CN109966275A - Quinoid chalcone compound application in preparation of anti-tumor drugs - Google Patents
Quinoid chalcone compound application in preparation of anti-tumor drugs Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K38/19—Cytokines; Lymphokines; Interferons
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Abstract
The present invention provides a kind of quinoid chalcone compound application in preparation of anti-tumor drugs, the quinoid chalcone is the quinoid chalcone compound that A ring has isopentene group, additionally provide application of this kind of compound in tumor disease therapeutic as single medicine or drug combination, the quinoid chalcone itself has stronger anti-tumor capacity, when being combined with anti-tumor drugs such as interferon, the tumour cell of differentiation can not only be killed, the tumor stem cell for entering suspend mode can also be killed, have the effect of thoroughly removing tumour cell.
Description
Technical field
The present invention relates to a kind of quinoid chalcone compound application in preparations of anti-tumor drugs, while being related to this kind ofization
Object is closed to combine in tumor disease therapeutic as the application of drug combination and a kind of anti-tumor medicinal preparation.
Background technique
Malignant tumour is a kind of disease by caused by abnormal cell proliferation, tumor stem cell to the survival of tumour, proliferation,
Transfer and recurrence play an important role.In essence, tumor stem cell maintains tumour thin by self-renewing and infinite multiplication
The vitality of born of the same parents group, movement and the ability of migrating impart the ability of tumour cell distal end invasion transfer.Recent study report
It has been shown that, tumor stem cell in a dormant state and can raise a variety of drug resistance developed by molecule and right for a long time in treatment clinical course
The extraneous chemical factors of killing tumor cell are insensitive.Tumor dormancy (tumor dormancy) is a kind of clinic serendipitous
State, including dormant cells, tumor vessel suspend mode and immune state suspend mode, are one of biological properties of malignant cell,
It is the one of the major reasons for leading to clinical tumor recurrent exerbation and distal end invasion transfer.Traditional operation, radiation and chemotherapy means
While obtaining certain therapeutic effect, more serious clinical side effects is accompanied by, and there is the risk of induction Tumor dormancy, found
Effectively, the small treatment method of toxic side effect improves the most important thing that life in patients has become medical research.
Cancer cell is killed using killer T cell in vitro, killer T cell number is more theoretically, killing
Effect is more significant, however inventor has found in the research by taking melanin tumour b16-OVA cell as an example, killer T cell
The killing of cancer cell is increased with concentration and is enhanced, even if however increase T cell number can not be thorough after reaching certain proportion
Remove B16-OVA cell.This phenomenon prompts, cancer cell there is a groups in treatment clinical course can not be by specificity T
The rest cell of cell killing, and these suspend mode cancer cells have buried hidden danger in tumor patient body, in current clinical treatment
Since the cancer cell of dormant state can not be thoroughly removed, and clinical patients is made to lead to death there are tumor recurrence or transfer
Risk.
Although constantly there is the appearance of anti-tumor drug result of study, the work for finding more effective drug and means does not stop
Only, the method for removing suspend mode tumour cell is found, tumour is really effectively removed, reaches cancer in thoroughly treatment clinical tumor patient body
The purpose of cell is that insider makes great efforts the target sought and the whole society is expected.
Summary of the invention
One of the technical problems solved by the invention is to provide a kind of quinoid chalcone compounds in the preparation of antitumor drugs
Application can not only kill tumour using the micromolecular inhibitor of this special construction, can more assist making for interferon
With, achieve the effect that kill suspend mode tumour cell.
The present invention also provides the quinoid chalcone as the drug that is divided into of activity with interferon drug combination antitumor
Application in treating, and the anti-tumor agent combination that a kind of active constituent includes the quinoid chalcone and interferon is provided.
One aspect of the present invention provides a kind of quinoid chalcone compound in the drug of preparation treatment tumor disease
Application, the quinoid chalcone is the quinoid chalcone compound that one group of A ring has isopentene group, Chinese patent application
Detailed disclosure and elaboration have been carried out to the quinoid chalcone compound in CN201410220017.8, thus related content is equal
It is merged into the application, becomes a part of teachings herein.
Above-mentioned A ring has the quinoid chalcone compound of isopentene group, has following general formula structure I:
In the formula I, R represents 1-4 substituent group being connected on B ring, can be independently selected from: hydrogen, hydroxyl, sulfydryl,
Methoxyl group, amino, nitro, halogen (such as relatively common be chlorine, bromine), cyano, methylsulphur acidic group or formyl etc..
Inventor has found there is above-mentioned quinoid chalcone structure using one kind on the basis of largely exploring early period
Micromolecular inhibitor is used as single medicine, shows the significant antitumous effect of comparison, and is combined with clinical antineoplastic medicine,
The dormant state that tumour cell can more be broken, compared to the effect for being applied alone anti-tumor drug to show more preferably to inhibit and kill cancer cell
Fruit, this tumour cell for thoroughly removing patient's body cure tumor disease important in inhibiting.
According to the result of study of inventor, above-mentioned quinoid chalcone compound is small molecule inhibitor (this hair
Represented in bright using " HB ") as single medicine or it is combined medicine, tumor disease applicatory includes the solid tumors of various clinical diagnosises and white
Blood disease, such as malignant mela noma, lung cancer, liver cancer, breast cancer, cancer of pancreas or leukaemia etc..
