HRP20020658A2 - A composition comprising camptothecin and a pyrimidine derivative for the treatment of cancer - Google Patents
A composition comprising camptothecin and a pyrimidine derivative for the treatment of cancer Download PDFInfo
- Publication number
- HRP20020658A2 HRP20020658A2 HRP20020658A HRP20020658A2 HR P20020658 A2 HRP20020658 A2 HR P20020658A2 HR P20020658 A HRP20020658 A HR P20020658A HR P20020658 A2 HRP20020658 A2 HR P20020658A2
- Authority
- HR
- Croatia
- Prior art keywords
- cancer
- treatment
- capecitabine
- cpt
- combination
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 33
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 18
- 201000011510 cancer Diseases 0.000 title claims abstract description 17
- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 17
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 229940127093 camptothecin Drugs 0.000 title claims abstract description 5
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 239000000203 mixture Substances 0.000 title description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical group C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims abstract description 39
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims abstract description 36
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229960004117 capecitabine Drugs 0.000 claims abstract description 35
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 17
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 10
- 229960005277 gemcitabine Drugs 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 14
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 10
- 229960002949 fluorouracil Drugs 0.000 description 10
- 229960004768 irinotecan Drugs 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 7
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 6
- -1 substituted alkyl radical Chemical class 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000006820 DNA synthesis Effects 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000001177 diphosphate Substances 0.000 description 4
- 235000011180 diphosphates Nutrition 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- 206010061818 Disease progression Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
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- 231100000682 maximum tolerated dose Toxicity 0.000 description 3
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- 235000011178 triphosphate Nutrition 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- YMOXEIOKAJSRQX-QPPQHZFASA-N Gemcitabine triphosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 YMOXEIOKAJSRQX-QPPQHZFASA-N 0.000 description 2
- 208000002375 Hand-Foot Syndrome Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
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- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 2
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- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
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- 201000002528 pancreatic cancer Diseases 0.000 description 2
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- 239000000243 solution Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000011806 swiss nude mouse Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- HWPZZUQOWRWFDB-UHFFFAOYSA-N 1-methylcytosine Chemical compound CN1C=CC(N)=NC1=O HWPZZUQOWRWFDB-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 229940117937 Dihydrofolate reductase inhibitor Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
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- 108010011356 Nucleoside phosphotransferase Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000009097 Phosphorylases Human genes 0.000 description 1
- 108010073135 Phosphorylases Proteins 0.000 description 1
- 102000000505 Ribonucleotide Reductases Human genes 0.000 description 1
- 108010041388 Ribonucleotide Reductases Proteins 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
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- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- BZRPOJFQTMPGJK-UHFFFAOYSA-N carbamic acid;2-fluoropyrimidine Chemical compound NC(O)=O.FC1=NC=CC=N1 BZRPOJFQTMPGJK-UHFFFAOYSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
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- 210000001072 colon Anatomy 0.000 description 1
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- 231100000026 common toxicity Toxicity 0.000 description 1
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- WKPZKRWOIZKCDN-WAQYZQTGSA-N ctp-11 Chemical compound Cl.C=1C=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=1OC(=O)N(CC1)CCC1N1CCCCC1 WKPZKRWOIZKCDN-WAQYZQTGSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
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- 238000003745 diagnosis Methods 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
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- 239000000839 emulsion Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- FRQISCZGNNXEMD-QPPQHZFASA-N gemcitabine diphosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O1 FRQISCZGNNXEMD-QPPQHZFASA-N 0.000 description 1
- OKKDEIYWILRZIA-OSZBKLCCSA-N gemcitabine hydrochloride Chemical compound [H+].[Cl-].O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 OKKDEIYWILRZIA-OSZBKLCCSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
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- 201000010536 head and neck cancer Diseases 0.000 description 1
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- 230000036541 health Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
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- 239000007924 injection Substances 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
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- 150000003254 radicals Chemical class 0.000 description 1
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- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
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- 230000009885 systemic effect Effects 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Ova prijava se poziva na privremene prijave U. S. Provisional Application No. 0/185,378, predano 28. 02. 2000 i U. S. Provisional Application No. 60/208,938 predano 05. 06. 2000.
Predmetni izum se odnosi na terapeutske farmaceutske kompozicije koje obuhvaćaju efikasnu količinu derivata pirimidina u kombinaciji s efikasnom količinom kamptotecina ili derivata kamptotecina koji su korisni u liječenju raka.
Izum se odnosi na liječenje raka, naročito čvrstih tumora, asocijacijama derivata kamptotecina i drugih lijekova protiv raka te upotrebu takvih asocijacija za poboljšanu terapiju.
Određenije, izum se odnosi na liječenje raka asocijacijama derivata kamptotecina kao što je irinotekan (CPT - 11; Camptosar®), topotekan, 9 aminokamptotecin i 9-nitrokamptotecin, i derivata pirimidina. Derivati pirimidina uključuju spojeve koji sadrže uracil, timin, citozin, matilcitozin i tiamin. Primjeri takvih derivata pirimidina su kapecitabin, gemcitabin i višestruko ciljani antifolat (MTA) poznat kao pemetrexed.
Evropski patent EP 137,145, uključen ovdje, opisuje derivate kamptotecina formule:
[image]
u kojoj, određenije, R1 je vodik, halogen ili alkil, X je atom klora ili NR2R3 gdje R2 i R3, koji mogu biti identični ili različiti, mogu predstavljati atom vodika, alkilni radikal supstituiran po izboru, karbocikličku ili heterocikličku skupinu koje po izboru mogu biti supstituirane, ili alkilne radikale (po izboru supstituirane) koji s atomom dušika na koji su vezani tvore heterociklički prsten koji sadrži drugi heteroatom izabran između O, S i/ili NR4, gdje R4 je atom vodika ili alkilni radikal i gdje se grupa X-CO-O- nalazi na položaju 9, 10 ili 11 na prstenu A.
Ovi derivati kamptotecina su sredstva protiv raka koja inhibiraju topoizomerazu I, među kojima je irinotekan, u kojem K-CO-O- je [4-(1-piperidino-1-piperidino]karboniloksi, aktivni princip koji je naročito efikasan u liječenju čvrstih tumora, i naročito kolorektalnog karcinoma.
Evropska patentna prijava EP 74,256 također opisuje druge derivate kamptotecina koji se također spominju kao sredstva protiv raka, određenije derivati strukture analogne gore danoj strukturi i u kojoj se X-CO-O- nadomješta radikalom -X'R' za koji X' je O ili S i R' je atom vodika ili alkilni ili acilni radikal.
Također su opisani drugi derivati kamptotecina, na primjer u patentima ili patentnim prijavama
EP 56,692, EP 88,642, EP 296,612, EP 321,122, EP 325,247, EP 540,099, EP 737,686, WO 90/03169, WO 96/37496, WO 96/38146, WO 96/38449, WO 97/00876, US 7,104,894, JP 57 116,015, JP 57 116,074, JP 59 005,188, JP 60 019,790, JP 01 249,777, JP 01 246,287 i JP 91 12070 ili Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diego –12-16 April), Canc. Res., 55(3):603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PB-55 (Seoul - 27 July-1 August).
Derivati kamptotecina obično se daju injekcijama, određenije intravenozno u obliku sterilne otopine ili emulzije. Derivati kamptotecina, međutim, mogu se također davati oralno u obliku čvrstih ili tekućih kompozicija.
CPT-11 je jedno od najjače aktivnih novih sredstava za kolorektalni karcinom. Kolorektalni karcinom je vodeći uzrok razbolijevanja i smrtnosti s oko 300000 novih slučajeva i 200000 smrti u Evropi i SAD svake godine (vidi P. Boyle, Some Recent Developments in the Epidemiology of Colorectal Cancer, str. 19-34 in Management of Colorectal Cancer, Bleiberg H., Rougier P., Wilke H.J., eds, (Martin Dunitz, London 1998); and - Midgley R.S., Kerr D.J., Systemic Adjuvant Chemotherapy for Colorectal Cancer, str 126-27 in Management of Colorectal Cancer, Bleiberg H., Rougier P., Wilke H.J., eds, (Martin Dunitz, London 1998).)
Iako se oko pedeset posto pacijenata izliječi samo kirurškim putem, druga polovica konačno će umrijeti uslijed metastatičkih bolesti što uključuje otprilike 25% pacijenata koji imaju dokazane metastaze u vrijeme dijagnoze.
Kod pacijenata s kolorektalnim karcinomom otpornim na 5-FU, samo sredstvo CPT-11 ispitano u dva velika ispitivanja faze III slučajnim izborom dovelo je do duljeg preživljavanja i bolje kvalitete života u usporedbi samo sa njegom i skrbi (D. Cunningham, S. Pyrhönen, RD. James et al, The Lancet, 352 (9138) : 1413-1418 (1998)) i također do duljeg preživljavanja bez opadanja kvalitete života u usporedbi s 5-FU/FA najbolji infuzijskim režimima (P. Rougier, E. van Cutsem et al; The Lancet, 352 (9138): 1407 -1418 (1998)). CPT-11 je prema tome referentni lijek za metastatični kolorektalni karcinom (MCRC) nakon neuspjeha prethodnog liječenja s 5-FU.
Također je pokazano da je CPT-11 barem jednako aktivan kao takozvani standardni 5-FU / FA bolus u kemoterapiji naivnih pacijenata s MCRC [Proc. Am. Soc. Clin. Oncol., vol 13 (1994), (Abstr. #573) ; J. Clin Oncol, 14 (3): 709 - 715 (1996); J. Clin Oncol, 15 (1) : 251 - 260 (1997).
Kombinacije irinotekana (CPT-11) i 5-FU također su proučavane u ispitivanjima faze I u Japanu i naznačavaju u preliminarnim rezultatima da je istovremeno davanje ostvarivo s obzirom na sigurnost (L. Saltz et al. Eur. J. Cancer 32A, suppl 3: S24 - 31 (1996)).
Studija u vezi s CPT-11 koju su objavili D. Cunningham, Eur. J. Cancer 32A supl. 3: SI - 8 (1996) zaključila je da CPT-11 nudi različit citotoksični pristup koji može biti komplementaran upotrebi 5-FU/folinske kiseline kod kolonorektalnog karcinoma.
Za prikazivanje efikasnosti kombinacije može biti potrebno da se usporedi maksimalna tolerirana doza kombinacije s maksimalnom toleriranom dozom svakog pojedinačnog sastojka o kojem se radi u ispitivanju. Ova efikasnost može se izraziti kvantitativno, na primjer preko log10 uništenih stanica, što je određeno sljedećom formulom:
log10 uništenih stanica = T - C (dani)/3,32 x Td
gdje T - C predstavlja vrijeme uzeto za rast stanica koje je srednje vrijeme u danima za tumore liječene grupe (T) i tumora liječene grupe (C) do postignute prethodno određene vrijednosti (npr. 1 g) i Td predstavlja vrijeme potrebno za volumen tumora u kontrolnim životinjama (T.H. Corbett et al., Cancer, 40, 2660 . 2680 (1977); F. M. Schabel et al., Cancer Drug Development, Part B, Methods in Cancer Research, 17, 3-51, New York, Academic Press Inc. (1979)). Za produkt se smatra da je aktivan ako je log10 uništenih stanica veći ili jednak 0,7. Produkt se smatra da je jako aktivan ako je log10 uništenih stanica veći od 2,8.
Efikasnost kombinacije može se također pokazati određivanjem terapijske sinergistike. Kombinacija pokazuje terapijsku sinergisitku ako je terapijski superiorna jednom ili drugom sastojku uzetom u optimalnoj dozi (T.H. Corbett at al., Cancer Treatment Reports, 66, 1187 (1982)).
Sada je nađeno da je kombinacija derivata kamptotecina s derivatima pirimidina naročito efikasna u liječenju čvrstih tumora kao što je rak jajnika, NSCLC i kolonorektalni karcinom. Među efikasnim derivatima pirimidina su gemcitabin, MTA i kapecitabin.
Gemcitabin pokazuje antitumorsku aktivnost. Sol gemcitabina, 2'-deoksi-2',2'-difluorcitidin monohidroklorid, raspoloživ je za kliničku upotrebu kao intravenozna otopina za liječenje čvrstih tumora kao što je rak pluća ne-malih stanica (NSCLC).
Gemcitabin pokazuje specifičnost stanične faze tako što primarno uništava stanice u kojima se odvija sinteza DNK (DNA) (S-faza) i također blokira napredovanje stanica kroz G1/S granicu faza. Gemcitabin se metabolizira intracelularno nukleozid kinazama do aktivnog difosfat (dFdCDP) i trifosfat (dFdCTP) nukleozida. Citotoksični efekt gemcitabina pripisuje se kombinaciji dvaju djelovanja difosfat i trifosfat nukleozida što dovodi do inhibicije sinteze DNK. Prvo gemcitabin difosfat inhibira ribonukleotid reduktazu koja je odgovorna za kataliziranje reakcija koje generiraju deoksinukleozid trifosfate za sintezu DNK. Inhibiranje ovog enzima difosfat nukleozidima uzrokuje smanjenje koncentracije deoksinukleozida, uključujući dCTP. Drugo, gemcitabin trifosfat se natječe s dCTP za ugrađivanje u DNK. Smanjenje intracelularne koncentracije dCTP (djelovanjem difosfata) pojačava ugrađivanje gemcitabin trifosfata u DNK (samopojačavanje). Nakon što se gemcitabin nukleotid ugradi u DNK, samo jedan dodatni nukleotid se ugradi u DNK. Nakon ovog dodavanja dolazi do inhibiranja daljnje sinteze DNK.
Gemcitabin u kombinaciji s CPT-11 pokazao se obećavajućim kao lijek za rak gušterače u studijama faze II.
MTA (više ciljani antifolat) je antimetabolit koji je antagonist folata, inhibitor dihidrofolat reduktaze i inhibitor timidilat sintetaze. Raspoloživ je za upotrebu kao intravenozna otopina i nađeno je da inhibira rast tumora u miševima. Sada se ispituje na ljudima za liječenje ne-malog raka pluća, mezotelioma, melanoma, raka mjehura, raka dojke, raka gušterače, kolorektalnog raka i drugih čvrstih tumora.
Kapecitabin je fluorpirimidin karbamat s antineoplastičnom aktivnosti. To je prolijek 5'-deoksi-5-fluoruridina (5'-DFUR) za oralno davanje koji se pretvara u tijelu u 5-fluoruracil. U pretkliničkim ispitivanjima kapecitabin je pokazao aktivnost u kolorektalnim karcinomima, karcinomima dojke i glave i vrata, uključujući one otporne na 5-FU.
Kemijski naziv za kapecitabin je 5'-deoksi-5-fluor-N-[(pentiloksi) karbonil]-citidin i ima molekulsku težinu 359,35. Kapecitabin ima sljedeću strukturnu formulu:
[image]
kapecitabin
Kapecitabin ima jedinstven mehanizam aktivacije koji koristi visoke koncentracije enzima fosforilaze u tkivu tumora u usporedbi sa zdravim tkivom, što dovodi do tumorski selektivnog generiranja 5-FU.
Dvije studije slučajnog uzorka faze III pokazale su da je oralni kapecitabin efikasna terapija prve linije za metastatički kolorektalni karcinom koja postiže vrhunski stupanj odgovora i barem ekvivalentno preživljavanje i vrijeme prema napredovanju bolesti u usporedbi s intravenoznim (i.v.) 5-FU/leukovorinom (režim Klinike Mayo). Kapecitabin je također pokazao povoljniji sigurnosni profil u usporedbi s režimom Klinike Mayo.
Predmetni izum je ilustriran ali ne i ograničen dolje danim primjerima.
PRIMJER 1
Davanje oralnog CPT-11 i oralnog kapecitabina, samih i zajedno, ocijenjeno je prema soju humanog karcinoma kolona HCT-116 usađenog u švicarske gole miševe. Kada su ta dva spoja davana zajedno, davani su u razmaku od dva sata, a CPT-11 je dan prvi. Volumen davanja svakog spoja bio je 0,2 ml p.o. Tablica dolje pokazuje da su maksimalna tolerirana doza svakog pojedinog sredstva i kombiniranih spojeva bile visoko aktivne.
Tablica 1
Simultana oralna kombinacija CPT-11/kapecitabin u miševima s HCT-116
Sredstvo Dnevna doza Raspored Logl0T-C Komentar
(mg/kg/dav) (dani) stanica (dani)
uništeno
[image]
HNTD: najviša netoksična doza
T - C usporavanje rasta tumora
Ovi rezultati su indicirali da bi drugi rasporedi mogli optimizirati kombinaciju i, zaista, primjer 2 dolje pokazuje da polu-simultano davanje kapecitabina i CPT-11 dovodi do terapijske kombinacije koja je vrlo aktivna protiv ispitivanih tumora; to znači da je kombinacija kapecitabin/CPT-11 dala vrijednost log10 uništenih stanica veću od 2,8.
PRIMJER 2
Zajedničko davanje oralnog CPT-11 i oralnog kapecitabina ocijenjeno je kod švicarskih golih miševa sa ranim stadijem karcinoma kolona HCT-116. Tri količine doziranja CPT-11 davane su same na dane 18 - 22 da se ustanovi najviša netoksična doza. Tri količine doziranja kapecitabina davane su same na dane 18 - 22 i 25 - 29. U kombinaciji ispitana su dva poluistovremena rasporeda. Prvi raspored uključio je davanje 4 razine CPT-11 na dane 18 -22 uz davanje 4 razine kapecitabina na dane 18 -22 i 25 - 29. U drugom rasporedu, kapecitabin je davan prvi na dane 18 - 22 nakon čega je slijedilo simultano davanje 4 razine doziranja CPT-11 na dane 25 - 29.
Našlo se da su dva kombinirana redoslijeda jednako aktivna kao najbolje pojedinačno sredstvo i moglo se davati 42 % i 55 % najviše netoksične doze svakog pojedinačnog sredstva bez preklapanja toksičnosti za domaćina. Redoslijed davanja izgleda da inducira razliku u toleranciji kombiniranih lijekova. Kada se kapecitabin davao prvi, rezultat je djelovao manje toksično i bolje se tolerirao nego kada je CTP-11 davan prvi. U oba načina davanja, međutim, efikasnost kombinacije ostala je ista.
Rezultati dobiveni u ispitivanju pojedinačnih sredstava i kombinacije CPT-11/kapecitabin dani su dolje u sljedećoj tablici. Kombinacije su bile vrlo aktivne s log uništenih stanica većim od 2,8.
Tablica 2
Polusimultana oralna kombinacija CPT-11/kapecitabin u miševima s HCT-116
Sredstvo Dnevna doza Raspored Log10 T-C Komentar
(mg/kg/dav) (dani) stanica (dani)
uništeno
[image] HNTD: najviša netoksična doza
T - C usporavanje rasta tumora
PRIMJER 3
Sigurnost i efikasnost dva rasporeda davanja irinotekana (CPT-11) u kombinaciji sa isprekidanim standardnom dozom kapecitabina ispitivane su kod pacijenata s uznapredovalim/metastatičkim kolorektalnim karcinomom.
Primarni cilj studije bio je da se usporedi sigurnosni profil rasporeda liječenja.
Sekundarni cilj bio je da se usporede brzine reagiranja tumora u dvije skupine liječenja.
Pacijenti su dobili irinotekan i. v. 300/mg/m u jednom od dva rasporeda doziranja uz isprekidani oralni kapecitabin u ciklusu liječenja od 21 dana (slike 1 i 2).
Dan 1 8 15 21
Irinotekan 300 mg/m kao ↑
90-min i.v. infuzija │
Oralni kapecitabin
1,250 mg/m dvaput na dan Dani 2-15
Slika 1. Raspored liječenja za ogranak A
Dan 1 8 15 21
Irinotekan 300 mg/m kao ↑ ↑
90-min i.v. infuzija │ │
Oralni kapecitabin
1,250 mg/m dvaput na dan Dani 2-15
Slika 2. Raspored liječenja za ogranak B
Ukupno 19 pacijenata s neliječenim ili prethodno liječenim uznapredovalim kolorektalnim karcinomom uključeno je u ovo izvidno ispitivanje. Liječenje je provođeno do pojave napredovanja bolesti ili kroz maksimalno 10 ciklusa liječenja kod pacijenata s tumorskim odgovorom ili stabilnom bolešću.
Pacijenti s mjerljivim, uznapredovalim ili metastatičkim kolorektalnim adenokarcinomom bili su pogodni za uključivanje. To je uključilo pacijente starosti 18 - 75 godina s očekivanjem preživljavanja najmanje 3 mjeseca i ECOG statusom performanse 0-2. Pacijenti starosti 70 - 75 godina trebali su imati ECOG status performanse 0 - 1.
Osnovne karakteristike 19 pacijenata prikazane su u tablici 3.
Tablica 3
Karakteristike pacijenata
broj pacijenata
Liječenje ogranka A 10
Liječenje ogranka B* 9 ;Muški / ženski 11/8 ;Srednja starost (godine) [raspon] 56[33 - 70] ;Primarni tumor ;Kolon 13 ;Rektalni 6 ;Bez prethodne kemoterapije 9 ;Prethodna kemoterapija + ;Pomoćno stanje 6 ;Metastatičko stanje 5 ;Mjesto metastaza ;Jetra 15 ;Pluća 4 ;Lokalni povratni tumor 2 ;Primarni tumor 3 ;*Jedan pacijent u ogranku liječenja B je umro (neovisno o liječenju) nakon primanja dva ciklusa liječenja
+Jedan pacijent je primio liječenje u oba stanja
Sigurnost je ocjenjivana kod svih pacijenata koji su primili najmanje jednu dozu ispitivane medicines nepovoljnim događajima ocijenjenim prema kriterijima National Cancer Institute Common Toxicity Criteria (NCI CTC). Sindrom šaka - stopalo ocijenjen je 1 - 3. Tumore su procijenili istraživači u baznim i 9 - tjednim intervalima temeljeno na kriterijima World Health Organization. Učestalost nepovoljnih pojava povezanih s terapijom u 19 do sada liječenih pacijenata pokazana je u tablici 4. Nije bilo nepovoljnih pojava stupnja 4 povezanih s terapijom. Samo jedan pacijent je trebao modifikaciju doze za podešavanje toksičnosti.
Tablica 4
Učestalost nepovoljnih pojava povezanih s terapijom
Broj pacijenata
Terapija ogranak A Terapija ogranak B
(n=10) (n=9)
Dijareja
ocjena 2 4 4
Neutropenija
ocjena 2 3 -
ocjena 3 2
Šaka-stopalo sindrom
ocjena 2 4 3
ocjena 3 1 -
Mučnina
ocjena 3 - 1
Osamnaest pacijenata bilo je raspoloživo za reagiranje na terapiju (tablica 5)
Tablica 5
Antitumorska aktivnost režima kombinacije kapecitabin/irinotekan kod pacijenata s uznapredovalim/metastatičkim kolorektalnim karcinomom
Broj pacijenata
Reakcija tumora
Terapija ogranak A Terapija ogranak B
(n=10) (n=9)
Parcijalna 8 5
Stabilna bolest 2 1
Bolest u napredovanju - 2
Ovi preliminarni podaci pokazuju da dva režima od 21 dan koji kombiniraju isprekidano davanje oralnog kapecitabina s i. v. irinotekanom 300 mg/m u jednoj dozi (dan 1) ili raspoređeno u dvije jednake doze (dani 1 i 8) imaju pogodne sigurnosne profile i pokazuju ohrabrujuću antitumorsku aktivnost kod pacijenata s uznapredovalim metastatičkim kolorektalnim karcinomom. Od 10 pacijenata u ogranku A, 8 ih je imalo djelomičnu reagiranje a 2 su stabilizirana. Nijedan nije pokazao napredovanje bolesti.
Tako kombinacija CPT-11 i derivata pirimidina, kapecitabina, dovodi do vrlo aktivne kombinacije za liječenje raka kao što je kolorektalni karcinom.
Claims (12)
1. Terapeutska farmaceutska kompozicija naznačena time da obuhvaća efikasnu količinu kamptotecina ili njegovog derivata u kombinaciji s efikasnom količinom derivata pirimidina za liječenje raka.
2. Terapeutska farmaceutska kompozicija naznačena time da obuhvaća efikasnu količinu CPT-11 u kombinaciji s efikasnom količinom derivata pirimidina za liječenje raka.
3. Terapeutska farmaceutska kompozicija prema jednom od zahtjeva 1 ili 2 naznačena time da derivat pirimidina je kapecitabin
4. Terapeutska farmaceutska kompozicija prema jednom od zahtjeva 1 ili 2 naznačena time da derivat pirimidina je gemcitabin.
5. Terapeutska farmaceutska kompozicija prema jednom od zahtjeva 1 ili 2 naznačena time da derivat pirimidina je MTA.
6. Terapeutska farmaceutska kompozicija prema jednom od zahtjeva 1 ili 2 naznačena time da rak koji se liječi je karcinom kolona.
7. Terapeutska farmaceutska kompozicija naznačena time da obuhvaća efikasnu količinu CPT-11 u kombinaciji s efikasnom količinom kapecitabina za liječenje karcinom kolona.
8. Postupak za liječenje raka naznačen time da se pacijentu koji boluje od navedenog raka daje efikasna količina kamptotecina ili njegov derivat u kombinaciji s efikasnom količinom derivata pirimidina.
9. Postupak prema zahtjevu 8 naznačen time da je derivat kamptotecina CPT-11 i derivat pirimidina je kapecitabin.
10. Postupak prema zahtjevu 8 naznačen time da se CPT-11 i kapecitabin daju polusimultano.
11. Postupak prema zahtjevu 9 naznačen time da se CPT-11 i kapecitabin daju odvojeno.
12. Postupak prema zahtjevu 9 naznačen time da se CPT-11 i kapecitabin daju simultano.
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| PCT/EP2001/002723 WO2001062235A2 (en) | 2000-02-28 | 2001-02-26 | A composition comprising camptothecin and a pyrimidine derivative for the treatment of cancer |
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| TW (1) | TWI239841B (hr) |
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| YU (1) | YU64602A (hr) |
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| GB9808052D0 (en) | 1998-04-17 | 1998-06-17 | Secr Defence | Implants for administering substances and methods of producing implants |
| US20080113025A1 (en) * | 1998-11-02 | 2008-05-15 | Elan Pharma International Limited | Compositions comprising nanoparticulate naproxen and controlled release hydrocodone |
| US20030092608A1 (en) * | 2001-08-21 | 2003-05-15 | Takayuki Kawaguchi | Pharmaceutical composition for inhibiting the metastasis or preventing the recurrence of malignant tumor |
| AU2003277424A1 (en) * | 2002-10-17 | 2004-05-04 | New York University | Method of orally treating inflammatory skin conditions with prodrugs of 5-fluorouracil |
| ITMI20030317A1 (it) * | 2003-02-21 | 2004-08-22 | Pharmacia Italia Spa | Terapia combinata comprendente un derivato dell'indolopirrolocarbazolo ed un altro agente antitumorale. |
| US20050153885A1 (en) * | 2003-10-08 | 2005-07-14 | Yun Anthony J. | Treatment of conditions through modulation of the autonomic nervous system |
| WO2005049031A1 (en) * | 2003-11-13 | 2005-06-02 | Pharma Mar, S.A.U. | Combination |
| CN1964979B (zh) | 2004-04-09 | 2011-07-27 | 中外制药株式会社 | 新颖的水溶性前药 |
| MXPA06013902A (es) * | 2004-05-28 | 2007-01-26 | Pfizer Prod Inc | Procedimiento para tratar el crecimiento de celulas anormal. |
| EP1761281A1 (en) * | 2004-06-04 | 2007-03-14 | Pfizer Products Incorporated | Method for treating abnormal cell growth |
