CN102274512A - LXR (liver X receptor) agonist capable of stimulating macrophage interferon gamma expression and inhibiting tumor growth - Google Patents

Abstract

The invention relates to a novel method for treating tumors. IFN (interferon) gamma is an important cytokine of resisting virus and tumor, and LXR (liver X receptor) is a ligand activated transcription molecule. Researches find that: the liver X receptor agonist stimulates macrophage IFN gamma to inhibit tumor growth, so that the liver X receptor regulates expression of the macrophage IFN gamma. The macrophage is widely distributed and has large quantity, so that the regulation of the LXR on macrophage IFN gamma expression plays a great effect in inhibiting tumors, and a novel way for preventing and treating tumors with definite mechanism is established.

Description

Lxr agonist stimulates the macrophage interferon gamma to express, suppress tumor growth

Technical field

The present invention relates to the new way that LXR regulation and control macrophage interferon gammas (interferon γ, IFN γ) performance in suppressing tumor greatly acted on and set up clear and definite prevention of a kind of mechanism and treatment tumor.

Background technology

Lung tumor is one of research focus of current oncotherapy, opens and is the tumor that is in the mortality rate first place at present, 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 indeterminate 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, though 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.Research to the LXR function concentrates on the macrophage basically.Macrophage is a widely distributed cell in the body, because the requirement of aspects such as infection, antiviral, enhance 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, has tangible feasibility by the growth that stimulates macrophage IFN γ to suppress tumor.

Summary of the invention

In order to solve the treatment of lung tumor, the present invention relates to LXR regulation and control 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 of treatment tumor.One of purpose of the present invention is to illustrate the mechanism that lxr agonist suppresses tumor growth, and studies the effect of its prevention and treatment tumor based on this.

The invention has the beneficial effects as follows: at first lxr agonist can stimulate the 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 the growth that suppresses tumor by stimulation, thereby reaches the purpose of prevention and treatment.

Description of drawings:

Accompanying drawing 1:LXR is to the stimulation of IFN γ promoter activity

Accompanying drawing 2:T0901317 raises the level of mice in-vivo tissue IFN γ

Accompanying drawing 3:LXR agonist T0901317 suppresses to transplant the interior growth of body of lung tumor cell

The specific embodiment

1. testing the preventive effect of lxr agonist: A) to lung tumor. we are with parallel employing wild-type mice and IFN γ knock-out mice, give mouse feeding lxr agonist 7-10 days, set up the mouse lung tumor model afterwards, 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, can survey tumor in tumour transplatation 1 week back appearance, in the 3-4 week after tumor occurs, the half mice is death successively.Therefore, to the transplantation tumor model mouse, giving about 3-4 part mice termination experiment to survival about week, 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.Can remaining survival part mice then continue medication to observe and prolong life, improve the various infringements that caused by tumor.Adopting the inductive lung tumor of carcinogen dead then longer time (18-24 week) of needs on the one hand to occur also causing, then is that tumor mass appears at pulmonary on the other hand, can't estimate, and adopts the living imaging technology to detect the time, size etc. of lung tumor appearance.Proceed to about 18 weeks in experiment, to stop experiment to the part survival mice, by collection, analysis to sample, determine that lxr agonist is to the inductive lung tumor preventive effect of carcinogen, and the difference between comparison wild mouse and the IFN γ knock-out mice, thereby determine the dependency of preventive effect to IFN γ.Remaining survival mice then continues medication, and observes preventive effect more over a long time further.

2. the test lxr agonist adopts carry out early, middle and late stage phase respectively to the therapeutic effect of lung tumor.Tumor cell appearance after transplanting for 1 week can be surveyed tumor mass, and tumor propagations are obviously accelerated more than half dead mouses about 4 weeks after 2 weeks; The inductive lung tumor of carcinogen 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 detailed observation, record being carried out in appearance, the growth of transplantation type and induction type tumor with kind of calliper and living imaging technology.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 (3)

1. Be 1.LXR agonist regulation and control macrophage IFN γ suppresses the function Characteristics of tumor growth: lxr agonist can raise the expression of macrophage IFN γ, and this rise is to play a role on transcriptional level.Macrophage is as infection, tumor forefront cell, is distributed widely in the body and produces controlled.Set up the new way of clear and definite prevention of a kind of mechanism and treatment tumor based on this;
2. According to claims formed prevention of 1 described the present invention and the treatment tumor new way;
3. According to claims formed prevention of 1 described the present invention and the treatment tumor mechanism.

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