CN101134046A - Application of TLR4 and TLR9 agonist compound in the restraint of tumour metastasis - Google Patents
Application of TLR4 and TLR9 agonist compound in the restraint of tumour metastasis Download PDFInfo
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Abstract
The present invention discloses the application of compound of TLR4 excitant as LPS from Porphyromonas gingivalis and TLR9 excitant of E.coli 0111:B4 LPS in preparing medicine for preventing tumor metastasis, and is especially the application of TLR4 excitant and TLR9 excitant in inhabiting pulmonary tumor metastasis. The present invention discloses one kind of medicine composition including TLR4 excitant, TLR9 excitant and pharmaceutically acceptable carrier. The experiment with high pulmonary tumor metastasis mouse model shows that the compound of TLR4 excitant and TLR9 excitant can inhibit the metastasis of mouse pulmonary tumor caused by melanoma.
Description
Technical field
The present invention relates to the application in suppressing neoplasm metastasis of TLR4 and TLR9 agonist compound.
Background technology
Neoplasm metastasis is the basic reason that causes tumor to be difficult to effect a radical cure, and the malignant tumor patient more than 60% has been found transfer when ID according to statistics.As the about 800,000 solid carcinoma patients of the annual diagnosis of the U.S., find to have neoplasm metastasis person about 500,000 when diagnosing at first, the clinical tumor patient dies from neoplasm metastasis more than 90%.It is about 1,800,000 to 2,000,000 that the annual average cancer of China is sent out number, has approximately and die from neoplasm metastasis on 80%～90%, if do not controlled, the cancer mortality number will be doubled after 20 years.
Innate immunity reaction and the acquired immune response have been participated in the generation and the development of tumor directly.Immune system in the generation of tumor and development, serve a dual purpose [1.Karin E.de Visser, Alexandra Eichten and Lisa M.Coussens.Paradoxical roles of the immunesystem during cancer development.Nature reviews/cancer.2006; 6:24-37.].On the one hand, immune system can be passed through chronic inflammatory reaction equivalent damage DNA, discharges cytokine, chemotactic factor, somatomedin, MMPs etc. and promotes neovascularity to generate and reconstructed tissue, suppresses antineoplastic immune, promotes the generation and the development of tumor; On the other hand, immune system can produce antitumor t cell response and cytokine mediated ground tumor cell splitting action, thereby suppresses the generation and the development of tumor.Therefore, in antineoplastic immune, immune short tumor growth and neoplasm growth effect exist balance, and the character of inflammatory reaction and intensity have determined developing direction [2.Lisa M.Coussens, the Zena Werb.Inflammation and cancer.NATURE.2002 of tumor; 420 (19): 860-867.3.].Produce the small amounts of cells factor or a lot of anti-inflammatory cytokines, then can produce limited inflammation and neovascularity reaction of formation, the restriction tumor growth; Very strong inflammatory reaction can suppress the growth of tumor neovascularity, makes tumor regression; A large amount of chemotactic factors, appropriate inflammation can make a large amount of neovascularity generate, and tumor is grown fast.
TLRs is the important component part of innate immunity in the body, mainly on macrophage and dendritic cell, express, by activation DCs, start the specificity acquired immunity and reply [1.Karin E.de Visser, Alexandra Eichten and Lisa M.Coussens.Paradoxical roles ofthe immune system during cancer development.Nature reviews/cancer.2006; 6:24-37.].The aglucon of TLR is a para-immunity adjuvant [3.Pulendran B.Modulating vaccine responses with dendritic cells and Toll-like receptors.Immunol Rev.2004; 199:227-50.], the character of adjuvant has determined the unique types of downstream immunne response, regulate based on this that immunoreation trends towards that CTL replys, the Th of antibody response, special type replys or the antibody isoform is replied, activate TLR9 as CpG, producing strong Th1 type and CTL replys, LPS activates TLR4, produces the Th1 type and replys, and PG activates TLR2 makes immunologic balance trend towards the Th2/Treg direction.There are some researches show that 50% tumor patient after the surgical resection primary tumo(u)r, owing to contact LPS in the operation process, has promoted the neoplasm metastasis process.CpG can produce the effect that suppresses the reaction of Th2 type, strengthens the reaction of Th1 type, is to produce by the expression that promotes IFN-γ and IL-10; The expression of IL-10 simultaneously can suppress the overresponse of Th1 type.When using separately, CpG can not produce tangible inhibiting effect on tumor metastasis, share as adjuvant and tumor antigen or antitumor drug, can produce significantly neoplasm growth and transferance [4.Mark M.Whitmore, et.al.Synergistic Activation of InnateImmunity by Double-Stranded RNA and CpG DNA Promotes EnhancedAntitumor Activity.CANCER RESEARCH.2004; 64:5850-5860.5.Kunihiko Kitagaki, et.al.Immunomodulatory Effects of CpGOligodeoxynucleotides on Established Th2 Responses.CLINICAL ANDDIAGNOSTIC LABORATORY IMMUNOLOGY.2002; 1260-1269.6.Lucia Sfondrini, et.al.CpG-Oligodeoxynucleotides activatetyrosinase-related protein 2-specific T lymphocytes but do not lead to aprotective tumor-specific memory response.Cancer Immunol Immunother.2004; 53:697-704.7.Pratesi G, et.al.Therapeutic synergism ofgemcitabine and CpG-oligodeoxynucleotides in an orthotopic humanpancreatic carcinoma xenograft.Cancer Res.2005; 65 (14): 6388-93.].
Summary of the invention
The technical problem that will solve of the present invention is, provides a kind of method of new inhibition neoplasm metastasis, i.e. TLR4 agonist and the TLR9 agonist compound application in preparation prophylaxis of tumours diversion medicaments.
Preferred TLR4 agonist is LPS from Porphyromonasgingivalis according to the present invention.
The preferred TLR9 agonist E.coli0111:B4LPS according to the present invention.
The tumor that the prevention of TLR4 agonist and TLR9 agonist compound is shifted according to the present invention is lung tumor preferably.
The present invention also provides a kind of pharmaceutical composition, and it comprises carrier commonly used on TLR4 agonist and TLR9 agonist and the pharmaceutics.
In order to solve technical problem of the present invention, the present invention adopts following technical scheme:
The inventor is by activating different TLR pattern recognition receptors before tumor produces or after producing, strengthening innate immunity replys, change the character and the intensity of inflammatory reaction, observation is to the influence of tumor growth and transfer, thereby antineoplastic active part in the research and utilization inflammatory reaction, the activity that suppresses its short tumor is developed antineoplastic immunity adjuvant and therapeutic vaccine on this basis.
In other words, the present inventor is by finding that to the systematic study of the influence of tumor growth and transfer TLR4+TLR9 agonist mixture shifts to an earlier date the transfer that administration significantly suppresses melanoma induced mice lung tumor to Toll sample receptor (TLRs) agonist.
Particularly, C57BL/6 mouse inbred lines tail vein injection melanin tumour b16 F10 causes the high metastasis model of mouse lung tumor, respectively at injecting TLR2 agonist (LPS-PG) or TLR4 (LPS-EC)+TLR9 (CpG) agonist mixture with the modeling pneumoretroperitoneum before the modeling, positive control drug is a cyclophosphamide.After 2 weeks of modeling, put to death mice and get mouse lung counting lung tuberosity number and RT-PCR detection Th1, Th2 and Treg mRNA expression of cytokines level.
Experimental result finds that TLR4+TLR9 agonist mixture shifts to an earlier date administration and significantly reduces melanoma induced mice lung tuberosity number and lung index, and effect and cyclophosphamide are suitable, and administration does not have effect to lung tuberosity number and lung index after the modeling.Prevention of TLR2 agonist and treatment administration lung tuberosity number and lung index all do not have effect.RT-PCR result shows that TLR4+TLR9 agonist mixture significantly increases IFN γ/IL-13, IFN γ/TGF β and MMP2/TIMP1 ratio, and significantly reduces the expression of IL-4.
Illustrate that TLR4+TLR9 agonist mixture shifts to an earlier date the transfer that administration significantly suppresses melanoma induced mice lung tumor, Th1/Th2, Th1/Treg balance are offset towards Th1.TLR4+TLR9 agonist mixture cure neoplasm metastasis effect may with level of inflammation in the mice body that raises in advance, suppressing tumor, to produce the immune inflammation reaction relevant.
Description of drawings
Sham: sham operated rats;
Mod: model group;
CTX: cyclophosphamide group;
TLR2bef:TLR2 shifts to an earlier date the administration group;
(TLR4+TLR9) bef:(TLR4+TLR9) shift to an earlier date the administration group;
TLR2aft:TLR2 treatment administration group;
(TLR4+TLR9) treatment administration group aft:(TLR4+TLR9).
#P<0.05，
##P<0.01，
###P<0.001vs?Sham；
*P<0.05，
**P<0.05，
***P<0.001vs?Mod。
Fig. 1 .TLRs agonist is to lung metastatic nodules and the exponential influence of lung.
Figure A: mouse lung photo;
Figure B: lung index;
Figure C: lung tuberosity number.
Fig. 2.
Fig. 2-A TLRs agonist is to the influence of IFN γ/IL-13 ratio.
Fig. 2-B TLRs agonist is to the influence of IFN γ/TGF β ratio.
Fig. 2-C TLRs agonist is to the influence of IL-4 ratio.
Fig. 2-D TLRs agonist is to the influence of MMP2/TIMP1 ratio.
The specific embodiment
Of the present invention the specifying that the following examples are can not be interpreted as limitation of the present invention.
Embodiment 1
1. test material and method
1.1 material
TLR2 agonist LPS-PG (P.gingivalisLPS, ultra pure), TLR4 agonist LPS-EC (E.coli0111:B4LPS, ultra pure) are all available from InvivoGen company.TLR9 agonist CpG-ODN1826 is by Beijing match Parkson gene technology company limited synthetic (sequence: 5 '-tcc atg acg ttc ctg acg tt-3 ', omnidistance thio-modification, order number 0404-230).
1.2 the preparation of melanoma mouse lung metastasis model
1.2.1 animal is selected: the C57BL/6 mouse inbred lines, female 5～6 ages in week, 14-16g;
1.2.2 tumor strain: the high melanoma b16 F10 cell strain that shifts;
1.2.3 the cultivation of oncocyte: the B16 cell places the DMEM culture medium to cultivate (10%FBS+ penicillin+streptomycin), 37 ℃, 5%CO
2
1.2.4 the preparation of tumor liquid: with EDTA digestion exponential phase B16 cell, PBS flushing twice is suspended in again and makes 2.5 * 10 among the PBS
6Individual/the ml tumor cell suspension.
1.2.5 tumor inoculation method: the tumor liquid 300 μ L that prepare are placed in the EP pipe, and tail vein injection 200 μ L are equivalent to every mouse inoculation 5 * 10 in the C57BL/6 mice under the aseptic condition
5Individual oncocyte.
1.3 test method
1.3.1 test grouping
The C57BL/6 mouse inbred lines is divided into 7 groups, 15 every group.Model group, mouse tail vein melanoma suspension 200 μ L/ are only; Sham operated rats, tail vein injection PBS200 μ L/ is only; TLR2 shifts to an earlier date the administration group, the 7th, 4,1 day lumbar injection LPS-PG25 μ g/kg before the mice modeling; TLR2 treatment group, the 1st, 4,7 day lumbar injection LPS-PG25 μ g/kg after the mice modeling; The TLR4+TLR9 mixture shifts to an earlier date the administration group, the 7th, 4,1 day lumbar injection 12.5 μ g/kg LPS-EC+250 μ g/kg CpG-ODN1826 before the mice modeling; TLR4+TLR9 mixture treatment group, the 1st, 4,7 day lumbar injection 12.5 μ g/kg LPS-EC+250 μ g/kgCpG-ODN1826 after the mice modeling; Cyclophosphamide (CTX) treatment group, give CTX20mg/kg, 2 weeks of successive administration every day after the mice modeling.After 2 weeks of modeling, put to death mice.Get spleen, lungs and serum, preserve to be detected.
1.3.2 detection index
1.3.2.1 neoplasm metastasis situation (n=10): after last administration 24 hours, disconnected marrow is put to death, and claims the lung amount, and 4% paraformaldehyde is fixed, (10 times) numeration lung surface tumor tuberosity number under anatomic microscope.
1.3.2.2 mouse lung immunity environmental monitoring:
Innate immunity situation: RT-PCR detects TLR2, TLR4, TLR9 expression.
The acquired immunity situation:
Th1:RT-PCR and ELISA detect IFN-γ, IL-8, IL-6, TNF-α, IL-12,
IL-18 cytokine-expressing level;
Th2:RT-PCR and ELISA detect IL-4, IL-5, IL-13 expression;
Treg:RT-PCR detects TGF-β, IL-10, Foxp3 expression.
2. result
2.1TLRs the influence that agonist shifts the tumor lung
TLR4+TLR9 agonist mixture shifts to an earlier date administration and significantly reduces mouse lung tuberosity number (P＜0.001vs model group) and lung index (P＜0.001vs model group), and TLR4+TLR9 agonist mixture treatment administration does not have effect to mouse lung tuberosity number and lung index.TLR2 receptor stimulating agent no matter in advance administration is still treated administration mouse lung tuberosity number average is not had effect.Positive control drug significantly reduces mouse lung tuberosity number (P＜0.001vs model group) and lung index (P＜0.05vs model group) (Fig. 1).
2.2TLRs agonist is to the influence of Th1, Th2 and Treg cytokine-expressing
TLR4+TLR9 agonist mixture shifts to an earlier date administration and significantly increases IFN γ/IL-13 ratio (P＜0.05vs model group) (Fig. 2 A), IFN γ/TGF β ratio (P＜0.01vs model group) (Fig. 2 C) and MMP2/TIMP1 ratio (P＜0.05vs model group) (Fig. 2 D), and significantly reduces the expression (P＜0.01vs model group) (Fig. 2 B) of IL-4.
Inquire into the TLRs agonist to the inhibiting amynologic mechanism of neoplasm metastasis.
Discuss
The TLR4+TLR9 agonist shifts to an earlier date the expression that administration significantly increases IFN γ/IL-13 ratio and IL-4, illustrate that the TLR4+TLR9 agonist shifts to an earlier date the balance that administration may change mouse lung microenvironment Th1/Th2 cytokine in advance, the Th1/Th2 balance is offset towards the Th1 immunne response.The TLR4+TLR9 agonist shifts to an earlier date administration and also significantly increases IFN γ/TGF β ratio, and the Th1/Treg balance also is offset towards the Th1 immunne response.This effect that improves level of inflammation in the body in advance may be one of mechanism of TLR4+TLR9 agonist inhibition neoplasm metastasis.
In a word, TLR4+TLR9 agonist mixture shifts to an earlier date the transfer that administration significantly suppresses melanoma induced mice lung tumor, and Th1/Th2, Th1/Treg balance are offset towards Th1.TLR4+TLR9 agonist mixture cure neoplasm metastasis effect may with level of inflammation in the mice body that raises in advance, suppressing tumor, to produce the immune inflammation reaction relevant.TLR4+TLR9 agonist mixture provides new Therapeutic Method for prophylaxis of tumours shifts.
Claims (6)
1.TLR4 agonist and the TLR9 agonist compound application in preparation prophylaxis of tumours diversion medicaments.
2. according to the application of claim 1, it is characterized in that described TLR4 agonist is LPSfrom Porphyromonas gingivalis.
3. according to the application of claim 1, it is characterized in that described TLR9 agonist is E.coli0111:B4 LPS.
4. according to the application of claim 1, it is characterized in that described tumor is a lung tumor.
5. a pharmaceutical composition is characterized in that, comprises carrier commonly used on TLR4 agonist and TLR9 agonist and the pharmaceutics.
6. a pharmaceutical composition is characterized in that, comprises carrier commonly used on LPS from Porphyromonasgingivalis and E.coli 0111:B4 LPS and the pharmaceutics.
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| JP2016526049A (en) * | 2013-06-04 | 2016-09-01 | インフェクシャス ディズィーズ リサーチ インスティチュート | Compositions and methods for reducing or preventing metastasis |
| CN106177953A (en) * | 2016-07-08 | 2016-12-07 | 中国医学科学院基础医学研究所 | TLR3 inhibitor prevents and treats the application in neoplasm metastasis product in preparation |
| WO2016196062A1 (en) * | 2015-05-29 | 2016-12-08 | Dynavax Technologies Corporation | Intrapulmonary administration of polynucleotide toll-like receptor 9 agonists for treating cancer of the lung |
| CN106573043A (en) * | 2014-08-04 | 2017-04-19 | 日东电工株式会社 | Vaccine pharmaceutical composition for suppressing apoptosis of ctl or inhibiting suppression of induction of ctl |
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| CA2289912C (en) * | 1997-05-07 | 2011-07-26 | Schering Corporation | Human receptor proteins; related reagents and methods |
| CN1642982A (en) * | 2001-07-26 | 2005-07-20 | 唐诚公司 | Agents that activate or inhibit Toll-like receptor 9 |
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| EP3650028A1 (en) * | 2013-06-04 | 2020-05-13 | Infectious Disease Research Institute | Compositions and methods for reducing or preventing metastasis |
| JP2016526049A (en) * | 2013-06-04 | 2016-09-01 | インフェクシャス ディズィーズ リサーチ インスティチュート | Compositions and methods for reducing or preventing metastasis |
| EP3003367A4 (en) * | 2013-06-04 | 2017-01-11 | Infectious Disease Research Institute | Compositions and methods for reducing or preventing metastasis |
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| CN106177953B (en) * | 2016-07-08 | 2019-05-14 | 中国医学科学院基础医学研究所 | Application of the TLR3 inhibitor in preparation prevention and treatment metastases product |
| CN106177953A (en) * | 2016-07-08 | 2016-12-07 | 中国医学科学院基础医学研究所 | TLR3 inhibitor prevents and treats the application in neoplasm metastasis product in preparation |
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