| CA2569139A1 (en) * | 2004-06-04 | 2005-12-22 | Smithkline Beecham (Cork) Limited | Lapatinib with letrozole for use in a treatment of breast cancer |
| US8569277B2 (en) | 2004-08-11 | 2013-10-29 | Palo Alto Investors | Methods of treating a subject for a condition |
| ES2327195B1 (es) * | 2005-04-12 | 2010-07-09 | Elan Pharma International Limited | Composiciones de liberacion modificada que comprenden un derivado de fluorocitidina para el tratamiento del cancer. |
| BRPI0613796A2 (pt) * | 2005-06-07 | 2011-02-15 | Univ Yale | composicões farmacêuticas e seus usos, e métodos de tratamento de cáncer e outras condições ou estados patológicos, por meio do uso de clevudina (lfmau) e telbivudina (ldt) |
| TW200744603A (en) | 2005-08-22 | 2007-12-16 | Chugai Pharmaceutical Co Ltd | Novel anticancer concomitant drug |
| AU2010246067B2 (en) | 2009-05-04 | 2016-07-07 | Eyepoint Pharmaceuticals Us, Inc. | Porous silicon drug-eluting particles |
| EP3117709B1 (en) * | 2010-03-12 | 2018-08-01 | Genzyme Corporation | Combination therapy for treating breast cancer |
| AU2011323524B2 (en) | 2010-11-01 | 2016-12-08 | Eyepoint Pharmaceuticals Us, Inc. | Bioerodible silicon-based devices for delivery of therapeutic agents |
| AU2014235051B2 (en) | 2013-03-15 | 2019-01-17 | Eyepoint Pharmaceuticals Us, Inc. | Bioerodible silicon-based compositions for delivery of therapeutic agents |
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| US4399276A (en) | 1981-01-09 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | 7-Substituted camptothecin derivatives |
| JPS57116015A (en) | 1981-01-09 | 1982-07-19 | Yakult Honsha Co Ltd | Antitumor agent |
| JPS57116074A (en) | 1981-01-09 | 1982-07-19 | Yakult Honsha Co Ltd | Novel camptothecin derivative and its preparation |
| US4473692A (en) | 1981-09-04 | 1984-09-25 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
| JPS58154582A (ja) | 1982-03-10 | 1983-09-14 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体およびその製造法 |
| JPS595188A (ja) | 1982-06-30 | 1984-01-12 | Yakult Honsha Co Ltd | １０−ヒドロキシカンプトテシンの製造法 |
| JPS5951289A (ja) | 1982-09-17 | 1984-03-24 | Yakult Honsha Co Ltd | 新規な９−置換−カンプトテシン誘導体 |
| JPS6019790A (ja) | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
| US4981968A (en) | 1987-03-31 | 1991-01-01 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
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| US5004758A (en) | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
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| JP2524804B2 (ja) | 1988-03-29 | 1996-08-14 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体及びその製造法 |
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| EP0540099B1 (en) | 1991-10-29 | 1996-04-17 | Glaxo Wellcome Inc. | Water soluble camptothecin derivatives |
| AU671491B2 (en) * | 1992-12-18 | 1996-08-29 | F. Hoffmann-La Roche Ag | N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidines |
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| US5670500A (en) | 1995-05-31 | 1997-09-23 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
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| EP1139754A4 (en) * | 1998-12-31 | 2002-12-18 | Sugen Inc | 3-HETEROARYLIDENYL-2-INDOLINONE COMPOUNDS FOR MODULATION OF PROTEIN KINASE ACTIVITY AND IN CANCER CHEMOTHERAPY |
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| GB9925127D0 (en) * | 1999-10-22 | 1999-12-22 | Pharmacia & Upjohn Spa | Oral formulations for anti-tumor compounds |
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