WO2013100500A1 - Composition pharmaceutique pour le traitement du cancer, comprenant un peptide, le 5-fluorouracile, et des cellules dendritiques matures - Google Patents
Composition pharmaceutique pour le traitement du cancer, comprenant un peptide, le 5-fluorouracile, et des cellules dendritiques matures Download PDFInfo
- Publication number
- WO2013100500A1 WO2013100500A1 PCT/KR2012/011291 KR2012011291W WO2013100500A1 WO 2013100500 A1 WO2013100500 A1 WO 2013100500A1 KR 2012011291 W KR2012011291 W KR 2012011291W WO 2013100500 A1 WO2013100500 A1 WO 2013100500A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mature dendritic
- cancer
- dendritic cells
- fluorouracil
- peptide
- Prior art date
Links
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960002949 fluorouracil Drugs 0.000 title claims abstract description 76
- 210000004443 dendritic cell Anatomy 0.000 title claims abstract description 69
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 61
- 201000011510 cancer Diseases 0.000 title claims abstract description 57
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 108090000765 processed proteins & peptides Proteins 0.000 title description 7
- 108010056859 Trp-Lys-Tyr-Met-Val-Met Proteins 0.000 claims abstract description 72
- 230000000694 effects Effects 0.000 claims abstract description 25
- 238000011260 co-administration Methods 0.000 claims description 19
- 239000002246 antineoplastic agent Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 238000011394 anticancer treatment Methods 0.000 claims description 7
- 230000002708 enhancing effect Effects 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 210000002751 lymph Anatomy 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000001093 anti-cancer Effects 0.000 abstract description 27
- 206010027476 Metastases Diseases 0.000 abstract description 9
- 230000009401 metastasis Effects 0.000 abstract description 9
- 230000008105 immune reaction Effects 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 230000001629 suppression Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 25
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 17
- 210000001744 T-lymphocyte Anatomy 0.000 description 15
- 230000001965 increasing effect Effects 0.000 description 13
- 210000000822 natural killer cell Anatomy 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 229940041181 antineoplastic drug Drugs 0.000 description 9
- 230000028993 immune response Effects 0.000 description 7
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000007929 subcutaneous injection Substances 0.000 description 6
- 238000010254 subcutaneous injection Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 108010065805 Interleukin-12 Proteins 0.000 description 5
- 102000013462 Interleukin-12 Human genes 0.000 description 5
- 229940117681 interleukin-12 Drugs 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 4
- 102000008070 Interferon-gamma Human genes 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical group O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 4
- 229960003130 interferon gamma Drugs 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- FMBGOORJEKQQLG-JUZZZACGSA-N (2s)-6-amino-2-[[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]amino]-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(=O)N[C@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 FMBGOORJEKQQLG-JUZZZACGSA-N 0.000 description 2
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 description 2
- 206010065553 Bone marrow failure Diseases 0.000 description 2
- 102000003952 Caspase 3 Human genes 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 231100000405 induce cancer Toxicity 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- VELGMVLNORPMAO-JTFNWEOFSA-N n-[(e)-1-[(3r,4r,5s,6r)-5-[(2s,3r,4r,5r,6r)-5-[(2s,3r,4r,5r,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)-4-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxym Chemical compound O[C@@H]1[C@@H](O)C(OCC(NC(=O)CCCCCCCCCCCCCCCCC)C(O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 VELGMVLNORPMAO-JTFNWEOFSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- VQBTUIJFUPRJOH-LXOXETEGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-methylbutanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)C(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 VQBTUIJFUPRJOH-LXOXETEGSA-N 0.000 description 1
- 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 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 229940046168 CpG oligodeoxynucleotide Drugs 0.000 description 1
- 102100033215 DNA nucleotidylexotransferase Human genes 0.000 description 1
- 108010008286 DNA nucleotidylexotransferase Proteins 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 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
- 229930182816 L-glutamine Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 238000013042 tunel staining Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a pharmaceutical composition for treating cancer, comprising a WKYMVm peptide having a sequence of SEQ ID NO: 1, and comprising 5-fluorouracil and / or mature dendritic cells.
- the present invention has been made to solve the above problems in the prior art, comprising a WKYMVm peptide having a sequence of SEQ ID NO: 1, 5-fluorouracil and / or mature dendritic cells (mature dendritic) It is an object of the present invention to provide a pharmaceutical composition for treating cancer comprising an effective amount of cells).
- the present invention provides a pharmaceutical composition for treating cancer comprising an effective amount of a WKYMVm peptide having a sequence of SEQ ID NO: 1 and 5-fluorouracil.
- the present invention provides a pharmaceutical composition for treating cancer comprising an effective amount of the WKYMVm peptide having a sequence of SEQ ID NO: 1 and mature dendritic cells.
- the present invention also provides a pharmaceutical composition comprising an effective amount of a WKYMVm peptide having a sequence of SEQ ID NO: 1, 5-fluorouracil, and mature dendritic cells.
- the composition is characterized in that it is used to suppress cancer derived from colon cancer or lymph cells.
- the present invention provides a method of increasing the anti-cancer treatment effect by using a combination of WKYMVm peptide having a sequence of SEQ ID NO: 1 and 5-fluorouracil.
- the present invention provides a method of increasing the anti-cancer treatment effect by co-administration of WKYMVm peptide having a sequence of SEQ ID NO: 1 and mature dendritic cells.
- the present invention provides a method of increasing the anti-cancer treatment effect by concurrently administering the WKYMVm peptide having a sequence of SEQ ID NO: 1, 5-fluorouracil and mature dendritic cells.
- Concomitant administration of 5-fluorouracil and / or mature dendritic cells, comprising the WKYMVm peptide according to the present invention can effectively reduce side effects and resistance caused by anticancer drugs because it can increase the immunity of the body and reduce the amount of anticancer drugs.
- it is expected to be applicable to the treatment of cancer because it can significantly increase the anticancer effect.
- the type of anticancer agent can be freely used to treat various types of cancer.
- 1 is a schematic diagram of a method of administering the WKYMVm peptide, 5-fluorouracil, mature dendritic cells.
- Figure 2 shows the results of measuring the anticancer effect of WKYMVm peptide, 5-fluorouracil, mature dendritic cells alone and in combination administration.
- Figure 3 shows the results of measuring the effect of cancer cell death induced by WKYMVm peptide, 5-fluorouracil, mature dendritic cells alone and in combination.
- Figure 4 shows the results of measuring the effect of inducing the migration of immune cells to tumor tissue by co-administration of WKYMVm peptide, 5-fluorouracil, mature dendritic cells.
- FIG. 5 shows the effect of anti-CD8 antibody, anti-CD4 antibody and anti-asialo-GM1 antibody on the effect of inducing the migration of immune cells into tumor tissue by coadministration of WKYMVm peptide, 5-fluorouracil, and mature dendritic cells. It is a figure which shows the result of having measured.
- Figure 6 shows the results of measuring the anticancer effect of CD8 T lymphocytes and NK cells induced by the co-administration of WKYMVm peptide, 5-fluorouracil, and mature dendritic cells.
- Fig. 7 shows the results of measuring the effect of the combined administration of WKYMVm peptide, 5-fluorouracil, and mature dendritic cells on the amount of cytokines in cancer tissues or peripheral blood.
- Fig. 8 shows the results of measuring cancer metastasis inhibitory effect of WKYMVm peptide, 5-fluorouracil, and mature dendritic cell co-administration.
- Fig. 9 shows the results of measuring anticancer effects of WKYMVm peptide, 5-fluorouracil, and mature dendritic cell co-administration.
- the inventors have previously described peptide ligands (Trp-Lys-Tyr-Met-Val-D-Met-NH 2 : SEQ ID NO: 1, hereinafter, “WKYMVm that increase leukocyte cells such as monocytes, neutrophils, etc.).
- Peptides (Bae et al., 1999, J. Leukoc. Biol. 65, 241-248). Therefore, the present inventors have completed the present invention by studying a method of increasing the anticancer effect while reducing the amount of the anticancer agent by simultaneously using an anticancer agent while promoting an immune response using the WKYMVm peptide.
- 5-fluorouracil 5-fluorouracil
- thymine a precursor of DNA, which inhibits DNA synthesis of cancer cells and shows anticancer effects.
- side effects such as bone marrow depression and diarrhea.
- dendritic cells have been suggested to be able to be used for immune chemotherapy by promoting the immune response in the body, many studies have been conducted, but the situation is still insufficient in the anti-cancer effect.
- the present inventors tried to use WKYMVm peptide and dendritic cells that can promote the immune response in the body and 5-fluorouracil, an anticancer agent, for use in anticancer treatment.
- administration of 5-fluorouracil and / or mature dendritic cells in combination with WKYMVm peptide, 5-fluorouracil, or mature dendritic cells alone increases the volume of cancer. It was confirmed that it can be reduced by about 5 times (see Example 1), and in other examples, it was confirmed that the metastasis of cancer can be inhibited by 5 times or more through co-administration. It was confirmed that the survival rate can be significantly increased (see Examples 6 and 7).
- the present invention includes a WKYMVm peptide having a sequence of SEQ ID NO: 1, and provides a method of enhancing anti-cancer treatment effect by concurrently administering 5-fluorouracil and / or mature dendritic cells. do.
- the present invention provides a pharmaceutical composition for treating cancer comprising a WKYMVm peptide having a sequence of SEQ ID NO: 1, an effective amount of 5-fluorouracil and / or mature dendritic cells to provide.
- a pharmaceutical composition for treating cancer comprising a WKYMVm peptide having a sequence of SEQ ID NO: 1, an effective amount of 5-fluorouracil and / or mature dendritic cells to provide.
- a pharmaceutical composition for treating cancer comprising a WKYMVm peptide having a sequence of SEQ ID NO: 1, an effective amount of 5-fluorouracil and / or mature dendritic cells to provide.
- the type of cancer to which the pharmaceutical composition for treating cancer of the present invention can be applied.
- it can be used to suppress colon cancer or cancer derived from lymphoid cells.
- the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier may include physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, and the like, but is not limited thereto.
- Another aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a WKYMVm peptide having a sequence of SEQ ID NO: 1, comprising 5-fluorouracil and / or mature dendritic cells as an active ingredient
- a method of treating cancer is provided by administering a pharmaceutically effective amount to a subject.
- an individual means a subject in need of treatment of a disease, and more specifically, a human, or a non-human primate, a mouse, a rat, a dog, a cat, a horse, a cow, and the like.
- the pharmaceutically effective amount in the present invention may be variously adjusted in the range depending on the weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease of the patient. Do.
- the preferred dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration, and the duration, and may be appropriately selected by those skilled in the art. However, preferably, it is administered at 0.001 to 100 mg / kg body weight per day, more preferably 0.01 to 30 mg / kg body weight. Administration may be administered once a day or may be divided several times.
- WKYMVm peptide, 5-fluorouracil, and / or mature dendritic cells having the sequence of SEQ ID NO: 1 of the present invention are preferably 0.0001 to 10% by weight, based on the total weight of the total composition, preferably May be present in an amount from 0.001 to 1% by weight.
- the pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, and the like by various routes.
- the method of administration is not limited, and may be administered by oral, rectal, or intravenous, intramuscular, subcutaneous, intrauterine dural, or intra cerbroventricular injection.
- mice treated with nothing, WKYMVm peptide, 5-FU, or mature dendritic cells alone or in combination of the two groups were divided and administered with the experimental group. And the volume of the cancer was quantified using the following formula.
- a schematic diagram of the experimental procedure is shown in FIG. 1, and the experimental results are shown in FIG. 2.
- the volume of cancer (mm 3) length (mm) X width (mm) 2/2
- Example 2 To determine whether the anticancer effect of the combination of WKYMVm peptide, 5-fluorouracil (5-FU), and mature dendritic cell (mDC) is due to induction of apoptosis, the same method as in Example 1 39 days later, the cancer was removed from the mouse, fixed with 10% neutral phosphate buffered formalin (NBF), and then cut into several layers and stained with paraffin. For morphological analysis, stained with hematoxylin and eosin (H & E) and observed through light microscopy. For immunological analysis, anti-murine cleaved caspase-3 antibody or anti-murine FAS antibody was used.
- NPF neutral phosphate buffered formalin
- TUNEL staining, FAS and Caspase-3 staining all showed similar results.
- WKYMVm peptide or mature dendritic cells alone the cells were almost dead, and when treated with 5-FU alone, some of the cells were dead.
- 5-FU alone some of the cells were dead.
- WKYMVm peptide, 5-FU, and mature dendritic cells almost all of the cells were confirmed to be dead.
- co-administration of KYMVm peptide, 5-FU, and mature dendritic cells was confirmed to induce apoptosis and kill cancer cells.
- rat anti-mouse CD8 antibodies rat anti-mouse asialo-GM1 antibodies, or rat anti-mouse CD4 antibodies to confirm that CD8 T lymphocytes and natural killer (NK) cells do not influence each other to gather around cancer.
- 100 ⁇ g of each was intraperitoneal injection one day prior to subcutaneous injection of cancer into the mouse, the day of subcutaneous injection, and 5 days after subcutaneous injection. And stained in the same manner as above and observed through a fluorescence microscope. The results are shown in FIG.
- CD8 T lymphocytes were not induced around the cancer, but NK cells were confirmed to be collected around the cancer.
- anti-asialo-GM1 antibody treated NK cells did not induce cancer, but CD8 T lymphocytes gathered around cancer, and anti-CD4 antibody treated CD8 T lymphocytes and NK cells. It was confirmed that the induced around.
- rat anti-mouse CD8 antibody rat anti-mouse asialo- 100 ⁇ g of the GM1 antibody or the rat anti-mouse CD4 antibody was intraperitoneally injected in the same manner as in Example 3, and then the volume of the cancer was measured by date. The results are shown in FIG.
- interferon-gamma IFN-gamma
- IL-12 interleukin-12
- rat anti-mouse CD8 antibody administration of 100 ⁇ g of rat anti-mouse CD8 antibody, rat anti-mouse asialo-GM1 antibody, or rat anti-mouse CD4 antibody in the same manner as in Example 3 resulted in a sharp reduction in the amount of interferon-gamma and interleukin-12. I could confirm that.
- CT-26 cell line was injected into the tail of the mouse and WKYMVm peptide, 5-FU, and mature dendritic cells were co-administered for 2 weeks, followed by the same method as in Example 2. Lungs were stained and observed with hematoxylin and eosin (H & E). The results are shown in FIG.
- the pharmaceutical composition for cancer treatment comprising the WKYMVm peptide according to the present invention and containing an effective amount of 5-fluorouracil and / or mature dendritic cells can reduce the amount of anticancer agent by enhancing the body's immunity, Side effects and resistance can be effectively reduced.
- the pharmaceutical composition for cancer treatment comprising the WKYMVm peptide according to the present invention and containing an effective amount of 5-fluorouracil and / or mature dendritic cells can reduce the amount of anticancer agent by enhancing the body's immunity, Side effects and resistance can be effectively reduced.
- anticancer drugs when combined with various types of anticancer drugs can significantly increase the anticancer effect, it can be used as a pharmaceutical composition for treating various types of cancer.
- composition comprising peptide, 5-fluorouracil, and mature
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une composition pharmaceutique pour le traitement du cancer, comprenant le peptide WKYMVm ayant la séquence de SEQ ID NO:1, et contenant une quantité efficace de 5-fluorouracile et/ou des cellules dendritiques matures. Selon la présente invention, la composition pharmaceutique améliore la réaction immunitaire in vivo, présentant ainsi une augmentation des effets anticancéreux, des effets secondaires faibles, une inhibition élevée de la métastase, et similaires.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2011-0142340 | 2011-12-26 | ||
| KR1020110142340A KR101361445B1 (ko) | 2011-12-26 | 2011-12-26 | 펩타이드, 5-플루오로우라실, 및 성숙수지상세포를 포함하는 암 치료용 약학적 조성물 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013100500A1 true WO2013100500A1 (fr) | 2013-07-04 |
Family
ID=48697876
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2012/011291 WO2013100500A1 (fr) | 2011-12-26 | 2012-12-21 | Composition pharmaceutique pour le traitement du cancer, comprenant un peptide, le 5-fluorouracile, et des cellules dendritiques matures |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR101361445B1 (fr) |
| WO (1) | WO2013100500A1 (fr) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9730984B2 (en) | 2012-05-11 | 2017-08-15 | Gemvax & Kael Co., Ltd. | Composition for preventing or treating rheumatoid arthritis |
| US9907838B2 (en) | 2013-04-19 | 2018-03-06 | Gemvax & Kael Co., Ltd. | Composition and methods for treating ischemic damage |
| US9937240B2 (en) | 2014-04-11 | 2018-04-10 | Gemvax & Kael Co., Ltd. | Peptide having fibrosis inhibitory activity and composition containing same |
| US10034922B2 (en) | 2013-11-22 | 2018-07-31 | Gemvax & Kael Co., Ltd. | Peptide having angiogenesis inhibitory activity and composition containing same |
| US10039811B2 (en) | 2012-05-11 | 2018-08-07 | Gemvax & Kael Co., Ltd. | Anti-inflammatory peptides and composition comprising the same |
| US10383926B2 (en) | 2013-06-07 | 2019-08-20 | Gemvax & Kael Co., Ltd. | Biological markers useful in cancer immunotherapy |
| US10463708B2 (en) | 2014-12-23 | 2019-11-05 | Gemvax & Kael Co., Ltd. | Peptide for treating ocular diseases and composition for treating ocular diseases comprising same |
| US10561703B2 (en) | 2013-06-21 | 2020-02-18 | Gemvax & Kael Co., Ltd. | Method of modulating sex hormone levels using a sex hormone secretion modulator |
| US10662223B2 (en) | 2014-04-30 | 2020-05-26 | Gemvax & Kael Co., Ltd. | Composition for organ, tissue, or cell transplantation, kit, and transplantation method |
| US10835582B2 (en) | 2015-02-27 | 2020-11-17 | Gemvax & Kael Co. Ltd. | Peptide for preventing hearing loss, and composition comprising same |
| US10898540B2 (en) | 2016-04-07 | 2021-01-26 | Gem Vax & KAEL Co., Ltd. | Peptide having effects of increasing telomerase activity and extending telomere, and composition containing same |
| US10967000B2 (en) | 2012-07-11 | 2021-04-06 | Gemvax & Kael Co., Ltd. | Cell-penetrating peptide, conjugate comprising same and composition comprising same |
| US11015179B2 (en) | 2015-07-02 | 2021-05-25 | Gemvax & Kael Co., Ltd. | Peptide having anti-viral effect and composition containing same |
| US11058744B2 (en) | 2013-12-17 | 2021-07-13 | Gemvax & Kael Co., Ltd. | Composition for treating prostate cancer |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102576410B1 (ko) | 2020-11-09 | 2023-09-08 | 충남대학교산학협력단 | 바실러스 균주와 5-fu를 유효성분으로 하는 대장암 치료용 약학 조성물 |
| KR20240041258A (ko) | 2022-09-22 | 2024-03-29 | (의) 삼성의료재단 | 종양 혈관 파괴용 약학 조성물 |
| WO2024063569A1 (fr) | 2022-09-22 | 2024-03-28 | (의) 삼성의료재단 | Composition pharmaceutique pour perturber des vaisseaux sanguins tumoraux |
| WO2024063566A1 (fr) | 2022-09-22 | 2024-03-28 | (의) 삼성의료재단 | Composition pharmaceutique pour la destruction de vaisseaux sanguins tumoraux |
| KR20240041259A (ko) | 2022-09-22 | 2024-03-29 | (의) 삼성의료재단 | 종양 혈관 파괴용 약학 조성물 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20080071194A (ko) * | 2005-12-23 | 2008-08-01 | 주식회사 포스코 | 펩타이드 함유 항암제 |
| KR20110121208A (ko) * | 2010-04-30 | 2011-11-07 | 경북대학교 산학협력단 | 수지상 세포를 포함하는 신세포암의 치료용 조성물 |
-
2011
- 2011-12-26 KR KR1020110142340A patent/KR101361445B1/ko not_active Expired - Fee Related
-
2012
- 2012-12-21 WO PCT/KR2012/011291 patent/WO2013100500A1/fr active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20080071194A (ko) * | 2005-12-23 | 2008-08-01 | 주식회사 포스코 | 펩타이드 함유 항암제 |
| KR20110121208A (ko) * | 2010-04-30 | 2011-11-07 | 경북대학교 산학협력단 | 수지상 세포를 포함하는 신세포암의 치료용 조성물 |
Non-Patent Citations (3)
| Title |
|---|
| KIM, H. ET AL.: "Granulocyte function is stimulated by a novel hexapeptide, WKYMVm, in chemotherapy-treated cancer patients.", EXPERIMENTAL HEMATOLOGY., vol. 34, 2006, pages 407 - 413 * |
| LEE, H. ET AL.: "Trp-Lys-Tyr-Met-Val-Met stimulates phagocytosis via phospholipase D- dependent signaling in mouse dendritic cells.", EXPERIMENTAL AND MOLECULAR MEDICINE., vol. 36, no. 2, 2004, pages 135 - 144 * |
| NAGASAKI, E. ET AL.: "Combined Treatment With Dendritic Cells and 5-fluorouracil Elicits Augmented NK Cell-mediated Antitumor Activity Through the Tumor Necrosis Factor- alpha Pathway.", JOURNAL OF IMMUNOTHERAPY., vol. 33, no. 5, June 2010 (2010-06-01), pages 467 - 474 * |
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11857607B2 (en) | 2012-05-11 | 2024-01-02 | Gemvax & Kael Co., Ltd. | Anti-inflammatory peptides and composition comprising the same |
| US10960056B2 (en) | 2012-05-11 | 2021-03-30 | Gemvax & Kael Co., Ltd. | Anti-inflammatory peptides and composition comprising the same |
| US9907837B2 (en) | 2012-05-11 | 2018-03-06 | Gemvax & Kael Co., Ltd. | Composition for preventing or treating cachexia |
| US11369665B2 (en) | 2012-05-11 | 2022-06-28 | Gemvax & Kael Co., Ltd. | Anti-inflammatory peptides and composition comprising the same |
| US9844584B2 (en) | 2012-05-11 | 2017-12-19 | Gemvax & Kael Co., Ltd. | Composition for preventing or treating sepsis |
| US10039811B2 (en) | 2012-05-11 | 2018-08-07 | Gemvax & Kael Co., Ltd. | Anti-inflammatory peptides and composition comprising the same |
| US12168039B2 (en) | 2012-05-11 | 2024-12-17 | Gemvax & Kael Co., Ltd. | Anti-inflammatory peptides and composition comprising the same |
| US9730984B2 (en) | 2012-05-11 | 2017-08-15 | Gemvax & Kael Co., Ltd. | Composition for preventing or treating rheumatoid arthritis |
| US12156902B2 (en) | 2012-05-11 | 2024-12-03 | Gemvax & Kael Co., Ltd. | Anti-inflammatory peptides and composition comprising the same |
| US10967000B2 (en) | 2012-07-11 | 2021-04-06 | Gemvax & Kael Co., Ltd. | Cell-penetrating peptide, conjugate comprising same and composition comprising same |
| US9907838B2 (en) | 2013-04-19 | 2018-03-06 | Gemvax & Kael Co., Ltd. | Composition and methods for treating ischemic damage |
| US10383926B2 (en) | 2013-06-07 | 2019-08-20 | Gemvax & Kael Co., Ltd. | Biological markers useful in cancer immunotherapy |
| US10561703B2 (en) | 2013-06-21 | 2020-02-18 | Gemvax & Kael Co., Ltd. | Method of modulating sex hormone levels using a sex hormone secretion modulator |
| US10034922B2 (en) | 2013-11-22 | 2018-07-31 | Gemvax & Kael Co., Ltd. | Peptide having angiogenesis inhibitory activity and composition containing same |
| US11058744B2 (en) | 2013-12-17 | 2021-07-13 | Gemvax & Kael Co., Ltd. | Composition for treating prostate cancer |
| US9937240B2 (en) | 2014-04-11 | 2018-04-10 | Gemvax & Kael Co., Ltd. | Peptide having fibrosis inhibitory activity and composition containing same |
| US10662223B2 (en) | 2014-04-30 | 2020-05-26 | Gemvax & Kael Co., Ltd. | Composition for organ, tissue, or cell transplantation, kit, and transplantation method |
| US11077163B2 (en) | 2014-12-23 | 2021-08-03 | Gemvax & Kael Co., Ltd. | Peptide for treating ocular diseases and composition for treating ocular diseases comprising same |
| US10463708B2 (en) | 2014-12-23 | 2019-11-05 | Gemvax & Kael Co., Ltd. | Peptide for treating ocular diseases and composition for treating ocular diseases comprising same |
| US10835582B2 (en) | 2015-02-27 | 2020-11-17 | Gemvax & Kael Co. Ltd. | Peptide for preventing hearing loss, and composition comprising same |
| US11015179B2 (en) | 2015-07-02 | 2021-05-25 | Gemvax & Kael Co., Ltd. | Peptide having anti-viral effect and composition containing same |
| US10898540B2 (en) | 2016-04-07 | 2021-01-26 | Gem Vax & KAEL Co., Ltd. | Peptide having effects of increasing telomerase activity and extending telomere, and composition containing same |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101361445B1 (ko) | 2014-02-12 |
| KR20130074325A (ko) | 2013-07-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2013100500A1 (fr) | Composition pharmaceutique pour le traitement du cancer, comprenant un peptide, le 5-fluorouracile, et des cellules dendritiques matures | |
| JP3723206B2 (ja) | ムラミルペプチドとサイトカインとを組み合わせることを特徴とするヒトに用いる治療用組成物 | |
| Hunter et al. | Production of gamma interferon by natural killer cells from Toxoplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha | |
| Iigo et al. | Inhibitory effects of bovine lactoferrin on colon carcinoma 26 lung metastasis in mice | |
| Vujanovic et al. | Antitumor activities of subsets of human IL-2-activated natural killer cells in solid tissues. | |
| CN101631850B (zh) | 增加和转移造血干细胞的方法 | |
| Ogawa et al. | Multiple roles of interferon-γ in the mediation of interleukin 12-induced tumor regression | |
| US5382427A (en) | Use of IL-4 to treat solid tumors | |
| EP1951233B1 (fr) | Compositions de pirfenidone et d'agonistes du recepteur toll-like et leurs methodes d'utilisation pour stimuler la production du facteur stimulant la colonisation des granulocytes | |
| KR20020016844A (ko) | 반응성 산소 대사산물 저해제를 이용한 세포독성 림프구의활성화 및 보호 | |
| US20110064691A1 (en) | Method to enhance hematopoiesis | |
| Pope et al. | 7-Allyl-8-oxoguanosine (loxoribine) inhibits the metastasis of B16 melanoma cells and has adjuvant activity in mice immunized with a B16 tumor vaccine | |
| KR100913860B1 (ko) | 올리고뉴클레오타이드 조성물 및 세포 분화 유도시 이의용도 | |
| WO2013032096A1 (fr) | Acide caprique ayant un effet inhibiteur sur la formation des ostéoclastes et composition pharmaceutique le contenant | |
| Liu et al. | Interferon‐γ and interleukin‐12 genes are preferentially expressed during early experimental African trypanosomiasis and suppressed by denervation of the spleen | |
| US5716612A (en) | Use of IL-4 for potentiation of chemotherapeutic agents | |
| WO2020197296A1 (fr) | Composition pour prévenir ou traiter une maladie du greffon contre l'hôte comprenant un agoniste de tlr5 dérivé de la flagelline comme composant efficace | |
| WO2025048206A1 (fr) | Cellules lymphoïdes innées de type 2 à activité cytotoxique, leur procédé de production et utilisation associée | |
| Wu et al. | Anti‐tumor Effects of Interleukin‐4 and Interleukin‐5 against Mouse B Cell Lymphoma and Possible Mechanisms of Their Action | |
| WO2020190071A1 (fr) | Composition pharmaceutique destinée à la prévention ou au traitement du cancer, et son utilisation | |
| CN115282280A (zh) | TGF-β1信号抑制剂的新用途 | |
| Satoh et al. | A murine plasmacytoma MOPC 104E resistant to cyclophosphamide is resistant to immunotherapy | |
| Averbook et al. | Coinfusion of irradiated splenocytes with low titer tumor-infiltrating lymphocytes augments antitumor efficacy in adoptive immunotherapy | |
| KAMBE et al. | Induction of Natural Killer (NK) Activity in Mice by Injection of Chromomycin A3 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12862681 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 12862681 Country of ref document: EP Kind code of ref document: A1 |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 12862681 Country of ref document: EP Kind code of ref document: A1 |