According to the solution of the present invention, the treatment tumor disease drug comprising the quinoid chalcone active constituent can be single
Position preparation, the more conducively use in clinical treatment.It, can in the drug of the unit formulation according to the state of an illness of tumor type and patient
Using the quinoid chalcone compound comprising 1-5 milligrams as active constituent.The dosage form of the pharmaceutical composition can be injection
Dosage form or peroral dosage form etc..
According to the solution of the present invention, the drug comprising the quinoid chalcone ingredient can be used for single therapy, can also be with
Be combined with current clinical antitumor agents, for example, the treatment tumor disease drug may be including interferon with it is described
The formulation compositions of quinoid chalcone compound.
The treatment tumor disease drug of same consideration, formulation compositions form may be unit formulation.It can be
The quinoid chalcone compound and a effective amount of interferon of oncotherapy comprising 1-5 milligrams as active constituent.At one
In embodiment, the drug of the unit formulation of the formulation compositions form may include 1 × 107~4 × 107The interferon of U, or
Dosage is determined according to tumor type and patient's course of disease.
Another aspect of the invention provides a kind of formulation compositions of anti-tumor drug, and therapeutic activity therein is at subpackage
Include interferon and the quinoid chalcone compound.
Micromolecular inhibitor used in the present invention, at present by as in anti-inflammatory component, such as CN201410220017.8
Disclose the treatment that can be used for blood vessel and neuroinflammatory disorder and immune inflammation disease, but the studies have shown that of inventor
Its for tumour cell killing effect and and joint interferons anti-tumor drug further promoted to malignancy disease
The cooperative effect of therapeutic effect, it is even more unexpected.
About the structure and physicochemical property and preparation method of the quinoid chalcone compound, Chinese patent application can refer to
CN201410220017.8.As an example, being listed below the applicable quinoid chalcone compound in part:
The research of inventor has shown that, the medicine prepared using quinoid chalcone compound provided by the invention as active constituent
Object can be used as single medicine for tumor disease therapeutic, and reaching at least can partially kill tumor function, can be with interferons clinic
Anti-tumor drug combination, effectively kills dormant state tumour cell, to provide possibility to thoroughly remove patient's body cancer cell.
On the other hand, the drug that quinoid chalcone compound (HB) provided by the invention prepares as active constituent, is used for
It in antineoplaston, can also be combined with other clinical antitumor agents, for example, being combined with anti-tumor vaccine, alternatively, with change
Drug combination etc. is treated, suspend mode tumour cell can be effectively killed, thus to thoroughly remove patient's body malignant tumor cells
There is provided may.
Quinoid chalcone of the present invention can be commercially available or according to relevant disclosure (such as in aforementioned patent discloses
Hold) voluntarily it is synthetically prepared, interferons drug IFN can be the interferon beta and γ of current clinical use, that is, IFN-β, IFN-γ.
In order to study and prove killing and inhibition of the micromolecular inhibitor to dormant state tumour cell, inventor uses 3D
Glue cultivates tumour cell to obtain tumor stem cell, compared to the method for tradition separation tumor stem cell, 3D glue culture
The stem cell that technology obtains has many characteristics, such as that proliferative capacity is strong, drug resistance is high, one-tenth knurl ability is strong, distal end invasion transfer ability height.And
And inventor uses the administration studies have shown that micromolecular inhibitor from people or the experiment of mouse tumour cell and bearing mouse model not
Only have the effect of inhibiting and killing tumour, the expression of CD8+T cell PD-1 can be more reduced significantly, for inhibiting Kyn to mediate
PD-1 express up-regulation, enhance killing of the specific C D8+T cell to corresponding tumour cell, more have an unexpected effect,
It is reasonable to expect that, which combines the antitumor of current clinical antineoplastic medicine IFN or anti-tumor vaccine, chemotherapeutic etc.
Pharmaceutical preparation combination can not only kill the tumour cell of differentiation, can also kill the tumor stem cell for entering suspend mode.
As previously mentioned, in antitumor single medicine provided by the invention and anti-tumor medicinal preparation combination, micromolecular inhibitor HB
Single medicine and interferon (IFN) all can be unit formulations.The unit formulation is effective component needed for meeting single administration
Preparation, such as a unit (needle) injection, the preparation of dosage can be met as single medication by being also possible to a piece of (grain) or ball etc..Suffer from
Unit needed for the amount of drug needed for person's applied once passes through the weight for calculating patient and patient's a drug with can be convenient
The product of body weight dose obtains.For example, during preparing drug, it is considered that adult weight is 50-70kg, can be initial
Dosage can be determined by the dose, equivalent conversion relation between experimental animal and the per weight dosage of people.For example, can
With the instruction proposed according to medicine administrative organs such as FDA, SFDA, see also (Huang is after Chinese etc., " animal in pharmacological testing
Between between animals and human beings body equivalent dose conversion ", " Chinese Clinical pharmacology and acology ", 2004Sep；9(9):1069-
1072) it determines.In embodiments of the present invention, the body surface area conversion factor 0.0026 according to people and mouse can be used
Come the dosage of convert people and mouse.
In embodiments of the invention, the mouse for being 20g for weight, micromolecular inhibitor HB is with 5mg/kg Mice Body
The amount application of weight, IFN-β is then with 5 × 104-1×105The amount of U is applied.For example, HB inhibitor water or drug solvent are prepared
For solution, to mouse gavaging or implement intratumor injection according to design dosage, and IFN-β is usually intratumor injection administration.
Further, according to the experimental result for being directed to mouse, people (such as the 50- for nomal body weight range is converted to
70kg weight) administration designs, and include 1-5mgg active constituent in HB unit formulation drug, includes 1 × 10 in IFN unit formulation7
~4 × 107The IFN of U.When being made into formulation compositions, the content of HB and interferon also meets above-mentioned dosage.
The administration mode of anti-tumor drug and pharmaceutical preparation provided by the invention combination are as follows: to thering is what treatment needed to suffer from tumour
Drug of individual (the can be people or mammal) application comprising the HB inhibitor or anti-tumor medicinal preparation combination, example
Such as, (stomach-filling) or injection (vein, injection, intraperitoneal or intratumor injection) HB drug are taken orally when single therapy；It is quiet when drug combination
Arteries and veins, intraperitoneal or intratumor injection IFN, Combined with Oral (stomach-filling) or injection (intravenous injection, intraperitoneal or intratumor injection) HB medicine
Object.
What the present invention used contains drug of the HB as active constituent, but according to any medicine group made of pharmaceutical technology
Close object or preparation, the content of the HB as active ingredient can be such as 0.1~95% weight, can be made ordinary preparation,
It can be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery systems.It can be given in a unit in treatment
Medicine, administration route can be vivo medicine-feeding or local administration, such as enteron aisle or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral cavity
Mucous membrane, skin, peritonaeum or rectum etc.；Can be drug administration by injection, including intravenous injection, intramuscular injection, subcutaneous injection, intracutaneous injection and
Acupoint injection therapy etc.；It can also be liquid dosage form, solid dosage forms, as liquid dosage form can be true solution class, colloidal type, fine granule
Type, emulsion dosage form, mixed suspension form；Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspension
Agent, emulsion, granule, suppository, freeze drying powder injection etc..
The present invention also provides a kind of methods for treating or preventing tumour, swell including giving to suffer from the individual of tumour or have
What individual (can be people or mammal) the application anti-tumor drug or anti-tumor medicinal preparation of tumor occurrence tendency combined
Process.For example, giving oral (stomach-filling) or injection (intravenous injection, intraperitoneal or intratumor injection) HB drug when single therapy；Connection
When sharing medicine, injection IFN (vein, abdominal cavity or intratumor injection), Combined with Oral (stomach-filling) or injection (intravenous injection, abdominal cavity are given
Interior or intratumor injection) administration HB.
According to the solution of the present invention, the therapeutic administratp dosage of the quinoid chalcone compound drug and interferon can be with
Control as needed, recommendation, the unit formulation of various dose, the administration of the convenient tumor patient to different phase can be prepared.
When using HB joint interferon administration, order of administration is not specially required and is limited, for example, can be administered simultaneously,
Or two kinds of medicines sequence is applied, and it is general between two kinds of medicines it is not recommended that too big dosing interval, for example, it may be 30 minutes to 60 minutes
Interior completion administration can also be administered with completion in 1-12 hour or in 1-2 days, can also according to doctor's advice by every kind of medicine according to
Respective treatment sequence or period application.
Interferon (such as IFN-β or IFN-γ) is a kind of cell factor generated by fibroblasts to secrete, is had
Antiviral, adjusting inherent immunity reaction and antitumor properties are a kind of common anti-tumor biological factors.It is studied in the applicant
Middle discovery, although interferon has relatively good antitumous effect in the application of clinical treatment, but still after having a certain amount for the treatment of
Patient the case where will appear tumor recurrence or even transfer, reason is that IFN-β or IFN-γ, which is used alone, can only kill portion
Divide the tumour cell in differentiation state, not killed tumour cell has stem cell properties, and enters dormant state, exactly
The presence of these suspend mode tumour cells so that clinical tumor patient a period of time (several years) afterwards again can face tumor recurrence or
The risk of transfer.The applicant has found that above-mentioned Α ring has the quinoid chalcone conduct of iso-amylene by lot of experiments
The drug of active constituent not only itself can kill tumour cell, with IFN-β or IFN-γ combination medicine-feeding, kill the swollen of differentiation
While oncocyte, the purpose to suspend mode tumor cytotoxicity more can be realized, and drop is also realized while significant synergy
The dosage of low list medicine.
Anti-tumor medicinal preparation combination provided by the invention can also be above-mentioned quinoid chalcone compound for active constituent
With the joint of clinical antitumor agents, such as the anti-tumor vaccine, all kinds of chemotherapeutics that clinically use, the treatment of diseased individuals
In be given in combination the drug that quinoid chalcone compound of the invention is active constituent, the dosage form of the drug, dosage and give
Medicine approach and mode, referring to aforementioned.
To sum up, the solution of the present invention has the effect that
1, the application utilizes the anti-swollen of the quinoid chalcone (such as HB-2 and its analogue of embodiment) preparation
Tumor medicine preparation be used alone can part killing tumor cell, and be used in combination with interferon beta, or with other clinical antineoplastics
Drug combination can not only kill the tumour cell of differentiation, and can kill the tumour cell into suspend mode, have thoroughly clear
Except the effect of tumour cell.
2, anti-tumor medicinal preparation of the invention combination not only can be realized by enhancing systemic immune response and kill tumour
Effect, obstructed can also overregulate systemic immune response and direct killing effect is generated to tumour, thus with high security,
The advantages of having no toxic side effect.
Detailed description of the invention
Fig. 1 shows solid tumor and leukemia tumor regenerative cell's apoptosis effect under micromolecular inhibitor HB induction 3D culture.
A-F in figure respectively illustrate the quinoids chalcone analogue such as DMF, HB-2 induction 3D cultivate lower A375,
The effect of A549, HepG2, MCF-7, PANC-1 and HL-60 tumor regrowth Apoptosis.
Fig. 2 is inhibition of the micromolecular inhibitor HB to solid tumor and leukaemia tumor growth.
In figure A-F respectively illustrate using the quinoids chalcone analogue such as DMF, HB-2 to A375, A549, HepG2,
The therapeutic effect of MCF-7, PANC-1 and HL-60 tumor-bearing mice.
Fig. 3 shows that influence of the IFN-β to the 3D tumor regrowth Apoptosis cultivated is used in combination in HB-2.
In figure:
A is to detect it using people's Human melanoma cell line A375 under IFN β and HB-2 combination processing 3D condition of culture
Percentage of cerebral apoptosis；
B is to detect its Apoptosis using the human lung cancer cell A549 under IFN β and HB-2 combination processing 3D condition of culture
Percentage；
C is to detect its Apoptosis using the human liver cancer cell HepG2 under IFN β and HB-2 combination processing 3D condition of culture
Percentage；
D is to be detected its cell using the human breast cancer cell line Bcap-37 under IFN β and HB-2 combination processing 3D condition of culture and withered
Die percentage；
E is to detect its cell using the human pancreatic cancer cell PANC-1 under IFN β and HB-2 combination processing 3D condition of culture
Apoptosis percentage；
F is to be detected its cell using the human leukemia cell line HL-60 under IFN β and HB-2 combination processing 3D condition of culture and withered
Die percentage.
Fig. 4 is HB-2 and IFN β is combined the influence grown to solid tumor tumor-bearing mice.
Show that DMF, HB-2, IFN-β and joint IFN-β and HB-2 reduce the effect of mouse melanoma B16 knurl weight in figure.
Fig. 5 shows HB-2 to the mouse CD8 of in vitro culture+The influence of T cell PD-1 expression.
Fig. 6 shows that HB-2 combines specific C D8+The influence that T cell is adopted to tumor-bearing mice tumour growth.
Specific embodiment
Below in conjunction with specific embodiment the present invention is further explained scheme and implementation result, but it is not construed as to the present invention
The restriction of enforceable range.
Tumour cell, drug and experimental animal used in following experiments implementations:
OVA-B16 tumor cell line, B16 mouse melanin tumor cell system (also referred to as B16 tumor cell line), A375 people's black
Plain oncocyte system, A549 human lung cancer cell line, HepG2 Bel7402, MCF-7 human breast cancer cell line, PANC-1 people's pancreas
Gland cell system, HL-60 human leukemia cell line can be thin from the U.S. center ATCC or Beijing Union Medical College basic research institute
The purchase of born of the same parents center.
The HL-60 cell of luciferase label is to filter out after HL-60 cell transfecting luciferase reporter plasmid
Stablize the monoclonal cell for expressing the luciferase gene.
Experimental animal: Healthy female Balb/c mouse, C57BL/C mouse or female NOD-SCID mouse, 4-6 week old,
Purchased from Chinese Academy of Medical Sciences's Union Medical College Experimental Animal Center, and the zoopery obtains the human relations of Chinese Academy of Medical Sciences animal
The approval of the reason committee.
DMF (abbreviation of dimethylformamide) is purchased from U.S. SIGMA company, requires to be configured to according to experimental design corresponding
The solution of concentration or dosage；
Source of people or source of mouse IFN-β, cell factor are purchased from U.S. PeproTech company, require to be configured to according to experimental design
The solution of respective concentration or dosage；
Micromolecular inhibitor HB-2, HB-3, HB-7, HB-19, HB-25, HB-31, HB-33 and HB-46, in
Product synthesized by state's Academy of Medical Sciences drug, can also be according to method disclosed in Chinese patent application CN 201410220017.8
It voluntarily synthesizes, there is the quinoid chalcone compound (referred to as " micromolecular inhibitor of isopentene group for A ring of the present invention
HB "), specific structure is as follows, and the solution for being configured to respective concentration or dosage is required according to experimental design.
The soft gel of 3D fibrin (3D glue), RPMI-1640 culture medium, PBS are commercially available.
The statistical result of experimental data has a corresponding display in respective figure in following embodiment, marked in figure " * ",
" * * " and " * * * " respectively represents statistical difference P < 0.05, P < 0.01 and P < 0.001 of the result compared to control group result.
First part: micromolecular inhibitor HB is applied alone the effect to solid tumor and leukaemia to detect
Embodiment 1: quinoid chalcone compound list medicine of the invention uses the entity that can effectively induce under 3D condition of culture
Tumor and apoptosis of leukemia.
1, experimental procedure
Using 3D glue technology culture A375, A549, HepG2, MCF-7, PANC-1 and HL-60 cell, cell number about 10000
Left and right/hole, observes cell state after 2 days, in good situation, every kind of culture cell carries out dosing according to following group respectively:
Control group (control): the ordinary culture medium (such as RPMI-1640 culture medium) added with glutamine；
Experimental group: 10 μm of ol/ml are added in the ordinary culture medium (such as RPMI-1640 culture medium) added with glutamine
HB-2, HB-3, HB-7, HB-19, HB-25, HB-31, HB-33, HB-46, DMF is as positive control.
First drug is uniformly mixed with culture medium when dosing and is then added in each group experimental cell, dosing starts to be denoted as the 0th
It, carries out apoptosis detection to the cell in 3D glue in 96 hours (the 4th day).
2, experimental result
The other statistical result of each group is shown in Fig. 1, the results show that the drug of all experimental groups (including positive control DMF)
Different degrees of inducing entity tumor and apoptosis of leukemia have significant difference, wherein HB-2 is representative compared with the control group
Most inhibitor inducing entity tumors and apoptosis of leukemia effect it is more prominent, and be significantly better than positive control DMF.
Embodiment 2: the inhibition of micromolecular inhibitor HB-2 and its analogue to solid tumor and leukaemia tumor growth.
1. experimental procedure
(1) building of A375 tumor-bearing mice: NON-SCID mouse hypodermic inoculation 1 × 105A A375 cell is grown up to knurl
When to 5mm x 5mm, the quantity such as tumor-bearing mice are randomly divided into 10 groups, every group 7, give tumor-bearing mice or less different treatment sides
Formula:
Control group (control): PBS is given in stomach-filling；
Positive controls: stomach-filling is given DMF (10mg/kg), and every two days 1 time.
Experimental group (8 groups): every group respectively stomach-filling give HB-2, HB-3, HB-7, HB-19, HB-25, HB-31, HB-33,
HB-46,10mg/kg weight are administered once for every two days；
After 21st day puts to death mouse, subcutaneous tumor is removed, weighs and counts each group knurl weight.
(2) building of A549 tumor-bearing mice: NON-SCID mouse hypodermic inoculation 1 × 105A A549 cell is grown up to knurl
When to 5mm x 5mm, the quantity such as tumor-bearing mice are randomly divided into 10 groups, every group 7, give tumor-bearing mice or less different treatment sides
Formula:
Control group (control): PBS is given in stomach-filling；
Positive controls: stomach-filling is given DMF (10mg/kg weight), and every two days 1 time.
Experimental group (8 groups): HB-2, HB-3, HB-7, HB-19, HB-25, HB-31, HB-33, HB-46 are given in stomach-filling,
10mg/kg weight is administered once for every two days；
After 28th day puts to death mouse, subcutaneous tumor is removed, weighs and counts each group knurl weight.
(3) building of HepG2 tumor-bearing mice: NON-SCID mouse hypodermic inoculation 2 × 106A HepG2 cell, to knurl at
It is long to 5mm x 5mm when, the quantity such as tumor-bearing mice are randomly divided into 10 groups, every group 7, give tumor-bearing mice or less different treatments
Mode:
Control group (control): PBS is given in stomach-filling；
Positive controls: stomach-filling is given DMF (10mg/kg weight), and every two days 1 time.
Experimental group (8 groups): HB-2, HB-3, HB-7, HB-19, HB-25, HB-31, HB-33, HB-46 are given in every group of stomach-filling,
10mg/kg weight is administered once for every two days；
After 42nd day puts to death mouse, subcutaneous tumor is removed, weighs and counts each group knurl weight.
(4) building of MCF-7 tumor-bearing mice: NON-SCID mouse hypodermic inoculation 2 × 106A MCF-7 cell, to knurl at
It is long to 5mm x 5mm when, the quantity such as tumor-bearing mice are randomly divided into 10 groups, every group 7, give tumor-bearing mice or less different treatments
Mode:
Control group (control): PBS is given in stomach-filling；
Positive controls: stomach-filling is given DMF (10mg/kg weight), and every two days 1 time.
Experimental group (8 groups): HB-2, HB-3, HB-7, HB-19, HB-25, HB-31, HB-33, HB-46 are given in stomach-filling,
10mg/kg weight is administered once for every two days；
After 56th day puts to death mouse, subcutaneous tumor is removed, weighs and counts each group knurl weight.
(5) building of PANC-1 tumor-bearing mice: NON-SCID Mice Mice inoculates 5 × 106A PANC-1 cell, to
When knurl grows to 3mm x 3mm, the quantity such as tumor-bearing mice are randomly divided into 10 groups, every group 7, give tumor-bearing mice or less no
Same therapeutic modality:
Control group (control): PBS is given in stomach-filling；
Positive controls: stomach-filling is given DMF (10mg/kg weight), and every two days 1 time.
Experimental group (8 groups): HB-2, HB-3, HB-7, HB-19, HB-25, HB-31, HB-33, HB-46 are given in stomach-filling,
10mg/kg weight is administered once for every two days；
After 56th day puts to death mouse, subcutaneous tumor is removed, weighs and counts each group knurl weight.
(6) building of HL-60 leukemia mouse model: NON-SCID mouse tail vein injection 1 × 106A luciferase mark
The HL-60 cell of note after the quantity such as mouse are randomly divided into 10 groups, every group 7,7 days, gives mouse or less different treatment sides
Formula:
Control group (control): PBS is given in stomach-filling；
Positive controls: stomach-filling is given DMF (10mg/kg weight), and every two days 1 time.
Experimental group (8 groups): HB-2, HB-3, HB-7, HB-19, HB-25, HB-31, HB-33, HB-46 are given in stomach-filling,
10mg/kg weight is administered once for every two days；
It 42nd day, is distributed utilizing small animal living body imaging system to detect and count in leukaemia cell's body after mouse anesthesia
Situation.
2. experimental result
Each group tumor-bearing mice tumour growth situation statistical result showed A-F in Fig. 2.
As can be seen that compared with control group, the mono- medicine of all HB and the mono- medicine of DMF can delay and inhibit in various degree solid tumor
The growth of A375, A549, HepG2, MCF-7, PANC-1 and leukaemia cell HL-60, but DMF is compared, HB-2 effect is more aobvious
It writes.
It can be proved that micromolecular inhibitor HB of the present invention has in various degree in solid tumor and leukaemia cell's body
The inhibiting effect of growth effectively inhibits its malignancy.
Second part: micromolecular inhibitor HB-2 and IFN β detect the effect of solid tumor and leukaemia
Solid tumor cell and leukaemia cell under the significant induction 3D condition of culture of embodiment 3:IFN- β and HB-2 combination wither
It dies.
1, experimental procedure
Solid tumor cell A375, A549, HepG2, MCF-7, PANC-1 and leukaemia cell HL-60 are subjected to 3D glue respectively
It cultivates (24 orifice plates, cell density are 8000/ hole), second day observation cell state, in the good situation of cell survival conditions, point
Not An following grouping carry out agent-feeding treatment:
Control group 1 (control): ordinary culture medium and drug solvent；
Control group 2 (IFN β): ordinary culture medium be added 6ng/ml mouse with or 10ng/ml people's IFN β；
Experimental group 3 (HB-2): the HB-2 of 10 μm of ol/ml is added in ordinary culture medium；
Experimental group 4 (IFN β+DMF): 6ng/ml mouse use or 10ng/ml people's IFN β and 20 μm of ol/ are added in ordinary culture medium
Ml μM of DMF；
Experimental group 5 (IFN β+HB-2): 6ng/ml mouse use or 10ng/ml people's IFN β and 10 μm of ol/ are added in ordinary culture medium
The HB-2 of ml；
It needs first uniformly to mix drug with culture medium when dosing to be then added in each group experimental cell, cultivates 48 hours, adopt
With Apoptosis by Flow Cytometry situation.
Note: " mouse IFN β " or " people's IFN β " is used to be determined according to the attribute of cultivated tumour cell in experiment, below
Embodiment is all the same.
2, experimental result
Group of cells apoptosis rate result is shown in A-F in Fig. 3 in a manner of compareing.
It can be seen that IFN β and HB-2 are applied alone the killing to the solid tumor cell under 3D glue culture to have certain effect, but
IFN β is remarkably improved the killing ability to solid tumor cell compared to using single medicine with micromolecular inhibitor combination, and IFN β and
HB-2 be combined when it is more notable to the fragmentation effect of tumour be higher than IFN β is applied alone, HB-2 is applied alone and IFN β and DMF combination.
Embodiment 4: use in conjunction IFN-β and HB-2 can inhibit solid tumor tumor-bearing mice tumour growth, extend tumor-bearing mice
Life cycle.
2, the Experiment on therapy of use in conjunction IFN-β and HB-2 to C57BL/C mouse tumor
1) experimental procedure
Building tumor-bearing mice: B16 melanoma cells are inoculated in 4-6 week old C57BL/C mouse, and (inoculum concentration is 1 × 105It is a
Cell), 35 mouse are randomly divided into 5 groups, mouse weight is 20g or so, and tumour generation can be observed within 7 days or so；To tumor
When body grows to 5mm x 5mm, give tumor-bearing mice or less different therapeutic modalities according to group:
Control group 1 (control): only intratumor injection PBS；
Experimental group 2 (IFN-β): IFN-β individually handles tumor-bearing mice, every mouse intratumor injection 1 × 105The IFN-β of U,
Injection in every two days is primary, and co-injection 10 days；
Experimental group 3 (IFN-β/DMF): mouse gives IFN-β and DMF (i.e. use in conjunction IFN-β and DMF) respectively, administration
For mode with experimental group 4, the dosage of DMF is also identical as HB-2.
Experimental group 4 (HB-2): HB-2 individually handles tumor-bearing mice, and HB-2 dosage is every two days according to 5mg/kg mouse weight
Administration, mode are intratumor injection, co-injection 10 days；
Experimental group 5 (IFN-β+HB-2): mouse gives IFN-β and HB-2, IFN-β administration mode respectively are as follows: administration 1 in tumor
×105The IFN-β of U, every two days intratumor injections are primary, and co-injection 10 days；HB-2 administration mode are as follows: every two days intratumor injections administration
HB-2 (dose is 5mg/kg mouse weight), is administered 10 days altogether；There is no limit every time can be same for IFN-β and the order of administration of HB-2
When administration or sequentially successive administration；
Tumour is taken to weigh after 28th day execution mouse.
2) experimental result
The knurl situation situation of each group mouse is shown in Fig. 4:
It can be seen that compared with control group, although the treatment of experimental group is more apparent for inhibiting Melanoma Growth to have
Advantage, but IFN-β combination DMF and IFN-β combination HB-2 then show more to significantly inhibit melanoma tumor growth, and
HB-2 shows effect more better than DMF.
Part III: micromolecular inhibitor HB-2 is to CD8+The influence of T cell PD-1 expression
Embodiment 5:HB-2 can reduce mouse CD8+The expression of T cell PD-1 enhances the killing ability of T cell.
1, influence of the detection HB-2 to the mouse CD8+T cell PD-1 expression of activation
1) experimental procedure
Magnetic bead sorting obtain mouse spleen CD8+T cell, plant in 96 orifice plate of U-shaped bottom (100,000/hole), while be added AntiCD3 McAb/
CD28 magnetic bead activates T cell, and culture medium is that RPMI-1640 adds 10ng/mL mouse IL-2 and 50nM β mercaptoethanol.The T of activation is thin
Born of the same parents press following grouping dosing:
Control group 1 (PBS): add PBS in culture medium；
Experimental group 2 (Kyn): 200 μm of ol/ml of Kyn are added in culture medium；
Experimental group 3 (Kyn+DMF): 10 μm of ol/ml of Kyn 200 μm of ol/ml and DMF are added in culture medium simultaneously；
Experimental group 4 (Kyn+HB-2): 10 μm of ol/ml of Kyn 200 μm of ol/ml and HB-2 are added in culture medium simultaneously；
It is cultivated 48 hours after dosing, using the PD-1 expression of every group of T cell of Flow cytometry.
2) experimental result
Each group detection T cell PD-1 expression result, which counts, is shown in Fig. 5, and column diagram is sequentially control from left to right in figure
Group 1 (PBS), experimental group 2 (Kyn), the statistical result of experimental group 3 (Kyn+DMF) and experimental group 4 (Kyn+HB-2).
As can be seen that the CD8+T that HB-2 ratio DMF can more effectively inhibit Kyn (kynurenin, kynurenine) to mediate is thin
Born of the same parents PD-1 up-regulation, and result has significant difference, illustrates that HB-2 ratio DMF can more effectively inhibit small molecule receptor.
Embodiment 6:HB-2 joint specific C D8+T cell, which is adopted, treats the significant effect of mouse entity tumour.
1, experimental procedure
Building tumor-bearing mice: OVA-B16 melanoma cells are inoculated in 4-6 weeks C57BL/6 mouse, and (inoculum concentration is 1 × 105
A cell), mouse is randomly divided into 7 groups, every group 5, mouse weight is 20g or so, and it is raw tumour to can be observed within 7 days or so
At；When knurl grows to 5mm x 5mm, give tumor-bearing mice or less different therapeutic modalities according to group:
Control group 1 (PBS): only intratumor injection PBS；
Experimental group 2 (CD8+T): OT-1 mouse CD8+T cells i is adopted tumor-bearing mice, and 5 days are primary, and totally 3 times, each mistake
After 4x 106CD8+T cell；
Experimental group 3 (DMF): the mono- medicine intratumor injection tumor-bearing mice of DMF, once every two days, totally 10 times, each dosage is 5mg/
Kg tumor-bearing mice weight；
Experimental group 4 (HB-2): the mono- medicine intratumor injection tumor-bearing mice of HB-2, once every two days, totally 10 times, each dosage is
5mg/kg tumor-bearing mice weight；
Experimental group 5 (CD8+T+DMF): OT-1 mouse CD8+T cells i is adopted joint DMF intratumor injection, method and agent
Amount adopts with experimental group 2 and 3 and respectively follows the dosage period of setting with dosing techniques；
Experimental group 6 (CD8+T+HB-2): OT-1 mouse CD8+T cells i is adopted joint HB-2 intratumor injection, method and
Dosage adopts with experimental group 2 and 4 and respectively follows the dosage period of setting with dosing techniques；
Administration experiment starts daily measurement knurl size, calculates tumor volume change.
2, experimental result
The knurl variation statistical result of each group experiment mice is shown in Fig. 6.
As can be seen that simple CD8+T cell adopt or the mono- medicine of HB-2 have for the entity tumor of tumor-bearing mice it is certain
Therapeutic effect, but CD8+T cell adopts joint that micromolecular inhibitor therapeutic effect is relatively preferable, more outstanding is CD8+T thin
Born of the same parents adopt, and joint HB-2 is significant in efficacy to adopt joint DMF better than CD8+T cell.
Can illustrate that HB-2 ratio DMF can more effectively inhibit CD8+T cell small molecule receptor, lower its PD-1 inhibition by
Body surface reaches, and enhances killing ability in CD8+T cell body.
The above is only the part of test results in applicant's numerous studies, but can illustrate:
Micromolecular inhibitor (such as HB-2 and its analogue used in experiment) of the invention is used alone and can have
Effect inhibits the malignancy of solid tumor and leukaemia；
When micromolecular inhibitor HB (such as HB-2 etc.) and IFN β is used in combination, single medicine dosage can be greatly reduced
Under the premise of obtain more excellent therapeutic effect, this prompt micromolecular inhibitor HB collaboration IFN β can not only reduce effectively treatment make
With dosage, and curative effect is significantly increased, clinical use can achieve enhancing fragmentation effect and knurl is delayed to grow.
Micromolecular inhibitor of the invention (such as HB-2 and its analogue used in experiment) compared with DMF,
The expression of CD8+T cell PD-1 can be reduced more significantly, and it is thin to enhance specific C D8+T for the PD-1 up-regulation that more inhibition Kyn is mediated
Killing of the born of the same parents to corresponding tumour cell.
Claims (19)
1. a kind of application of quinoid chalcone compound in preparation treatment tumor disease drug, the quinoid chalcone compound
With following structure shown in formula I:
In the formula I, R represents 1-4 substituent group being connected on B ring, can be independently selected from hydrogen, hydroxyl, sulfydryl, methoxy
Base, amino, nitro, halogen, cyano, methylsulphur acidic group or formyl.
2. application according to claim 1, wherein the quinoid chalcone compound includes:
2- cinnamoyl -3,5- dihydroxy -6,6- diisoamyl alkenyl hexamethylene -2,4- dienone；
2- (4- cinnamoyl chloride base) -3,5- dihydroxy -6,6- diisoamyl alkenyl hexamethylene -2,4- dienone；
2- (4- methoxycinnamate acyl group) -3,5- dihydroxy -6,6- diisoamyl alkenyl hexamethylene -2,4- dienone；
2- (4- hydroxy cinnamate acyl group) -3,5- dihydroxy -6,6- diisoamyl alkenyl hexamethylene -2,4- dienone；
2- (4- hydroxy-3-methoxy cinnamoyl) -3,5- dihydroxy -6,6- diisoamyl alkenyl hexamethylene -2,4- dienone；
2- (3,4,5- trimethoxy cinnamoyl) -3,5- dihydroxy -6,6- diisoamyl alkenyl hexamethylene -2,4- dienone；
2- (4- cinnamyl bromide acyl group) -3,5- dihydroxy -6,6- diisoamyl alkenyl hexamethylene -2,4- dienone；
2- (4- fluorine cinnamoyl) -3,5- dihydroxy -6,6- diisoamyl alkenyl hexamethylene -2,4- dienone.
3. application according to claim 1 or 2, wherein the tumor disease include malignant mela noma, lung cancer, liver cancer,
Breast cancer, cancer of pancreas, brain tumor or leukaemia.
4. application according to claim 1-3, wherein the treatment tumor disease drug include injection type and
Peroral dosage form.
5. application according to claim 1-4, wherein the treatment tumor disease drug is unit preparation.
6. application according to claim 5, wherein in the drug of the unit formulation comprising 1-5 milligram as it is active at
The quinoid chalcone compound divided.
7. according to right want 1 or 2 described in application, wherein the treatment tumor disease drug be include interferon and the quinone
The formulation compositions of formula chalcone compound.
8. application according to claim 7, wherein the treatment tumor disease drug is unit preparation.
9. application according to claim 8, wherein in the drug of the unit formulation comprising 1-5 milligram as it is active at
The quinoid chalcone compound and a effective amount of interferon of oncotherapy divided.
10. application according to claim 9, wherein include 1 × 10 in the drug of the unit formulation7~4 × 107U's
Interferon.
11. application according to claim 1-6, wherein the treatment tumor disease drug be include clinical anti-
The formulation compositions of tumour medicine and the quinoid chalcone compound.
12. application according to claim 11, wherein the clinical antitumor agents include anti-tumor vaccine or chemotherapeutic
Object.
13. a kind of formulation compositions of anti-tumor drug, therapeutic activity ingredient therein includes in interferon and claims 1 or 2
The quinoid chalcone compound of record.
14. formulation compositions according to claim 13, wherein the pharmaceutical agent combinations are unit preparation.
15. formulation compositions according to claim 14, wherein in the unit formulation comprising 1-5 milligram as it is active at
The quinoid chalcone compound and a effective amount of interferon of oncotherapy divided.
16. formulation compositions according to claim 15, wherein include 1 × 10 in the unit formulation7~4 × 107U's is dry
Disturb element.
17. formulation compositions described in 3-16 according to claim 1, the interferon is selected from interferon beta or interferon gamma.
18. a kind of formulation compositions of anti-tumor drug, therapeutic activity ingredient therein includes that quinoid as claimed in claim 1 or 2 is looked into
That ketone compound and clinical antitumor agents.
19. formulation compositions according to claim 18, wherein the clinical antitumor agents include anti-tumor vaccine or change
Treat drug.
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