CN119074887B - Comprehensive targeted drug compound for treating tumors and preparation and application thereof - Google Patents
Comprehensive targeted drug compound for treating tumors and preparation and application thereof Download PDFInfo
- Publication number
- CN119074887B CN119074887B CN202411036399.9A CN202411036399A CN119074887B CN 119074887 B CN119074887 B CN 119074887B CN 202411036399 A CN202411036399 A CN 202411036399A CN 119074887 B CN119074887 B CN 119074887B
- Authority
- CN
- China
- Prior art keywords
- tumor
- cells
- cancer
- dbdx
- human
- 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.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 57
- 229940079593 drug Drugs 0.000 title claims abstract description 48
- 206010028980 Neoplasm Diseases 0.000 title claims description 49
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 title abstract description 8
- 229960000575 trastuzumab Drugs 0.000 claims abstract description 23
- 229960005395 cetuximab Drugs 0.000 claims abstract description 21
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 17
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 17
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 17
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims abstract description 16
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 16
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims abstract description 16
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 16
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 16
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 16
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims abstract description 15
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 201000004101 esophageal cancer Diseases 0.000 claims abstract description 15
- 206010041823 squamous cell carcinoma Diseases 0.000 claims abstract description 15
- 229960003957 dexamethasone Drugs 0.000 claims abstract description 14
- 229960002768 dipyridamole Drugs 0.000 claims abstract description 13
- 201000007270 liver cancer Diseases 0.000 claims abstract description 13
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 13
- 229950009811 ubenimex Drugs 0.000 claims abstract description 11
- 201000001441 melanoma Diseases 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 229960000397 bevacizumab Drugs 0.000 claims abstract description 9
- 229960004641 rituximab Drugs 0.000 claims abstract description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 7
- 201000005202 lung cancer Diseases 0.000 claims abstract description 7
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 7
- 201000004514 liver lymphoma Diseases 0.000 claims abstract description 6
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 claims abstract 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 229940041181 antineoplastic drug Drugs 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 15
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 53
- 230000000694 effects Effects 0.000 description 28
- 210000004881 tumor cell Anatomy 0.000 description 16
- 230000005917 in vivo anti-tumor Effects 0.000 description 14
- 238000011580 nude mouse model Methods 0.000 description 14
- 241000699660 Mus musculus Species 0.000 description 12
- 230000002195 synergetic effect Effects 0.000 description 12
- 230000008685 targeting Effects 0.000 description 12
- VGGGPCQERPFHOB-RDBSUJKOSA-N (2s)-2-[[(2s,3r)-3-amino-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-RDBSUJKOSA-N 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 10
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 6
- -1 4, 8-dipiperidinylpyrimido [5, 4-d ] pyrimidine-2, 6-diyl Chemical group 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 230000007750 drug combination effect Effects 0.000 description 5
- 238000011081 inoculation Methods 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 239000000890 drug combination Substances 0.000 description 4
- 230000009036 growth inhibition Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 102000001301 EGF receptor Human genes 0.000 description 3
- 108060006698 EGF receptor Proteins 0.000 description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 229940090044 injection Drugs 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 229940120638 avastin Drugs 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- XGDFITZJGKUSDK-UDYGKFQRSA-N Bestatin (hydrochloride) Chemical compound Cl.CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 XGDFITZJGKUSDK-UDYGKFQRSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010069729 Collateral circulation Diseases 0.000 description 1
- 206010055114 Colon cancer metastatic Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 238000011794 NU/NU nude mouse Methods 0.000 description 1
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102000019055 Nucleoside Transport Proteins Human genes 0.000 description 1
- 108010012315 Nucleoside Transport Proteins Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- FPVRUILUEYSIMD-RPRRAYFGSA-N [(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-RPRRAYFGSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- QAWIHIJWNYOLBE-OKKQSCSOSA-N acivicin Chemical compound OC(=O)[C@@H](N)[C@@H]1CC(Cl)=NO1 QAWIHIJWNYOLBE-OKKQSCSOSA-N 0.000 description 1
- 229950008427 acivicin Drugs 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000703 anti-shock Effects 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 229940117880 bevacizumab injection Drugs 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940114863 cetuximab injection Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229960003657 dexamethasone acetate Drugs 0.000 description 1
- 229960002344 dexamethasone sodium phosphate Drugs 0.000 description 1
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000003519 mature b lymphocyte Anatomy 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940113912 rituximab injection Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a pharmaceutical composition, which comprises a pharmaceutical composition DBDx and a second active ingredient, wherein the pharmaceutical composition DBDx consists of dipyridamole, ubenimex and dexamethasone, and the second active ingredient is selected from cetuximab, trastuzumab, rituximab or bevacizumab. The invention provides application of the medicine compound in preparing antitumor medicines, in particular pancreatic cancer, gastric cancer, esophageal cancer, squamous carcinoma, melanoma, lung cancer, liver cancer or lymphoma.
Description
Technical Field
The present invention relates to pharmaceutical complexes. In particular to a drug compound for targeting tumor cells and regulating tumor microenvironment, and also relates to a preparation and application of the compound.
Background
The current strategy for developing new antitumor drugs comprises two aspects, namely 1, drugs acting on tumor cells, wherein the drugs mainly act by inhibiting proliferation of the tumor cells, inducing apoptosis of the tumor cells and inducing differentiation of the tumor cells. 2. The medicine for regulating tumor microenvironment mainly has the functions of inhibiting tumor angiogenesis or interfering tumor vascular network, regulating immune cell and relevant cell factor in tumor, regulating growth factor secretion and growth factor receptor expression, inhibiting specific enzyme secretion and regulating corresponding inhibiting factor, and interfering the transmission, uptake and excretion of matter inside and outside tumor cell. The toxicity of the existing anti-tumor drugs applied clinically is a prominent problem which plagues tumor chemotherapy. Searching for the low toxicity of the anti-tumor drug and acting on a specific link or a molecular target point of a tumor microenvironment so as to improve the anti-tumor effect or reduce the toxicity of the anti-tumor drug, and the anti-tumor drug is a new direction for the research of the anti-tumor drug and is also an urgent need for clinical treatment of tumors.
Dipyridamole (Dipyridamole, DPM) and pharmaceutically acceptable derivatives or analogues thereof such as mopidamole (mopidamole), BIBW22BS, RA25 or pharmaceutically acceptable salts thereof are non-nitrate coronary artery dilators, and have the effects of dilating coronary vessels and promoting the formation of collateral circulation. Dipyridamole also has effects of inhibiting platelet aggregation and preventing thrombosis.
Dipyridamole chemical name 2,2',2", 2'" - [ (4, 8-dipiperidinylpyrimido [5, 4-d ] pyrimidine-2, 6-diyl) bisazo ] -tetraol, molecular formula C 24H40N8O4, is a potent nucleoside transport inhibitor that inhibits nucleoside transport by blocking the balanced nucleoside transport proteins hENT1 (NatMed, 1997, 3:89-93) and hENT2 (biochem. J,1997, 328:739-43). Dipyridamole as a nucleoside transport inhibitor can enhance the proliferation inhibition of tumor cells by antimetabolites acivicin. In terms of tumor treatment, dipyridamole can enhance the cytotoxic activity of various antitumor drugs such as 5-fluorouracil, methotrexate, doxorubicin, etoposide, vinca alkaloid, cisplatin, etc.
Ubenimex (Ubenimex, bestatin, BEN) and pharmaceutically acceptable derivatives or analogues thereof include AHPA-Val, bestatin Hydrochloride and the like. Ubenimex has chemical name of N- [ (2S, 3R) -4-phenyl-3-amino-2-hydroxybutyryl ] -L-leucine and molecular formula of C 16H24N2O4, shows various immunological activities, can not only enhance the function of lymphocytes, but also activate mononuclear macrophages, so that the killing activity of NK cells is enhanced. Ubenimex is commonly used for adjuvant treatment after tumor chemotherapy, radiotherapy and surgery, and can be used in combination with chemotherapy, radiotherapy and treatment of leukemia, multiple myeloma, lung cancer, breast cancer, etc. Ubenimex can also exert antitumor activity by acting directly on tumor tissue.
Glucocorticoids such as dexamethasone (Dexamethason, DEX) and pharmaceutically acceptable derivatives or analogues thereof, such as dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone sodium palmitate, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone, etc. have pharmacological effects such as anti-inflammatory, immunosuppressive, antitoxin, antishock, etc. Dexamethasone is widely used in the treatment of various diseases, such as autoimmune diseases, allergies, inflammation, asthma, dermatological, ophthalmic diseases, etc. The tumor is closely related to the inflammation, and the occurrence of the inflammation promotes the occurrence and the development of the tumor. Dexamethasone controls inflammatory responses through multiple pathways, inhibiting tumor progression. In terms of tumor treatment, dexamethasone can alleviate some side effects of cancer patients during chemotherapy and relieve nausea and vomiting symptoms after chemotherapy. Dexamethasone is also commonly used in the treatment of some hematological malignancies, and in the treatment of brain tumors, dexamethasone is commonly used to reduce the permeability of tumor-associated blood vessels to alleviate the progression of edema.
Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER 2), blocks the growth of tumor cells by preventing the attachment of human epidermal growth factor to HER2 by binding to HER 2. Trastuzumab can also stimulate the body's own immune cells to destroy tumor cells. Clinically, it is mainly used for metastatic breast cancer with HER2 over-expression.
Cetuximab specifically binds to EGF receptor expressed on the surfaces of normal cells and various tumor cells, is an IgG1 monoclonal antibody directed against the EGF receptor, and blocks intracellular signal transduction pathways by inhibiting Tyrosine Kinase (TK) bound to the EGF receptor after the specific binding, thereby inhibiting proliferation of tumor cells, inducing apoptosis of tumor cells, and reducing production of matrix metalloproteinases and vascular endothelial growth factors.
Bevacizumab (trade name Avastin) is a monoclonal antibody, can inhibit vascular endothelial growth factor, reduce generation of tumor blood vessel, inhibit tumor growth, and is used for treating various metastatic tumors, and is commonly used for treating patients with advanced metastatic colon cancer. In addition, bevacizumab can be combined with carboplatin and paclitaxel for the first-line treatment of advanced metastatic non-squamous non-small cell lung cancer, and has good clinical curative effect.
Rituximab is a chimeric murine/human monoclonal antibody that specifically binds to the CD20 antigen that is across the cell membrane. The antigen exists in pre-B and mature B lymphocytes, but does not exist in hematopoietic stem cells, post-B cells, normal plasma cells or other normal tissues, and is suitable for treating recurrent or drug-resistant follicular central lymphoma, and is mainly used for treating non-Hodgkin lymphoma.
Disclosure of Invention
The invention aims to provide a drug compound for targeting tumor cells and regulating tumor microenvironment. The invention aims to examine the combined action index of the pharmaceutical composition DBDx and various monoclonal tumor drugs and the influence on the growth inhibition of various tumor cells and provide a novel comprehensive targeting pharmaceutical composition with remarkable synergistic effect.
Based on this, the present invention provides a pharmaceutical composition comprising a pharmaceutical composition DBDx and a second active ingredient, said pharmaceutical composition DBDx consisting of component A, component B and component C,
The component A is dipyridamole, a derivative of dipyridamole which is acceptable in pharmacy, an analogue of dipyridamole which is acceptable in pharmacy or a pharmaceutically acceptable salt thereof;
The component B is ubenimex, a pharmaceutically acceptable derivative of ubenimex, a pharmaceutically acceptable analogue of ubenimex or a pharmaceutically acceptable salt thereof;
The component C is dexamethasone, a pharmaceutically acceptable derivative of dexamethasone, a pharmaceutically acceptable analogue of dexamethasone or a pharmaceutically acceptable salt thereof;
the second active ingredient is selected from cetuximab, trastuzumab, rituximab or bevacizumab.
The pharmaceutical composition DBDx of the present invention can be referred to the description of Chinese patent invention CN 201010133844.5, CN 201010133858.7, or Xiujun Liu et al ,A multifunctional drug combination shows highly potent therapeutic efficacy against human cancer xenografts in athymic mice.PLoS One.2014Dec 22;9(12):e115790.doi:10.1371/journal.pone.0115790.
As a particularly preferred embodiment, the mass ratio of component a, component B and component C is 100:20:1 as the mass ratio of dipyridamole, ubenimex and dexamethasone.
In the present invention, the mass ratio of the pharmaceutical composition DBDx to the second active ingredient is 121 (30-50).
The invention also provides application of the pharmaceutical composition in preparing medicines for treating pancreatic cancer, gastric cancer, esophageal cancer, squamous carcinoma, melanoma, lung cancer, liver cancer, lymphoma and the like.
Such tumors include, but are not limited to, pancreatic cancer, gastric cancer, esophageal cancer, squamous carcinoma, melanoma, lung cancer, liver cancer, lymphoma, and the like.
The pharmaceutical composition comprises a therapeutically effective amount of the anti-tumor drug and a pharmaceutically acceptable carrier.
Preferably, in the pharmaceutical composition, the weight content of the antitumor drug is 0.5-99.9%.
The pharmaceutically acceptable carrier refers to conventional pharmaceutical carriers in the pharmaceutical field, such as diluents, excipients, such as water, etc., fillers, such as starch, sucrose, etc., binders, such as cellulose derivative gelatin, polyvinylpyrrolidone, etc., lubricants, such as talc, etc.
The pharmaceutical composition of the invention can be prepared by a conventional method in the pharmaceutical field.
The invention has the advantages and positive effects that the anti-tumor comprehensive targeting drug compound disclosed by the invention achieves the aim of effectively treating tumors by mainly acting on tumor cells and adjusting tumor microenvironment, and the toxic and side effects caused by cytotoxic drugs are expected to be reduced.
The invention verifies that the pharmaceutical composition has remarkable synergistic effect, can be used for treating pancreatic cancer, gastric cancer, esophageal cancer, squamous carcinoma, melanoma, lung cancer, liver cancer and lymphoma, effectively improves the treatment effect on tumors, and reduces the occurrence and development of complications of patients.
Drawings
FIG. 1 is a graph showing the effect of the drug complex on human pancreatic cancer AsPC-1 cell tumor volume in an in vivo antitumor activity study of example 2;
FIG. 2 is the effect of the drug complex on the body weight of the experimental mice in the in vivo antitumor activity study of example 2;
FIG. 3 is a photograph of human pancreatic cancer AsPC-1 cells in an in vivo antitumor activity study of example 2;
FIG. 4 is the effect of the drug complex on tumor volume of human gastric cancer BCG823 cells in the in vivo antitumor activity study of example 2;
FIG. 5 is the effect of the drug complex on the body weight of the experimental mice in the in vivo antitumor activity study of example 2;
FIG. 6 is a photograph of human gastric cancer BCG823 cells in the in vivo antitumor activity study of example 2;
FIG. 7 is the effect of the drug complex on tumor volume of human squamous carcinoma A431 cells in vivo antitumor activity study of example 2;
FIG. 8 is the effect of the drug complex on the body weight of the experimental mice in the in vivo antitumor activity study of example 2;
FIG. 9 is a photograph of human squamous cell carcinoma A431 cells in the study of in vivo antitumor activity of example 2;
FIG. 10 is the effect of the drug complex on the tumor volume of KYSE150 cells of human esophageal cancer in the in vivo antitumor activity study of example 2;
FIG. 11 is the effect of the drug complex on the body weight of the experimental mice in the in vivo antitumor activity study of example 2;
FIG. 12 is a photograph of KYSE150 cells of human esophageal cancer in the in vivo antitumor activity study of example 2.
Detailed Description
The following examples serve to illustrate the technical solution of the invention without limiting it.
In the invention, unless otherwise specified, "%" used for explaining the concentration is mass percent, and ":" is mass ratio.
The invention relates to the following medicines and reagents:
Dipyridamole, dexamethasone, standard substances purchased from China medicine and biological product verification institute, ubenimex, zhejiang puluo Kang Yu pharmaceutical Co., ltd, dipyridamole tablet, yabao pharmaceutical groups Co., ltd, dexamethasone tablet, shanxi Dada pharmaceutical Co., ltd, ubenimex capsule, zhejiang puluo Kang Yu pharmaceutical Co., ltd, trastuzumab (herceptin) for injection, roche pharmaceutical Co., cetuximab injection (erbitux), merck pharmaceutical Co., rituximab injection (rituximab), luo pharmaceutical Co., bevacizumab injection (avastin), and Roche pharmaceutical Co., ltd.
The weight ratio of the three components of the antineoplastic medicine composition DBDx is always kept to be 100:20:1.
The present invention relates to the following tumor cells:
Human pancreatic cancer AsPC-1 cells, human gastric cancer BCG823 cells, human esophageal cancer KYSE150, KYSE520 cells, human squamous carcinoma A431 cells, mouse melanoma B16 cells, human non-small cell lung cancer A549 cells, human liver cancer HepG2 cells, human non-Hodgkin lymphoma Z-138 cells, human lymphoma Maver cells, human diffuse large B lymphoma WSU-DLCL2 cells and human non-small cell lung cancer HCC827 cells are all purchased from the cell center of the basic medical institute of China medical science.
The invention relates to the following experimental animals:
BALB/c female nude mice, 6-8 weeks, weight 18-22g.
Example 1 investigation of IC50 of combination drug DBDx and second active ingredient trastuzumab, cetuximab, rituximab, bevacizumab in comprehensive Targeted drug Complex, and in vitro combination action index for separate combination
The IC50 was determined by MTT method according to the prior art by setting the concentration gradient of DBDx to the concentration gradient of trastuzumab, cetuximab, rituximab, bevacizumab. Meanwhile, cells were administered singly and in combination, and the CDI value of the drug combination effect index was calculated from the survival rate of the cells, and the results are shown in tables 1 to 4.
Table 1 proliferation inhibition effect of comprehensive targeting drug complex (DBDx and trastuzumab) on human pancreatic cancer, human gastric cancer, human non-small cell lung cancer and human liver cancer cells
TABLE 2 proliferation inhibition of human non-Hodgkin's lymphoma, human diffuse large B lymphoma cells by comprehensive targeted drug complex (DBDx and rituximab)
Table 3 proliferation inhibition effect of comprehensive targeting drug complex (DBDx and cetuximab) on human squamous carcinoma, human non-small cell lung cancer, human esophageal cancer, mouse melanoma and human liver cancer cells
Table 4 proliferation inhibition of human non-small cell lung cancer and human liver cancer cells by comprehensive targeting drug complex (DBDx and bevacizumab)
The results show that the CDI index of DBDx and trastuzumab combined in an in vitro cell experiment on human pancreatic cancer, human gastric cancer, human non-small cell lung cancer and human liver cancer cells is less than 1, and the synergistic effect is shown, wherein the CDI index on human pancreatic cancer AsPC-1 cells and human gastric cancer BCG823 cells is less than 0.8, so that the moderate synergistic effect is achieved.
The combination of DBDx with rituximab showed a synergistic effect with CDI index less than 1 for human non-hodgkin lymphoma Z-138 cells and human diffuse large B lymphoma WSU-DLCL2 cells.
DBDx in combination with cetuximab showed a synergistic effect on CDI indexes of less than 1 for human squamous carcinoma a431 cells, human non-small cell lung cancer a549 cells, human esophageal cancer KYSE150, KYSE520 cells, mouse melanoma B16 cells and human liver cancer HepG2 cells, wherein CDI indexes of less than 0.8 for human squamous carcinoma a431 cells, human esophageal cancer KYSE520 cells and mouse melanoma B16 cells were achieved to achieve a moderate synergistic effect.
The combination of DBDx and bevacizumab has CDI index smaller than 1 on human non-small cell lung cancer A549 cells, human non-small cell lung cancer HCC827 cells and human liver cancer HepG2 cells, and shows synergistic effect.
The calculation formula of the CDI value of the drug combination effect index is as follows:
the calculation was performed based on the number of living cells, that is, the absorbance value, AB is the ratio of the two-drug combination group to the control group, and A and B are the ratio of each of the individual administration groups to the control group. If CDI <1, the combination property of the two drugs is proved to be synergistic, cdi=1, the combination property of the two drugs is proved to be additive, and CDI >1, the combination property of the two drugs is proved to be antagonistic.
Example 2 study of the in vivo anti-tumor Activity of the comprehensive Targeted drug Complex (DBDx and trastuzumab)
Taking in vitro cultured human pancreatic cancer AsPC-1 cells and human gastric cancer BCG823 cells, respectively inoculating the cells to armpit skin on one side of a BALB/c nu/nu nude mouse, transferring for 2-3 generations, taking an underarm passage tumor, cutting into small blocks of about 1.5mm 3, inoculating the small blocks to armpit skin on one side of the nude mouse, inoculating the small blocks for 7 days, randomly grouping the small blocks according to tumor size after the tumor grows to 100-300 mm 3, and starting administration. In the human pancreatic cancer AsPC-1 nude mice engraftment model, DBDx doses were given 5 times per week for a total of 10 times per 2 weeks. Trastuzumab was administered once a week for 2 weeks for a total of 2 times. In the human gastric cancer BCG823 nude mice engraftment model, DBDx doses were given 5 times per week for 15 total times 3 weeks. Trastuzumab was administered once a week for 3 weeks. The control group was given physiological saline, and the other groups were given the drugs of the respective examples by oral administration DBDx and trastuzumab injection.
The major diameter a and minor diameter b of the tumor were measured daily and animal weights were recorded. The tumor volume is calculated according to the formula V=ab 2/2, a tumor growth curve is drawn, and the tumor inhibition rate is calculated.
The results are shown in Table 5 and FIGS. 1-3.
Table 5 growth inhibition of human pancreatic cancer AsPC-1 nude mice transplantable tumor by comprehensive targeting drug complex (DBDx and trastuzumab)
Animals in each group did not die from inoculation to day 17.
Comparison with control group p <0.05, p <0.01, p <0.001, p <0.0001, comparison with trastuzumab, comparison with DBDx, Δp <0.01.
The experimental result shows that the composition DBDx and trastuzumab have very remarkable inhibition effect on the growth of human pancreatic cancer AsPC-1 tumor transplanted by nude mice, and have obvious dose-effect relationship, and the effect is stronger than that of the composition and trastuzumab which are singly used. And the effect is durable, and the weight of experimental animals is not influenced.
The calculation formula of the CDI value of the drug combination effect index is as follows:
And calculating according to the tumor tissue weight obtained by sampling after the experiment is finished, wherein AB is the ratio of the tumor weights of the two-drug combined group to the control group, and A and B are the ratio of the tumor weights of each single administration group to the control group. If CDI <1, the combination property of the two drugs is proved to be synergistic, cdi=1, the combination property of the two drugs is proved to be additive, and CDI >1, the combination property of the two drugs is proved to be antagonistic, and the calculation methods of the following examples are the same.
The CDI value of the drug combination index was 0.64, and the obvious synergy is realized.
Human gastric cancer BCG823 transplanted in nude mice was examined in the same manner, and the results are shown in table 6 and fig. 4-6.
Table 6 growth inhibition of human gastric cancer BCG823 nude mice transplantable tumor by comprehensive targeting drug complex (DBDx and trastuzumab)
The administration was started 7d after tumor inoculation, DBDx times per week for 15 times and trastuzumab 1 time per week for 3 times. N=6, no death was observed for each group of animals at day 31.
Comparison with control group p <0.05, p <0.01, p <0.001, p <0.0001, comparison with trastuzumab, p <0.05, comparison with DBDx, p <0.01.
The experimental result shows that the composition and trastuzumab have very remarkable inhibition effect on the growth of human gastric cancer BCG823 tumor transplanted by nude mice, and have obvious dose-effect relationship, and the effect is stronger than that of the composition and trastuzumab used alone. And the effect is durable, and the weight of experimental animals is not influenced.
The CDI value of the drug combination index is 0.62, and the obvious synergy is realized.
Example 3 in vivo anti-tumor Activity of Co-targeting drug Complex (DBDx with cetuximab)
The experimental procedure was the same as in example 2, except that the experimental cells were human esophageal cancer KYSE150 cells and human squamous cell carcinoma A431 cells, respectively, cultured in vitro.
The administration was started 7d after inoculation, DBDx times per week for 3 weeks for 15 times, and cetuximab 1 time per week for 3 weeks for 3 times. 5 times per week for 2 weeks, and cetuximab once per week for 2 weeks. The control group was given physiological saline, and the other groups were given the drugs of the respective examples by oral administration DBDx and injection administration of cetuximab.
The results are shown in Table 7, FIGS. 7-9.
Table 7 inhibition of growth of human squamous carcinoma A431 nude mice transplantable tumor by comprehensive targeting drug complex (DBDx and cetuximab)
The dosing was started 7d after tumor inoculation, n=6, and no death was observed for each group of animals at day 17. Comparison with control group p <0.05, p <0.01, p <0.001, p <0.0001, comparison with cetuximab, p <0.0001, comparison with DBDx, p <0.01.
The experimental result shows that the composition DBDx and the cetuximab have very remarkable inhibition effect on the growth of human squamous carcinoma A431 tumor transplanted in a nude mouse, and have obvious dose-effect relationship, and the effect is stronger than that of the composition and the cetuximab which are singly used. And the effect is durable, and the weight of experimental animals is not influenced.
The CDI value of the drug combination effect index is 0.76, and the synergistic effect is shown.
Human esophageal carcinoma KYSE150 cells transplanted from nude mice were examined in the same manner, and the results are shown in Table 8, FIGS. 10-12. Table 8 growth inhibition of KYSE150 nude mice transplantable tumor against human esophageal cancer by comprehensive targeting drug complex (DBDx and cetuximab)
The administration was started 7d after inoculation, DBDx times per week for 3 weeks for 15 times, and cetuximab 1 time per week for 3 weeks for 3 times. N=6, no death was observed for each group of animals at day 31. Comparison with control group, < p <0.05, < p <0.01, < p <0.001, < p <0.0001, < p <0.001 > in combination group and cetuximab, and < p <0.0001 > in DBDx.
Experimental results show that DBDx and cetuximab have very remarkable inhibition effect on human esophageal cancer KYSE150 tumor growth transplanted in nude mice, and have obvious dose-effect relationship, and the effect is stronger than that of DBDx and cetuximab which are used independently. And the effect is durable, and the weight of experimental animals is not influenced.
The CDI value of the drug combination effect index is 0.40, and the obvious synergy is realized.
The result shows that the antibody medicine and the combined medicine DBDx in the comprehensive targeting medicine compound have very obvious synergistic effect, and the combination of the antibody medicine and the combined medicine can be used for treating pancreatic cancer, gastric cancer, esophageal cancer, squamous carcinoma, melanoma, lung cancer, liver cancer and lymphoma, so that the treatment effect on tumors is effectively improved, and the occurrence and development of complications of patients are reduced.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202411036399.9A CN119074887B (en) | 2024-07-31 | 2024-07-31 | Comprehensive targeted drug compound for treating tumors and preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202411036399.9A CN119074887B (en) | 2024-07-31 | 2024-07-31 | Comprehensive targeted drug compound for treating tumors and preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN119074887A CN119074887A (en) | 2024-12-06 |
| CN119074887B true CN119074887B (en) | 2025-01-28 |
Family
ID=93691708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202411036399.9A Active CN119074887B (en) | 2024-07-31 | 2024-07-31 | Comprehensive targeted drug compound for treating tumors and preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN119074887B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198139A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Pharmaceutical composition with antineoplastic effect, and application method thereof |
| CN102198150A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Antitumor drug with double active components and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT201800004082A1 (en) * | 2018-03-29 | 2019-09-29 | Berlin Chemie Ag | ANTI-CANCER PHARMACEUTICAL COMPOSITIONS FOR COMBINED THERAPY |
| CN116018131A (en) * | 2020-06-26 | 2023-04-25 | 阿普雷奇亚制药有限责任公司 | Rapid orodispersible tablet with internal cavity |
| CN117679427A (en) * | 2023-12-28 | 2024-03-12 | 中国医学科学院医药生物技术研究所 | Application of pharmaceutical composition in preparation of drug resistant drugs for treating tumors |
-
2024
- 2024-07-31 CN CN202411036399.9A patent/CN119074887B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198139A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Pharmaceutical composition with antineoplastic effect, and application method thereof |
| CN102198150A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Antitumor drug with double active components and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN119074887A (en) | 2024-12-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| MXPA05003595A (en) | Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability. | |
| WO2014142220A1 (en) | Anti-tumor agent | |
| JP2023542093A (en) | Use of thiauranib in combination with immune checkpoint inhibitors in antitumor therapy | |
| CN102198150B (en) | Antitumor drug with double active components and application thereof | |
| ES2279157T3 (en) | EXTRACT WITH ANTITUMORAL AND ANTIVENOUS ACTIVITY. | |
| CN119074887B (en) | Comprehensive targeted drug compound for treating tumors and preparation and application thereof | |
| CN111166878B (en) | Preparation method and application of combination of antibody targeting tumor antigen and iNKT cell | |
| CN109731019B (en) | A composition with chemotherapy synergistic effect comprises components, preparation and application | |
| JP7311177B2 (en) | Combined use of A-NOR-5α androstane drugs with anticancer drugs | |
| CN107261145B (en) | Anti-tumor combined medicine and application thereof in preparing anti-cancer medicine | |
| CN111617081B (en) | Pharmaceutical composition combining substituted butenamide and mTOR inhibitor and application of pharmaceutical composition | |
| WO2019034069A1 (en) | Antitumor combination drug and use thereof in preparation of anticancer drug | |
| CN101167741A (en) | Sulforaphane and platinum medicine anti-cancer combination preparation | |
| WO2021057764A1 (en) | Use of pd-1 antibody in combination with taxoid compound in preparation of drugs for treating triple-negative breast cancer | |
| CN113893256A (en) | Application of compound or pharmaceutically acceptable salt, dimer or trimer thereof in preparation of medicine for treating cancer | |
| CN113491769A (en) | Pharmaceutical combination | |
| TW201929900A (en) | Uses of PD-1 antibody combined with apatinib for treating triple-negative breast cancer | |
| EP3007712B1 (en) | Treatment of cancer | |
| WO2013037129A1 (en) | Antitumour pharmaceutical composition with two active components and use thereof | |
| CN111821304A (en) | Application of tyrosine kinase inhibitor and vinblastine drug in preparation of drugs for preventing or treating tumor diseases | |
| CN110314159A (en) | The purposes of tyrosine kinase inhibitor combination therapy tumor disease | |
| CN118717798A (en) | A drug for improving the effect of tumor chemotherapy and application of hydrogen molecules in the preparation of a drug for improving the effect of tumor chemotherapy | |
| HK40059774A (en) | Application of compound or pharmaceutically acceptable salt, dimer or trimer thereof in the preparation of medicament for treating cancer | |
| CN117281902A (en) | Application of pharmaceutical composition in preparation of melanoma treatment products | |
| TWI602563B (en) | Aurantiamide dipeptide derivatives for treatment or prevention of angiogenesis-related diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |