CN116514967A - 骨髓间充质干细胞外泌体及其在治疗癌症中的应用 - Google Patents
骨髓间充质干细胞外泌体及其在治疗癌症中的应用 Download PDFInfo
- Publication number
- CN116514967A CN116514967A CN202310519875.1A CN202310519875A CN116514967A CN 116514967 A CN116514967 A CN 116514967A CN 202310519875 A CN202310519875 A CN 202310519875A CN 116514967 A CN116514967 A CN 116514967A
- Authority
- CN
- China
- Prior art keywords
- flot2
- protein
- monoclonal antibody
- gastric cancer
- cell
- 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.)
- Pending
Links
- 210000001808 exosome Anatomy 0.000 title claims abstract description 24
- 210000002901 mesenchymal stem cell Anatomy 0.000 title claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 title abstract description 23
- 201000011510 cancer Diseases 0.000 title abstract description 10
- 210000001185 bone marrow Anatomy 0.000 title abstract description 9
- 210000004027 cell Anatomy 0.000 claims abstract description 39
- 101150042424 flot2 gene Proteins 0.000 claims abstract description 38
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 33
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 33
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 33
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 230000009702 cancer cell proliferation Effects 0.000 claims description 3
- 239000013598 vector Substances 0.000 claims description 2
- 108020004414 DNA Proteins 0.000 claims 2
- 102000053602 DNA Human genes 0.000 claims 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000013604 expression vector Substances 0.000 claims 1
- 210000004962 mammalian cell Anatomy 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 210000001236 prokaryotic cell Anatomy 0.000 claims 1
- 238000003259 recombinant expression Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 13
- 241000699670 Mus sp. Species 0.000 abstract description 11
- 230000001225 therapeutic effect Effects 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000035755 proliferation Effects 0.000 abstract description 8
- 230000000903 blocking effect Effects 0.000 abstract description 2
- 238000011282 treatment Methods 0.000 description 16
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 9
- 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 8
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 8
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 8
- 150000001413 amino acids Chemical group 0.000 description 8
- 210000004379 membrane Anatomy 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000013641 positive control Substances 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 7
- 229960002949 fluorouracil Drugs 0.000 description 7
- 210000004408 hybridoma Anatomy 0.000 description 7
- 238000002649 immunization Methods 0.000 description 7
- 230000003053 immunization Effects 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 108091037327 miR-449 stem-loop Proteins 0.000 description 6
- 108091040525 miR-449a stem-loop Proteins 0.000 description 6
- 206010003445 Ascites Diseases 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 231100000599 cytotoxic agent Toxicity 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000009545 invasion Effects 0.000 description 4
- 230000002147 killing effect Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- -1 ulifur Chemical compound 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 210000000683 abdominal cavity Anatomy 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012228 culture supernatant Substances 0.000 description 3
- 239000002619 cytotoxin Substances 0.000 description 3
- 229960000975 daunorubicin Drugs 0.000 description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 2
- 101800003838 Epidermal growth factor Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 2
- 102100025304 Integrin beta-1 Human genes 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000007910 cell fusion Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940116977 epidermal growth factor Drugs 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 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 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 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 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000005747 tumor angiogenesis Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(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]([C@@H](C)O)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](CCCNC(N)=N)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)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)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=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 230000008728 vascular permeability Effects 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- WUIABRMSWOKTOF-OCBSMOPSSA-N 3-[[2-[2-[2-[[2-[[4-[[2-[[6-amino-2-[3-amino-1-[(2,3-diamino-3-oxopropyl)amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxym Chemical compound OS([O-])(=O)=O.N=1C(C=2SC=C(N=2)C(=O)NCCC[S+](C)C)=CSC=1CCNC(=O)C(C(O)C)NC(=O)C(C)C(O)C(C)NC(=O)C(C(O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)NC(=O)C1=NC(C(CC(N)=O)NCC(N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OCBSMOPSSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 244000284152 Carapichea ipecacuanha Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015137 Eructation Diseases 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 239000005558 Fluroxypyr Substances 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010026389 Gramicidin Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 1
- 239000009471 Ipecac Substances 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 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
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 208000007433 Lymphatic Metastasis Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102100040681 Platelet-derived growth factor C Human genes 0.000 description 1
- 229920002534 Polyethylene Glycol 1450 Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101710105463 Snake venom vascular endothelial growth factor toxin Proteins 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 description 1
- 108010073925 Vascular Endothelial Growth Factor B Proteins 0.000 description 1
- 108010073923 Vascular Endothelial Growth Factor C Proteins 0.000 description 1
- 108010073919 Vascular Endothelial Growth Factor D Proteins 0.000 description 1
- 102100038217 Vascular endothelial growth factor B Human genes 0.000 description 1
- 102100038232 Vascular endothelial growth factor C Human genes 0.000 description 1
- 102100038234 Vascular endothelial growth factor D Human genes 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 108700041737 bcl-2 Genes Proteins 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004791 biological behavior Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- RSIHSRDYCUFFLA-DYKIIFRCSA-N boldenone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 RSIHSRDYCUFFLA-DYKIIFRCSA-N 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].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 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- NDAYQJDHGXTBJL-MWWSRJDJSA-N chembl557217 Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](NC(=O)CNC(=O)[C@@H](NC=O)C(C)C)CC(C)C)C(=O)NCCO)=CNC2=C1 NDAYQJDHGXTBJL-MWWSRJDJSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 description 1
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- RSIHSRDYCUFFLA-UHFFFAOYSA-N dehydrotestosterone Natural products O=C1C=CC2(C)C3CCC(C)(C(CC4)O)C4C3CCC2=C1 RSIHSRDYCUFFLA-UHFFFAOYSA-N 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 102000010660 flotillin Human genes 0.000 description 1
- 108060000864 flotillin Proteins 0.000 description 1
- MEFQWPUMEMWTJP-UHFFFAOYSA-N fluroxypyr Chemical compound NC1=C(Cl)C(F)=NC(OCC(O)=O)=C1Cl MEFQWPUMEMWTJP-UHFFFAOYSA-N 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000009950 gastric cancer growth Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229940029408 ipecac Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 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
- HNKLPNDFOVJIFG-UHFFFAOYSA-N oxalic acid;platinum Chemical compound [Pt].OC(=O)C(O)=O HNKLPNDFOVJIFG-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 108010017992 platelet-derived growth factor C Proteins 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 231100000336 radiotoxic Toxicity 0.000 description 1
- 230000001690 radiotoxic effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide 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](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 239000000107 tumor biomarker Substances 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Virology (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及骨髓间充质干细胞外泌体及其在治疗癌症中的应用，具体提供了一种针对Flot2蛋白的抗体及其在用于制备治疗胃癌的药物中的用途。所述抗体能够特异性识别并高亲和力结合Flot2蛋白，这确保了所述抗体能够阻断Flot2蛋白并抑制胃癌细胞的增殖。将所述抗体与骨髓间充质干细胞外泌体联用后，能够有效地抑制癌细胞在小鼠体内的增殖，体现了良好的治疗效果。
Description
技术领域
本申请涉及生物领域，更具体的涉及骨髓间充质干细胞外泌体及其在治疗癌症中的应用。
背景技术
胃癌是起源于胃黏膜上皮的恶性肿瘤，胃癌发病有明显的地域性差别，在我国的西北与东部沿海地区胃癌发病率比南方地区明显为高。好发年龄在50岁以上，男女发病率之比为2：1。由于饮食结构的改变、工作压力增大以及幽门螺杆菌的感染等原因，使得胃癌呈现年轻化倾向。胃癌可发生于胃的任何部位，其中半数以上发生于胃窦部，胃大弯、胃小弯及前后壁均可受累。绝大多数胃癌属于腺癌，早期无明显症状，或出现上腹不适、嗳气等非特异性症状，常与胃炎、胃溃疡等胃慢性疾病症状相似，易被忽略，因此，我国胃癌的早期诊断率仍较低。胃癌的预后与胃癌的病理分期、部位、组织类型、生物学行为以及治疗措施有关。
常用的胃癌化疗给药途径有口服给药、静脉、腹膜腔给药、动脉插管区域灌注给药等。常用的口服化疗药有替加氟、优福定、氟铁龙等。常用的静脉化疗药有氟尿嘧啶、丝裂霉素、顺铂、阿霉、依托泊苷、甲酰四氢叶酸钙等。近年来紫杉醇、草酸铂、拓扑酶抑制剂、希罗达等新的化疗药物用于胃癌治疗。近年来，肿瘤的治疗已成为众多医学工作者研究的热点，其中单克隆抗体靶向疗法治疗肿瘤显示出了良好的前景。其研究重点主要集中在将抗体与化学药物、酶、放射性核素、毒素和生物诱导剂等耦联后直接杀伤肿瘤或者利用抗体促进肿瘤细胞凋亡和抑制肿瘤血管生成等方面。目前，国际上与肿瘤治疗相关的抗体研究主要集中在将抗体与耦联物作用后直接杀伤肿瘤细胞，利用抗体促进肿瘤细胞凋亡和抑制肿瘤血管生成等方面。单抗与化疗药物相比具有治疗作用强、不良反应少、患者耐受性高等优点，因此单抗药物是未来重要的药物类型。
目前，临床上常用的治疗胃癌的单抗类药物根据其作用靶点主要分为作用于人表皮生长因子受体-2(HER-2)的抗HER-2单抗类药物、作用于人表皮生长因子受体-1(EGFR)的抗EGFR单抗类药物、作用于血管内表皮生长因子(VEGF)的抗VEGF单抗类药物、作用于血管内表皮生长因子受体(VEGFR)的抗VEGFR单抗类药物以及作用于程序性死亡受体-1(PD-1)的抗PD-1单抗类药物。
西妥昔单抗(cetuxiumab)是重组人鼠嵌合型IgG1单克隆抗体，可以选择性地作用于EGFR，抑制EGFR与EGFR配体特异性结合。抗肿瘤机制与EGFR引起的信号传达有关，可通过抑制EGFR胞外区结构区域与配体结合，抑制受体形成二聚体、抑制EGFR上酪氨酸残基自身磷酸化、下调下游的信号传导、抑制肿瘤细胞的增殖。还可通过上调凋亡效应酶caspase-3，P-27的基因转录，减少其蛋白降解；下调bcl-2的基因转录和蛋白的表达促进肿瘤细胞凋亡。VEGF为血管内表皮生长因子，VEGF家族主要有VEGF-A，VEGF-B，VEGF-C，VEGF-D，VEGF-E以及蛇毒VEGF(snakevenomVEGF，svVEGF)。VEGF的主要作用是刺激血管内皮细胞增殖以及增加血管通透性。贝伐珠单抗(bevaci-zumab)是一种特异性靶向VEGF-A的人源化单克隆抗体，可通过作用于VEGF，与VEGF特异性结合，抑制VEGF与受体VEGFR结合，抑制VEGFR磷酸化，阻断血管生成及下游信号转导，同时以内皮细胞为靶点可增加血管通透性，促使药物渗透至肿瘤细胞，抑制肿瘤细胞增殖，诱导肿瘤细胞凋亡。2002年获得FDA批准上市，用于一线治疗晚期结直肠癌。程序性死亡分子(PD-1)，是一种新型负性共刺激分子。程序性死亡分子配体(PD-L1)与PD-1结合后可产生抑制性信号，抑制免疫细胞的活化和增殖，诱导免疫细胞凋亡，使免疫细胞产生对癌症细胞的免疫应答困难，进而使肿瘤细胞增殖、肿瘤发展。pembrolizumab通过与PD-1结合，靶向作用于PD-1/PD-L1信号通路，抑制其信号传导，使T细胞恢复对癌症细胞的免疫应答，恢复抗肿瘤活性从而达到治疗胃癌的作用。
越来越多的研究发现其特征蛋白Flot2在肿瘤中异常表达，并且与肿瘤的侵袭转移相关，人Flot2的mRNA广泛表达于各类细胞。Flot2通过其SPFH结构域与肌动蛋白相互作用。此外，Flot2还可以通过磷酸化的方式增强细胞在细胞外基质的传播。这些研究提示Flot2与肿瘤的转移关系密切。在胃癌患者癌组织和癌旁组织中，Flot2基因在癌旁组织中的阳性表达率为27.8％，而在癌组织中的阳性表达率为93.3％，并且与组织学分级、浸润深度、淋巴结转移和TNM分期显著相关。采用siRNA干扰Flot2的表达后，胃癌细胞的增殖、迁移及转移能力都显著下降。这些结果表明Flot2蛋白的表达与胃癌的进展、预后不良密切相关，其机制可能与Flot2调控细胞增殖、转移和侵袭的能力有关。这些结果提示Flot2可能成为新的胃癌预后及治疗的靶点。胃癌细胞与正常胃黏膜上皮细胞相比，miR-449a表达下调，而Flot2表达上调。荧光素酶报告基因证实Flot2是miR-449a的一个新靶点。miR-449a通过抑制Flot2的表达来调控胃癌细胞的侵袭。一组上皮间质转化(EMT)标志物的表达分析显示，miR-449a降低间质标记物的表达和诱导上皮细胞标记物的表达，这与沉默Flot2的结果一致。此外，Flot2的上调是TGF-β诱导胃癌细胞产生EMT的必要因素。结果显示，miR-449a通过抑制TGF-β介导的EMT抑制Flot2的表达进而导致胃癌细胞的侵袭能力降低。这些结果显示，Flot2与胃癌的侵袭相关，并且受miR-449a的调控。因此，Flot2可以作为一个潜在的胃癌生物标志物和有前景的胃癌治疗靶点。但是针对Flot2常规的都是siRNA药物的开发，而针对该靶点开发疗效显著、提高患者生存质量且不易耐药的新型单抗是药学研发人员努力的方向。
发明内容
本发明首先提供了特异性针对Flot2的单克隆抗体。
进一步的，本发明单克隆抗体的重链可变区氨基酸序列如SEQ ID NO.1所示：轻链可变区氨基酸序列如SEQ ID NO.2所示。
进一步的，本发明还提供了一种改进的单克隆抗体，所述改进是在重链可变区氨基酸序列SEQ ID NO.1和轻链可变区氨基酸序列SEQ ID NO.2的基础上进行氨基酸的取代、缺失或者替换。
如SEQ ID NO：1中列出的)具有至少约50.0％、至少约60.0％、至少约80.0％、至少约85.0％、至少约90.0％、至少约95.0％、至少约98.0％以及至少约99.0％一致性的一种氨基酸序列可以用于本发明的单抗以及方法中。
如SEQ ID NO：2中列出的)具有至少约50.0％、至少约60.0％、至少约80.0％、至少约85.0％、至少约90.0％、至少约95.0％、至少约98.0％以及至少约99.0％一致性的一种氨基酸序列可以用于本发明的单抗以及方法中。
进一步的，所述抗体被保守性氨基酸取代包括这种取代，其中氨基酸残基被具有相似侧链的氨基酸残基所取代。具有相似侧链的氨基酸残基家族已在本领域进行定义。这些家族包括具有碱性侧链(例如，赖氨酸、精氨酸、组氨酸)，酸性侧链(例如，天冬氨酸、谷氨酸)，不带电荷的极性侧链(例如，甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)，非极性侧链(例如，丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、蛋氨酸)，β分支的侧链(例如，苏氨酸、缬氨酸、异亮氨酸)和芳香侧链(例如，酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此，优选用来自相同侧链家族的另一种氨基酸残基来代替在抗Flot2抗体中预定的非必需氨基酸残基。
进一步的，本发明还提供了含有Flot2抗体的药物组合物。
在另一方面，本发明描述了与诸如细胞毒素、药物(例如，免疫抑制剂)或放射性同位素的治疗成分结合的抗Flot2单克隆抗体。在本文中这种结合物称为“药物组合物”。包括一种或多种细胞毒素的免疫结合物称为“免疫毒素”。细胞毒素或细胞毒性剂包括对细胞有害的(例如，杀伤性)的任何试剂。其例子包括紫杉醇、细胞松弛素B、短杆菌肽D、溴化乙锭、吐根碱、丝裂霉素、足叶乙甙、tenoposide、长春新碱、长春花碱、秋水仙素、阿霉素、道诺红霉素、二羟基炭疽菌素二酮、米托蒽醌、光神霉素、放线菌素D、1-脱氢睾酮、糖皮质素、普鲁卡因、丁卡因、利多卡因、普萘洛尔、和嘌呤霉素及其类似物或同系物。
用于形成药物组合物的合适的治疗剂包括，但不限于抗代谢物(例如，氨甲蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氟尿嘧啶、达卡巴嗪)、烷化剂(例如，氮芥、thioepa苯丁酸氮芥、美法仑、卡莫司汀(BSNU)和洛莫司汀(CCNU)、环磷酰胺、白消胺、二溴甘露糖醇、链脲菌素、丝裂霉素C和顺二氯二胺铂(II)(DDP)顺铂)、蒽环类(例如，道诺红霉素(以前称之为道诺霉素)和阿霉素)、抗生素(例如，放线菌素(以前称之为更生霉素)、博来霉素、普卡霉素和氨茴霉素(AMC))，以及抗有丝分裂剂(例如，长春新碱和长春花碱)。在一个优选的实施方案中，治疗剂是一种细胞毒性剂或放射毒性剂。在另一个实施方案中，治疗剂是一种免疫抑制剂。还在另一个实施方案中，治疗剂是GM-CSF。在一个优选的实施方案中，治疗剂是阿霉素、顺铂、博来霉素、硫酸盐、卡莫司汀、苯丁酸氮芥、环磷酰胺或蓖麻毒素A。
进一步的，本发明还提供了Flot2抗体在制备用于抑制胃癌细胞增殖的药物组合物中的用途。
具体的，无论选择什么样的给药途径，可以以合适的水化形式应用的本发明的药用组合物，能通过本领域技术人员所公知的传统方法制备成可以药用的剂量形式。
具有本领域普通技能的医生能方便地确定并开出有效量的所需药用组合物。例如，医生开始使用的所述药用组合物中采用的本发明的化合物的量，低于获得理想治疗效果所需要的量，并逐渐增加剂量，直到获得理想的效果。一般地，本发明组合物的合适的每日剂量是有效产生治疗效果所需要的所述化合物的最低剂量。所述有效剂量通常取决于上述因素。优选通过静脉内、肌内、腹膜内或皮下途径使用，优选在靠近靶位点处给药。如果需要，治疗组合物的每日有效剂量可以按2个、3个、4个、5个、6个或更多个小剂量，在1天内以适当的时间间隔分别使用，选择性地以单位剂量形式使用。本发明的化合物尽管可以单独给药，但优选以药用制剂(组合物)形式给药该化合物。
有益效果
本发明涉及治疗性抗体以及外泌体领域，具体提供了一种针对Flot2蛋白的抗体及其在用于制备治疗胃癌的药物中的用途。所述抗体能够特异性识别并高亲和力结合Flot2蛋白，这确保了所述抗体能够阻断Flot2蛋白并抑制胃癌细胞的增殖。将所述抗体与骨髓间充质干细胞外泌体联用后，能够有效地抑制癌细胞在小鼠体内的增殖，体现了良好的治疗效果。
附图说明
图1各实验组对癌细胞数量的影响结果
图2各实验组对Flot2蛋白表达量的影响
具体实施方式
本发明可通过后续对于本发明一些实施方案描述以及其中所包括的实施例的详细内容而更容易被了解。在进一步叙述本发明之前，应明了本发明不会被局限于所述特定实施方案中，因为这些实施方案必然是多样的。亦应明了本说明书中所使用的用语仅是为了阐述特定实施方案，而非作为限制，因为本发明的范围将会被仅仅界定在所附的权利要求中。
下面通过具体实施例，并结合附图，对本发明的技术方案作进一步的具体说明。本发明中，若非特指，所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法，如无特别说明，均为本领域的常规方法。
实施例1本发明Flot2单克隆抗体的制备及鉴定
(1)免疫及细胞融合筛选
重组人Flot2蛋白，ab131919，abcam抗原和完全弗氏佐剂按照1：1的体积比混合均匀，乳化完全。选取6-8周龄、体重相等的雌性Balb/c小鼠。采用背部皮下多点注射的方法进行免疫，50μg/只，共免疫3只小鼠。分别于初次免疫后的第14和28天，进行第2、3次免疫，以不完全弗氏佐剂代替完全弗氏佐剂，免疫原剂量不变。第三次免疫7天后，采集尾静脉血，以间接ELISA法检测血清中抗体效价，其中小鼠A尾血效价为1:60000，小鼠B的尾血效价为1:40000，小鼠C的尾血效价为1:100000。选择小鼠C进行加强免疫，免疫量为80μg/只重组蛋白。
3天后取脾脏进行细胞融合，将脾脏B淋巴细胞悬液和骨髓瘤细胞悬液按7:1的比例混合均匀，补加40mL无血清培养基，1000rpm离心10min，将上清吸干，使细胞团松散成糊状均匀分布在离心管底。吸取1mL37℃预温的PEG1450促融液，在离心管口处沿管壁缓慢加入细胞中，并边加边转动离心管，在1min钟内完成融合。静置细胞1.5min，逐滴加入37℃预温的不含血清的1640培养基终止融合，在5min内完成，边加边转动离心管。37℃静置5min，1000rpm离心6min，弃去上清，加入含HAT的选择培养基，轻柔重悬细胞，避免反复吹打。将细胞悬液按100μL/孔加入已铺有饲养细胞层的96孔细胞培养板中，37℃、5％CO2培养箱中培养。培养4-5天后，按100μL/孔补加含HT的完全培养基。培养10天后，显微镜下观察杂交瘤克隆群的大小，待长势合适时采用间接ELISA法检测培养上清，共筛选阳性克隆13株，将3株杂交瘤细胞株进行4次亚克隆(有限稀释法)获得一株阳性最强分泌抗体最稳定的杂交瘤细胞株5G13。
(2)腹水单抗的制备
选取8-10周龄、状态良好的雌性Balb/c小鼠，将灭菌的液体石蜡预注射小鼠腹腔，0.5mL/只。10d后，将1×106个对数生长期的杂交瘤细胞接种于小鼠腹腔，0.5mL/只。10天后采取腹腔抽取法采集腹水。12000rpm/min离心5min，收集位于中间层的澄亮腹水于离心管，采用辛酸一硫酸铵沉淀法纯化腹水单抗，
-20℃冻存备用。
(3)单抗的效价和亚型以及浓度
采用间接ELISA法测定小鼠腹水单抗效价；按照小鼠Ig亚类(型)鉴定试剂盒说明书方法，鉴定杂交瘤培养上清中单抗亚类(型)。采用BCA法测定纯化单抗浓度，结果如表1所示。
表1单抗5G13性能鉴定结果
| 性能指标 | 鉴定结果 |
| 亚类(型) | IgG1(κ) |
| 纯化抗体效价 | 1×10-7 |
| 抗体定量结果 | 8.37mg/ml |
实施例2单抗5G13的亲和力测定
使用10μg/ml制备的Flot2蛋白与传感器进行固化结合，使用SDbuffer(PBS+0.02％Tween20+0.1％BSA)配制不同浓度的5G13单克隆抗体(566.7nM、283.3nM、141.7nM、70.8nM、35.4nM、17.7nM、8.84nM、4.42nM、2.21nM、1.10nM)作为流动相，使用分子间相互作用仪(OCTETK2，PALLlifescience)进行亲和力检测，程序设定为：Baseline240s，Loading360s，Baseline2180s，Association480s，Dissociation480s，使用AHC(Anti-hIgGFcCapture)传感器。结果显示，所制备的单克隆抗体5G13与Flot2的亲和力为4.05E-09(M)，显示了较好的亲和特性。
实施例3单克隆抗体杂交瘤细胞的抗体基因可变区测序
收获处于对数生长期的单克隆抗体5G13的杂交瘤细胞，TRIZOL裂解进行RNA提取，反转录后获得cDNA，采用本领域公知的轻重链可变区扩增引物进行扩增并获得重链和轻链可变区，非功能性VK基因去除，克隆至pMD18-T载体，测序，使用IMGT/V-QUEST数据库进行测序结果比对，进一步分析(委托南京铭研生物完成)。本发明单克隆抗体的重链可变区氨基酸序列如SEQ ID NO.1所示：轻链可变区氨基酸序列如SEQ ID NO.2所示。
实施例4单克隆抗体5G13对胃癌细胞株的杀伤作用
将胃癌细胞株SGC7901用10％胎牛血清的RPMI1640培养基重悬，接种到6孔板中，1×104/孔。设置空白对照组、阳性对照组和单抗实验组，实验组为再分高中低三个浓度组，每组平行3孔。待细胞贴壁后实验组添加5G13单抗，高中低浓度组的终浓度分别达到100μg/mL、50μg/mL、10μg/mL，空白对照组不作任何处理，阳性对照组为添加5-FU终浓度为50μg/mL；37℃条件下培养72h后，消化细胞进行计数，分析对照组和实验组之间的差异。
如图1所示，本发明的单克隆抗体5G13对胃癌细胞生长有明显抑制作用，与空白对照组相比差异极其显著(P<0.05)。并且随着单抗浓度的增加，细胞密度也是较快的减少，体现了剂量依赖性。与阳性对照组相比，单抗高浓度组的细胞密度也是显著的要小得多，说明了本发明的单克隆抗体在高浓度处理条件下，细胞密度只有(0.31±0.02)×106，比阳性对照组的(0.58±0.03)×106显著的减少。
实施例5单克隆抗体5G13对胃癌细胞中的Flot2蛋白表达的影响
将胃癌细胞株SGC7901用10％胎牛血清的RPMI1640培养基重悬，接种到6孔板中，1×104/孔。设置空白对照组、阳性对照组和单抗实验组，实验组为再分高中低三个浓度组，每组平行3孔。待细胞贴壁后实验组添加5G13单抗，高中低浓度组的终浓度分别达到100μg/mL、50μg/mL、10μg/mL，空白对照组不作任何处理，阳性对照组为添加5-FU终浓度为50μg/mL；37℃条件下培养72h。收集各实验组和对照组等量的细胞悬液至1.5mLEP管中，在冰上放置30min，期间震荡几次。4℃，13000g，离心15min，吸取上清蛋白液至新的预冷的1.5mLEP管中。上样前将样品浓度调整一致，按照比例添加上样缓冲液，混匀后100℃煮10min，使蛋白充分变性。SDS-PAGE蛋白电泳，当指示剂溴酚蓝跑到分离胶底端时终止。转膜，转膜完成后，将膜从电转槽中取出，浸没于含5％脱脂奶粉的抗原封闭液中，常温下水平摇床缓慢震荡1-2h。一抗孵育：将封闭好的PVDF膜，加入本发明的抗体5G13(1：1000稀释)，4℃冰箱孵育过夜。二抗孵育：次日取出PVDF膜，室温条件下用PBST洗涤3次，每次15min，，然后将膜放入HRP标记山羊抗小鼠(1：3000稀释)二抗溶液中，室温摇床上孵育2h，PBST洗涤3次，每次15min，。(3)显影：使用ECL显影液进行显影，将膜放置入凝胶成像仪自动曝光成像，并照相。
从图2的Flot2蛋白相对表达量结果可以看出，添加了单克隆抗体处理之后，无论是高剂量、中剂量还是低剂量单抗处理后，Flot2蛋白的表达均被显著的抑制，并且随着剂量的增加，蛋白的抑制效果越强，在高浓度单克隆抗体处理之后，Flot2蛋白表达只有空白对照组的(0.06±0.02)，抑制效果极好，而阳性对照组5-FU基本上对Flot2蛋白的表达影响较小，只抑制了极少的表达，表现了5-FU并不是直接通过Flot2作为抑制通路实现的癌细胞杀伤。
实施例6骨髓间充质干细胞外泌体的制备及其联合单克隆抗体5G13体内生物学验证
在无菌环境下用配置好的培养基冲洗大鼠胫骨骨髓腔，将得到的骨髓细胞种植在25cm2培养皿中，置于CO2细胞培养箱中培养，此后每2d更换1次培养基并观察细胞在显微镜下的形态和生长情况。当细胞生长至90％融合度时，用0.25％胰酶-EDTA溶液进行消化，以1：3传代。当传至第3代的骨髓间充质干细胞生长至约80％融合度时，用0.125％胰酶-EDTA溶液进行消化，并将其悬浮于含2％牛血清白蛋白的PBS中，随后将约1×105/管的细胞悬液进行CD45、CD29、CD90的表面标志物鉴定，结果显示细胞阳性表达CD90(阳性率97.3％)、CD29(阳性率99.9％)，阴性表达CD45(阳性率0.10％)，表面分离制备得到了骨髓间充质干细胞。
将骨髓间充质干细胞在含体积分数为10％胎牛血清和1％青霉素-链霉素的DMEM培养基中扩大培养，收集骨髓间充质干细胞的培养上清90mL，4℃，300×g持续离心10min以除去细胞，弃沉淀，取上清以2000×g离心10min以除去细胞碎片，取上清以10000×g离心30min以去除较大的囊泡，取上清经过超速离心(4℃，100000×g，2h)后弃去上清，沉淀即为外泌体，将其重悬于100μL PBS溶液中备用。取10μL外泌体悬液滴加于碳膜包被的铜网上，在25℃下静置10min，用滤纸除去多余液体后，用3％磷钨酸水溶液将外泌体染色5min；最后，使用100kV下运行的透射电子显微镜观察外泌体的直径分布在35-110nm的囊泡状结构。
将BALB/c小鼠用随机数字法分成如下五组，PBS对照组和外泌体免疫组，单抗单独治疗组，单抗联合外泌体治疗组，阳性对照组，每组10只，在每只小鼠右腋皮下接种1×106个胃癌细胞株SGC7901。PBS对照组不给药小鼠分别于左后腿根部皮下注射PBS(100μl/只)，外泌体免疫组给予前述制备的外泌体(10μg/只)，共免疫3次，每周1次。单抗联合外泌体治疗组予前述制备的外泌体(10μg/只)以及单克隆抗体5G13(50μg/只)，共免疫3次，每周1次。单抗治疗组予单克隆抗体5G13(50μg/只)，共免疫3次，每周1次。阳性对照组为给予5-FU(10μg/只)，共免疫3次，每周1次。最后一次注射后的第7天，对每只小鼠肿瘤大小进行观察测量，肿瘤体积以公式V＝ab'/2计算。结果如表2所示。
表2各组肿瘤体积的结果
| 组别 | 肿瘤体积(cm3) |
| PBS对照组 | 16.38±0.48 |
| 外泌体免疫组 | 6.27±0.34* |
| 单抗单独治疗组 | 4.31±0.26* |
| 单抗联合外泌体治疗组 | 2.02±0.17* |
| 阳性对照组 | 4.88±0.14* |
*表示与对照组相比，各治疗组效果显著差异，P<0.05。
从表2的结果可以看出，外泌体和单抗二者均可有效的抑制小鼠肿瘤的生长。特别是单抗联合外泌体一起作用后，使得肿瘤的生长体积能够被更有效的抑制，提交了较好的治疗效果。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。尽管已经示出和描述了本发明的实施例，本领域的普通技术人员可以理解：在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。
尽管以上结合附图对本发明的实施方案进行了描述，但本发明并不局限于上述的具体实施方案和应用领域，上述的具体实施方案仅仅是示意性的、指导性的，而不是限制性的。本领域的普通技术人员在本说明书的启示下和在不脱离本发明权利要求所保护的范围的情况下，还可以做出很多种的形式，这些均属于本发明保护之列。
Claims (7)
1.一种特异性针对Flot2蛋白的单克隆抗体，其特征在于单克隆抗体的重链可变区氨基酸序列如SEQ ID NO.1所示：轻链可变区氨基酸序列如SEQ ID NO.2所示。
2.编码如权利要求1所述抗体的DNA分子。
3.包含如权利要求2所述DNA分子的重组表达载体。
4.包含如权利要求3所述载体的宿主细胞，所述宿主细胞包含原核细胞、酵母或哺乳动物细胞。
5.一种抑制Flot2蛋白表达的药物组合物，所述组合物包含如权利要求1所述的抗体以及药用赋形剂、载体或稀释剂。
6.权利要求1所述的特异性针对Flot2蛋白的单克隆抗体在制备用于抑制胃癌细胞增殖的药物组合物或者制剂中的用途。
7.骨髓间充质干细胞外泌体以及权利要求1所述的特异性针对Flot2蛋白的单克隆抗体联合在制备用于抑制胃癌细胞增殖的药物组合物或者制剂中的用途。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310519875.1A CN116514967A (zh) | 2023-05-10 | 2023-05-10 | 骨髓间充质干细胞外泌体及其在治疗癌症中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310519875.1A CN116514967A (zh) | 2023-05-10 | 2023-05-10 | 骨髓间充质干细胞外泌体及其在治疗癌症中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116514967A true CN116514967A (zh) | 2023-08-01 |
Family
ID=87399122
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310519875.1A Pending CN116514967A (zh) | 2023-05-10 | 2023-05-10 | 骨髓间充质干细胞外泌体及其在治疗癌症中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116514967A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117844763A (zh) * | 2024-01-29 | 2024-04-09 | 杭州师范大学 | 一种制备非基因操作car-免疫细胞的方法及制得的car-免疫细胞和其的应用 |
-
2023
- 2023-05-10 CN CN202310519875.1A patent/CN116514967A/zh active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117844763A (zh) * | 2024-01-29 | 2024-04-09 | 杭州师范大学 | 一种制备非基因操作car-免疫细胞的方法及制得的car-免疫细胞和其的应用 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI443109B (zh) | 抗ｅｐｈａ２抗體 | |
| KR101683884B1 (ko) | 항-ＥｐＣＡＭ 항체 및 이의 용도 | |
| CN112703013B (zh) | Cd3抗原结合片段及其应用 | |
| MX2014009748A (es) | Composicion farmaceutica para el tratamiento y/o prevencion del cancer. | |
| US11066471B2 (en) | Antibodies to MICA and MICB proteins | |
| CN104168914A (zh) | Vegf/dll4结合剂及其应用 | |
| MX2014009749A (es) | Composicion farmaceutica para el tratamiento y/o prevencion del cancer. | |
| CN111777681A (zh) | 一种结合紧密连接蛋白-18.2的抗体及其用途 | |
| CN111944048B (zh) | 抗cldn抗体及其药物组合物和检测方法 | |
| JP2004534741A (ja) | 癌に対する抗体 | |
| US10611847B2 (en) | ABCG2 monoclonal antibody and uses thereof | |
| US11912777B2 (en) | Antibodies binding TNFR2 and uses thereof | |
| CN116514967A (zh) | 骨髓间充质干细胞外泌体及其在治疗癌症中的应用 | |
| JP6041333B2 (ja) | 抗腫瘍剤 | |
| WO2015076425A1 (ja) | 新規モノクローナル抗体 | |
| CN113474048A (zh) | 用于癌症治疗的组合物和方法 | |
| WO2019045086A1 (ja) | 活性型もしくは潜在型ＴＧＦ−β１特異的抗体の用途 | |
| CN116063478B (zh) | 干细胞细胞因子的制备方法及其抗体联用的制药用途 | |
| CN107488231B (zh) | 抗cd56抗体及其用途 | |
| WO2022152285A1 (zh) | Garp蛋白抗体及其应用 | |
| CN107446049B (zh) | 一种靶向人肝癌干细胞的单克隆抗体及其应用 | |
| WO2024017361A1 (zh) | 一种针对Trop2的单克隆抗体及其应用 | |
| CN113912721B (zh) | 一种抗人cd47的单克隆抗体及其应用 | |
| CN115894678B (zh) | 一种干细胞细胞因子的制备方法及其在制备药品中的用途 | |
| WO2023143444A1 (zh) | 抗dkk1抗体、其药物组合物及用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20230801 |