating EGFR expression and phosphorylation in induced preneoplastic liver foci in rats | |
| Clarke | Cryosurgical modeling: Cytotoxic agent addition enhances freezing-induced cell death in a prostate cancer cell model | |
| Myers | Mitochondrial Apoptosis: A New Foundation for Combing Agents in Prostate Cancer Treatment | |
| Arvanitakis et al. | Carcinoma in situ of the urinary bladder | |
| Knock et al. | Clinical cancer chemotherapy aimed at potential cell regulators | |
| Fakih et al. | Inhibition of Prostate Cancer Growth by Estramustine and Colchicine zyxwvutsrqpo | |
| Okaro | Anti-apoptotic proteins and cholangiocarcinoma |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050922 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050922 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20081128 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20081128 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090518 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090728 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20100201 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100510 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20100610 |
|
| A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20100716 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20121130 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20121206 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20121228 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130108 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130201 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130523 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 5280603 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |