JP6302239B2 - 抗腫瘍剤及びその製造方法 - Google Patents
抗腫瘍剤及びその製造方法 Download PDFInfo
- Publication number
- JP6302239B2 JP6302239B2 JP2013264582A JP2013264582A JP6302239B2 JP 6302239 B2 JP6302239 B2 JP 6302239B2 JP 2013264582 A JP2013264582 A JP 2013264582A JP 2013264582 A JP2013264582 A JP 2013264582A JP 6302239 B2 JP6302239 B2 JP 6302239B2
- Authority
- JP
- Japan
- Prior art keywords
- heat
- lactobacillus plantarum
- antitumor agent
- cells
- present
- 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
- 239000002246 antineoplastic agent Substances 0.000 title claims description 48
- 238000004519 manufacturing process Methods 0.000 title claims description 19
- 240000006024 Lactobacillus plantarum Species 0.000 claims description 52
- 235000013965 Lactobacillus plantarum Nutrition 0.000 claims description 51
- 229940072205 lactobacillus plantarum Drugs 0.000 claims description 51
- 230000004614 tumor growth Effects 0.000 claims description 47
- 230000002401 inhibitory effect Effects 0.000 claims description 30
- 235000013305 food Nutrition 0.000 claims description 29
- 238000010438 heat treatment Methods 0.000 claims description 26
- 230000000813 microbial effect Effects 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 230000001580 bacterial effect Effects 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 7
- 235000013361 beverage Nutrition 0.000 claims description 4
- 230000001747 exhibiting effect Effects 0.000 claims description 2
- 206010053759 Growth retardation Diseases 0.000 claims 2
- 210000004027 cell Anatomy 0.000 description 68
- 206010028980 Neoplasm Diseases 0.000 description 58
- 241000699670 Mus sp. Species 0.000 description 21
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 20
- 201000011510 cancer Diseases 0.000 description 17
- 102100037850 Interferon gamma Human genes 0.000 description 15
- 108010074328 Interferon-gamma Proteins 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 238000005259 measurement Methods 0.000 description 13
- 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 12
- 230000000259 anti-tumor effect Effects 0.000 description 12
- 241000894006 Bacteria Species 0.000 description 11
- 102000004127 Cytokines Human genes 0.000 description 11
- 108090000695 Cytokines Proteins 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 239000004310 lactic acid Substances 0.000 description 10
- 235000014655 lactic acid Nutrition 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 102100040247 Tumor necrosis factor Human genes 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 210000004989 spleen cell Anatomy 0.000 description 9
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000002504 physiological saline solution Substances 0.000 description 8
- 230000000638 stimulation Effects 0.000 description 8
- 102000013462 Interleukin-12 Human genes 0.000 description 7
- 108010065805 Interleukin-12 Proteins 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 102000003814 Interleukin-10 Human genes 0.000 description 6
- 108090000174 Interleukin-10 Proteins 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000036039 immunity Effects 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- 238000002054 transplantation Methods 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 5
- 239000006285 cell suspension Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000012894 fetal calf serum Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000013376 functional food Nutrition 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 238000010162 Tukey test Methods 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 235000015872 dietary supplement Nutrition 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 235000013402 health food Nutrition 0.000 description 3
- 230000007236 host immunity Effects 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 210000001215 vagina Anatomy 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 201000008808 Fibrosarcoma Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 210000004322 M2 macrophage Anatomy 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000006051 NK cell activation Effects 0.000 description 2
- 239000012979 RPMI medium Substances 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 210000003690 classically activated macrophage Anatomy 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000031261 interleukin-10 production Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 239000000592 Artificial Cell Substances 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000006478 Cecal Neoplasms Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 101150014058 MMP1 gene Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical compound CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 201000003959 cecum carcinoma Diseases 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 108700004333 collagenase 1 Proteins 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000013611 frozen food Nutrition 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 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
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 230000005745 host immune response Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000019734 interleukin-12 production Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 235000021056 liquid food Nutrition 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- CDUFCUKTJFSWPL-UHFFFAOYSA-L manganese(II) sulfate tetrahydrate Chemical compound O.O.O.O.[Mn+2].[O-]S([O-])(=O)=O CDUFCUKTJFSWPL-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000013406 prebiotics Nutrition 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000006041 probiotic Substances 0.000 description 1
- 230000000529 probiotic effect Effects 0.000 description 1
- 235000018291 probiotics Nutrition 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 235000012046 side dish Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000013322 soy milk Nutrition 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 235000015193 tomato juice Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 1
- 239000001393 triammonium citrate Substances 0.000 description 1
- 235000011046 triammonium citrate Nutrition 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
[1] ラクトバチルス・プランタラム(Lactobacillus plantarum)菌体を60〜80℃で加熱することにより、増強された腫瘍増殖抑制効果を示す加熱処理菌体を調製することを含む、抗腫瘍剤の製造方法。
[2] ラクトバチルス・プランタラムが、ラクトバチルス・プランタラムALAL006株(受託番号NITE BP-01754)である、上記[1]の方法。
[3] 前記加熱を5〜25分間行う、上記[1]又は[2]の方法。
[4]菌体を前記加熱後、乾燥させることをさらに含む、上記[1]〜[3]の方法。
[5] 乾燥が凍結乾燥である、上記[4]の方法。
[6] 上記[1]〜[5]の方法によって製造される、ラクトバチルス・プランタラムの加熱処理菌体を含む抗腫瘍剤。
[7] 上記[6]の抗腫瘍剤を含む、飲食品。
[8] 上記[6]の抗腫瘍剤を含む、腫瘍増殖抑制用の医薬。
本発明は、ラクトバチルス・プランタラム(Lactobacillus plantarum)菌体を比較的低温で加熱処理することにより得られる増強された腫瘍増殖抑制効果を示す加熱処理菌体を含む抗腫瘍剤及びその製造方法を提供する。
1白金耳量の植物発酵物由来乳酸菌ラクトバチルス・プランタラム(Lactobacillus plantarum)ALAL006株を、2mlのMRS(de MAN, ROGOSA, SHARPE)液体培地(組成:培地1L当たり、ペプトン10.0g、ラブ−レムコ末(肉エキス)8.0g、酵母エキス4.0g、ブドウ糖20.0g、モノオレイン酸ソルビタン1.0ml、リン酸水素二カリウム2.0g、酢酸ナトリウム三水和物5.0g、クエン酸トリアンモニウム2.0g、硫酸マグネシウム七水和物0.2g、及び硫酸マンガン四水和物0.05g、pH 6.2±0.2;関東科学株式会社、東京)に接種し、37℃で24時間培養して前培養液を調製した。この前培養液を1Lの本培養培地(上記と同じMRS液体培地)に接種(1×106〜1×107/ml)し、37℃で20時間培養した。培養終了後、冷却遠心機にて集菌し、生理食塩水にて洗浄後、菌体ペレットを滅菌蒸留水90mlに懸濁した。得られた菌懸濁液の30mlをそのまま凍結乾燥することにより生菌体乾燥物を調製した(サンプルP1)。また菌懸濁液の30mlを115℃にて15分、又は70℃にて15分加熱殺菌した後、凍結乾燥することにより、加熱死菌体を含む組成物(それぞれサンプルP2、P3)を得た。この加熱処理は、具体的には、菌懸濁液の30mlを100ml三角フラスコに入れ、オートクレーブ滅菌器にて115℃で15分加熱することにより、又は、菌懸濁液の30mlを100ml三角フラスコに入れ、湯浴中でマグネットスターラーにて撹拌しながら菌懸濁液の温度が70℃に達してから15分加熱することにより、実施した。凍結乾燥後の組成物の重量はいずれも培養液1L当たり2.2gであった。
5週齢のBALB/c系統の雌マウス(平均体重およそ16g)を対照群、P1投与群(0.2mg群、10mg群)、P2投与群(0.2mg群、10mg群)及びP3投与群(0.2mg群、10mg群)の各群にそれぞれ6匹ずつ割りつけた。投与群のマウスに与えるP1、P2及びP3懸濁液は、実施例1で調製したサンプルP1、P2及びP3のそれぞれについて10mg又は0.2 mgを生理食塩液0.2mLに混合することにより調製した。各投与群のマウスに、それぞれ指定された懸濁液(10mg又は0.2 mgのP1、P2又はP3/0.2mL)を3週間にわたり毎日1回ゾンデを用いて経口投与した。投与期間最終日の翌日に、マウス線維肉腫Meth-A(東北大学細胞センターより供与)1×106細胞をマウスの鼠経部皮下に移植した。移植後は隔日で、ゾンデを用いた各指定懸濁液の経口投与を継続した。対照群のマウスには、懸濁液に代えて生理食塩液(0.2mL)を用いること以外は、投与群と同じスケジュールで同様に経口投与及び移植を行った。腫瘍移植後、経時的に腫瘍の長径と短径をノギスで計測し、その積の平方根を腫瘍サイズとして算出し、そこから腫瘍増殖の推移を評価した。得られたデータについては、一元配置分散分析の後、Tukey又はDunnnetの多重比較検定を行った。統計的有意水準は5%未満とした。
サンプルP1、P2及びP3の投与による宿主免疫能の変化を抗腫瘍中和試験Winn assay(Saito M, et al., (1984) Int. J. Cancer, 33: p.271-276)を用いて評価した。
5週齢のBALB/c系統の雌マウスを対照群、P1投与群、P2投与群及びP3投与群の各群にそれぞれ6匹ずつ割りつけた。P1、P2及びP3投与群のマウスには、実施例2と同様にして調製した懸濁液(10mgのP1、P2又はP3/0.2mL/日)を3週間にわたり毎日1回ゾンデを用いて経口投与した。投与期間最終日の翌日に、Meth-A腫瘍1×106細胞をマウスの鼠経部皮下に移植した。対照群のマウスには、懸濁液に代えて生理食塩液(0.2mL)を用いること以外は、投与群と同じスケジュールで同様に経口投与及び移植を行った。腫瘍移植後20日目に各群それぞれのマウスから採取した脾細胞1×107細胞と新たなMeth-A腫瘍1×106細胞を混和(脾細胞数:腫瘍細胞数=30:1)し、それぞれ新たな6匹の5週齢のBALB/cマウスの鼠経部皮下に移植した。さらに、Meth-A腫瘍単独移植群として、マウス脾細胞と混和することなくMeth-A腫瘍単独を、6匹の5週齢のBALB/c雌マウスの鼠経部皮下に移植した。これらの腫瘍移植後、経時的に腫瘍の長径と短径をノギスで計測し、その積の平方根を腫瘍サイズとして算出し、そこから腫瘍増殖の推移を評価した。得られたデータについては、一元配置分散分析の後、Tukeyの多重比較検定を行った。統計的有意水準は5%未満とした。
以上の結果は、低温加熱処理物(P3)の投与により、脾細胞中に強い腫瘍増殖抑制作用を有する免疫細胞群を誘導できたことを示している。
経口投与した乳酸菌は、消化管のパイエル氏板の主にマクロファージに取り込まれ、宿主免疫を賦活すると考えられている(Hiramatsu Y., et al., Cytotechnology (2011) 63:307-317; Mowat A. M. and Bain C.C., J. Innate Immun., (2011) 3:550-564)。そこで、サンプルP1、P2及びP3がパイエル氏板の免疫細胞に及ぼす影響を、サイトカイン(TNF-α、IL-10、及びIFN-γ)産生誘導能に基づいて検討した。
サンプルP1、P2及びP3の投与が全身免疫に及ぼす影響を、脾臓細胞におけるサイトカイン(IL-12及びIFN-γ)産生能で評価した。IL-12はマクロファージや樹状細胞などから産生され、NK細胞の活性化やリンパ球からのIFN-γの産生を促進する。IFN-γには抗腫瘍作用やNK細胞活性化作用がある。いずれもNK細胞活性化を始めとする全身免疫の活性化において大きな役割を果たしている。
Claims (10)
- ラクトバチルス・プランタラム(Lactobacillus plantarum)菌体を60〜80℃で加熱することにより、増強された腫瘍増殖抑制効果を示す加熱処理菌体を調製することを含む、抗腫瘍剤の製造方法であって、ラクトバチルス・プランタラムが、ラクトバチルス・プランタラムALAL006株(受託番号NITE BP-01754)である、方法。
- 前記加熱を68〜72℃で行う、請求項1に記載の方法。
- 前記加熱を5〜25分間行う、請求項1又は2に記載の方法。
- 菌体を前記加熱後、乾燥させることをさらに含む、請求項1〜3のいずれか1項に記載の方法。
- 乾燥が凍結乾燥である、請求項4に記載の方法。
- 請求項1〜5のいずれか1項に記載の方法によって製造される、ラクトバチルス・プランタラムの加熱処理菌体を含む抗腫瘍剤。
- 請求項6に記載の抗腫瘍剤を含む、飲食品。
- 請求項6に記載の抗腫瘍剤を含む、腫瘍増殖抑制用の医薬。
- 請求項1〜5のいずれか1項に記載の方法によってラクトバチルス・プランタラムALAL006株(受託番号NITE BP-01754)の加熱処理菌体を調製し、その加熱処理菌体を含む飲食品を製造することを含む、腫瘍増殖抑制用の飲食品の製造方法。
- 請求項1〜5のいずれか1項に記載の方法によってラクトバチルス・プランタラムALAL006株(受託番号NITE BP-01754)の加熱処理菌体を調製し、その加熱処理菌体を含む医薬を製造することを含む、腫瘍増殖抑制用の医薬の製造方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013264582A JP6302239B2 (ja) | 2013-12-20 | 2013-12-20 | 抗腫瘍剤及びその製造方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013264582A JP6302239B2 (ja) | 2013-12-20 | 2013-12-20 | 抗腫瘍剤及びその製造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015120651A JP2015120651A (ja) | 2015-07-02 |
JP6302239B2 true JP6302239B2 (ja) | 2018-03-28 |
Family
ID=53532655
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013264582A Active JP6302239B2 (ja) | 2013-12-20 | 2013-12-20 | 抗腫瘍剤及びその製造方法 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP6302239B2 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102455428B1 (ko) * | 2015-11-24 | 2022-10-18 | 전남대학교산학협력단 | 암의 예방 또는 치료용 의약 조성물 및 건강기능식품 |
JP2019076089A (ja) * | 2017-10-23 | 2019-05-23 | 有限会社佐藤修商店 | 魚肉練製品及びその製造方法 |
KR102136772B1 (ko) * | 2018-12-10 | 2020-07-23 | 한국식품연구원 | 락토바실러스 사케아이 wikim30을 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물 |
JP7284467B1 (ja) | 2022-06-01 | 2023-05-31 | 国立大学法人信州大学 | 免疫賦活性マクロファージ誘導剤、癌微小環境改善剤、癌アポトーシス誘導剤及び免疫賦活性マクロファージ誘導方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4064481B2 (ja) * | 1996-10-11 | 2008-03-19 | ハウスウェルネスフーズ株式会社 | 免疫賦活剤 |
JP4712289B2 (ja) * | 2003-08-26 | 2011-06-29 | 株式会社エイ・エル・エイ | 免疫促進用組成物 |
-
2013
- 2013-12-20 JP JP2013264582A patent/JP6302239B2/ja active Active
Also Published As
Publication number | Publication date |
---|---|
JP2015120651A (ja) | 2015-07-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Ouwehand et al. | Probiotics: mechanisms and established effects | |
TWI359668B (ja) | ||
KR101580678B1 (ko) | 나노형 유산균 | |
JP5709883B2 (ja) | 新規なラクトバチルス・プランタラム及びこれを含む組成物 | |
ES2356315T3 (es) | Bacterias ácido-lácticas que presentan un efecto de inmunopotenciación de las mucosas. | |
JP7126004B2 (ja) | 組成物及びその使用 | |
JP7434375B2 (ja) | 腸管免疫調節のための新規なプロバイオティック組成物 | |
MX2013015175A (es) | Composiciones probioticas y metodos. | |
CN106413724B (zh) | 与多糖聚合物粘合剂缀合的鼠李糖乳杆菌rht-3201及其用途 | |
JP4712289B2 (ja) | 免疫促進用組成物 | |
JP5527690B2 (ja) | 免疫調節性機能誘導剤及び食品組成物 | |
Mehta et al. | The potential of paraprobiotics and postbiotics to modulate the immune system: A Review | |
JP5337535B2 (ja) | Nk活性増強剤 | |
JP6302239B2 (ja) | 抗腫瘍剤及びその製造方法 | |
JPWO2019045037A1 (ja) | ヒアルロン酸産生促進用組成物 | |
CN112351693A (zh) | 用于抑制流感的重症化的抗流感病毒剂 | |
JP5324283B2 (ja) | 感染防御剤 | |
WO2018190407A1 (ja) | Toll様受容体2活性化用組成物 | |
JP2024098008A (ja) | 免疫チェックポイント阻害療法を促進するための組成物 | |
JP5209294B2 (ja) | インターロイキン12産生促進剤 | |
JP2000247895A (ja) | 自己免疫疾患予防組成物 | |
WO2015046407A1 (ja) | 免疫疾患予防剤 | |
Nagpal et al. | Probiotics, prebiotics and synbiotics: An introduction | |
CN112312920A (zh) | 非存活两歧双歧杆菌及其用途 | |
KR20230057980A (ko) | 항암 활성을 갖는 신규 박테리아 균주 및 이를 이용한 암의 완화, 예방 또는 치료용 조성물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20161125 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170808 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20171002 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171206 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20180206 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20180302 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6302239 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |