CN102274513B - Tumor growth inhibited by ERK1/2 inhibitor through stimulating expression of macrophage interferon gamma - Google Patents
Tumor growth inhibited by ERK1/2 inhibitor through stimulating expression of macrophage interferon gamma Download PDFInfo
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- CN102274513B CN102274513B CN 201110187914 CN201110187914A CN102274513B CN 102274513 B CN102274513 B CN 102274513B CN 201110187914 CN201110187914 CN 201110187914 CN 201110187914 A CN201110187914 A CN 201110187914A CN 102274513 B CN102274513 B CN 102274513B
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Abstract
The invention relates to a new method of tumor treatment. IFN gamma is an important antiviral, antitumor cytokine; LXR is a ligand-activated transcription molecule; ERK1/2 inhibitor is a candidate drug for treating tumor which is used in clinical II-stage experiment. Our research finds that: the liver X receptor LXR ligand can stimulate the expression of macrophage IFN gamma, and inhibit tumor growth; the ERK1/2 inhibitor can significantly activate the expression of macrophage IFN gamma by activating LXR. Macrophages are widely distributed and large in quantity, and therefore, the ERK1/2 inhibitor can activate LXR and stimulate the expression of IFN gamma, which plays a great role in the inhibition of tumor growth; and thus a new approach for preventing and treating tumor with a definite mechanism is established.
Description
Technical field
The present invention relates to the new way that ERK1/2 inhibitor regulation and control macrophage interferon gammas (interferon γ, IFN γ) performance in suppressing tumor greatly acted on and set up the clear and definite prevention of a kind of mechanism and treatment tumor.
Background technology
Lung tumor is one of study hotspot of current oncotherapy, and is the tumor that is at present the mortality rate first place, and its control is had significant theory and using value.IFN γ is as viral infection resisting, antineoplastic important cytokine, and its expression regulation is limited in T cell and the NK cell always, and it is also indefinite how to regulate and control tissue, cell-specific and coherent signal path that IFN γ expresses.LXR is an important transcription factor that conducts a research in recent years, although the function of LXR in cholesterol and lipid metabolism has more detailed research, whether LXR brings into play function in tumor, immune system still unintelligible.Find in our early-stage Study: LXR ligand stimulation macrophage IFN γ expresses, suppresses tumor propagation; The ERK1/2 inhibitor activates the LXR deburring and swashs IFN γ expression.Macrophage is widely distributed cell in the body, because the requirement of the aspects such as infection, antiviral, enhancing immunity, macrophage is very abundant in pulmonary, in theory, macrophage whether expresses IFN γ and regulation and control are the blank in this field always, in actual applications, because popularity and quantity that macrophage distributes are huge, the growth that ERK1/2 inhibitor through stimulating expression of macrophage IFN γ expresses to suppress tumor has obvious feasibility.
Summary of the invention
In order to solve the treatment of lung tumor, the present invention relates to ERK1/2 inhibitor stimulating expression of macrophage IFN γ and express, suppress the effect of tumor growth and set up the clear and definite prevention of a kind of mechanism and the new way for the treatment of tumor.One of purpose of the present invention is to illustrate the mechanism of ERK1/2 inhibitors to inhibitor tumor growth, and studies based on this effect of its prevention and treatment tumor.
The invention has the beneficial effects as follows: the expression that at first the ERK1/2 inhibitor can stimulating expression of macrophage IFN γ, and the single signal path by transcriptional level is regulated, mechanism is clear and definite, and macrophage is widely distributed, especially in pulmonary, the macrophage IFN γ of pulmonary expresses to suppress the growth of tumor by stimulation, thereby reaches the purpose of prevention and treatment.
Description of drawings:
Accompanying drawing 1:ERK1/2 inhibitor stimulates macrophages in vitro IFN γ to express
Accompanying drawing 2:ERK1/2 inhibitor raises the level of the Mice Body IFN γ of inner tissue
Accompanying drawing 3:ERK1/2 inhibitor U0126 suppresses to transplant the tumor growth of lung tumor cell
The specific embodiment
1. test ERK1/2 inhibitor is to the preventive effect of lung tumor: A). and we are with parallel employing wild-type mice and IFN γ knock-out mice, give mouse feeding ERK1/2 inhibitor 7-10 days, set up afterwards the Lung Tumor model, continue medication during this period, observe gross tumor volume and the growing state of mice every day, the difference between test control group and the administration group.And judge the effect of its prophylaxis of tumours and the relation between the IFN γ by IFN γ knock-out mice group.B). on the same group mice not carried out IFN γ concentration detects in the serum, observe the relation between IFN γ concentration change and the tumor growth situation.Early stage the experimental result of wild mouse is observed discovery according to us, appearance can be surveyed tumor after 1 week of tumour transplatation, and in the 3-4 week after tumor occurs, the half mice is with dead successively.Therefore, to the neoplasm transplantation Mus, part mice to survival about administration 3-4 week stops experiment, collect tumor, tissue, blood equal samples, analyze IFN γ concentration in the wild mouse serum, to tissue, tumor etc. cut into slices, immunohistochemical analysis, observe the variation of the internal structure of tumor.Remaining survival part mice then continue medication observe can extending life, improve the various infringements that caused by tumor.The lung tumor that adopts carcinogen to induce occurs and causes the longer time (18-24 week) of dead then one side needs, then be that tumor mass appears at pulmonary on the other hand, can't estimate the time of adopting the living imaging technology to detect lung tumor to occur, size etc.Proceed to about 18 weeks in experiment, to stop experiment to the part survival mice, by collection, the analysis to sample, determine the lung tumor preventive effect that the ERK1/2 inhibitor is induced carcinogen, and the difference between comparison wild mouse and the IFN γ knock-out mice, thereby determine that preventive effect is to the dependency of IFN γ.Remaining survival mice then continues medication, and observes further preventive effect more over a long time.
2. test ERK1/2 inhibitor adopts respectively carry out early, middle and late stage phase to the therapeutic effect of lung tumor.Tumor cell appearance after transplanting for 1 week can be surveyed tumor mass, and tumor propagation is obviously accelerated more than half dead mouses about 4 weeks after 2 weeks; The lung tumor that carcinogen is induced then occurs about 16 weeks, death occurs then about 24 weeks.Therefore, the early, middle and late phase will be dependent on model and change.To transplantation type, we intend adopting 1 week behind the tumor cell transplantation, 2 weeks and the beginning administrations of 3 weeks.The carcinogen induction type is then begun administration about 10 weeks after the carcinogen injection, 15 weeks and 20 weeks.Before and after the administration respectively by with kind of calliper and living imaging technology detailed observation, record being carried out in appearance, the growth of transplantation type and induction type tumor.Experiment finishes in 4 weeks and 24 weeks respectively, before finishing the part survival mice is carried out the detection of IFN γ amount in the serum, and be associated with tumor growth, dead mice carries out sample of tissue, immunohistochemical analysis etc. before finishing for experiment, to determine efficacy of drugs and the stimulation that IFN γ is expressed.
Claims (2)
1.ERK1/2 inhibitor is for the preparation of the purposes in the medicine that suppresses tumor growth, wherein, described tumor is LLC pulmonary carcinoma, and wherein, described ERK1/2 inhibitor is PD98059 or U0126.
2.ERK1/2 the purposes of inhibitor in the IFN γ that stimulates macrophages in vitro expresses, wherein, described ERK1/2 inhibitor is PD98059 or U0126.
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| CN 201110187914 CN102274513B (en) | 2011-07-06 | 2011-07-06 | Tumor growth inhibited by ERK1/2 inhibitor through stimulating expression of macrophage interferon gamma |
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| CN 201110187914 CN102274513B (en) | 2011-07-06 | 2011-07-06 | Tumor growth inhibited by ERK1/2 inhibitor through stimulating expression of macrophage interferon gamma |
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| CN102274513A CN102274513A (en) | 2011-12-14 |
| CN102274513B true CN102274513B (en) | 2013-02-20 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6777415B2 (en) * | 2000-10-05 | 2004-08-17 | George Q. Daley | Methods of inducing cancer cell death and tumor regression |
| WO2004087941A1 (en) * | 2002-02-15 | 2004-10-14 | The General Hospital Corporation | Map-kinase inhibitors as regulators of tumor-associated antigen expression |
| JP2009519234A (en) * | 2005-12-01 | 2009-05-14 | ザ・プロウボウスト・フェロウズ・アンド・スカラーズ・オブ・ザ・カレッジ・オブ・ザ・ホリー・アンド・アンデバイデッド・トリニティ・オブ・クイーン・エリザベス・ニア・ダブリン | Compositions and methods for the treatment of cancer and infectious diseases |
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Non-Patent Citations (2)
| Title |
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| "Stimulation of IFN-γ production by garlic lectin in mouse spleen cells:Involvement of IL-12 via activation of p38 MAPK and ERK in macrophages";Qing Dong等;《Phytomedicine》;20110215;第18卷(第4期);309–316 * |
| Qing Dong等."Stimulation of IFN-γ production by garlic lectin in mouse spleen cells:Involvement of IL-12 via activation of p38 MAPK and ERK in macrophages".《Phytomedicine》.2011,第18卷(第4期),309–316. |
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