CN107441075A - A kind of antineoplastic combination medicine and its purposes in cancer therapy drug is prepared - Google Patents
A kind of antineoplastic combination medicine and its purposes in cancer therapy drug is prepared Download PDFInfo
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Abstract
The invention discloses a kind of antineoplastic combination medicine and its purposes in cancer therapy drug is prepared, the combination medicine includes the first preparation and the second preparation, the antineoplastic combination is calculated by weight as 10 40 parts of the first preparation, the second 2 40 parts of preparation with medicine.The invention also discloses purposes of the chlorogenic acid in cancer therapy drug toxic side effect inhibitor is prepared, the cancer therapy drug is the medicine using EGFR as target spot.It is the medicine of target spot in non-small cell carcinoma that technical scheme of the present invention, which can be improved using EGFR, breast cancer, the targeting in glioblastoma, nasopharyngeal carcinoma, reduces its toxic side effect, and reverse the drug resistance using EGFR as the medicine of target spot.
Description
Technical field
The present invention relates to biomedicine field, specially a kind of antineoplastic combination medicine and its in cancer therapy drug is prepared
Purposes.
Background technology
The carboxylic phenolic acid that chlorogenic acid is made up of caffeic acid (Caffeic acid) and chinic acid (Quinicacid).Chlorogenic acid
With extensive pharmacological action, including the bioactivity such as anti-oxidant, anti-inflammation, suppression tumour, hepatic cholagogic, promoting blood circulation decompression.
EGFR (EGF-R ELISA) (erbB-1/HER1) is a member in HER families, the other three member
It is：ErbB-2 (HER2/neu), erbB-3 (HER3) and erbB-4 (HER4).EGFR belongs to Receptor type tyrosine protein kinase
(RTK), have in the kinds of tumors such as non-small cell lung cancer, breast cancer, colorectal cancer, head and neck cancer, stomach cancer, oophoroma, and cancer of pancreas
It is overexpressed or unconventionality expression, generation, development with tumour has substantial connection.EGFR activation can be divided into 3 steps：(1) EGFR with
Acceptor can be caused to form homodimer after ligand binding, also can form heterodimer with other EGFR families；(2) dimerization
Acceptor crosslink phosphorylation, i.e. specific tyrosine residue phosphorylation on an acceptor and another acceptor, activate intracellular
The TK subprovinces in area, so as to excite next stage signal transduction.Cell cycle evolution is ultimately resulted in, apoptosis capacity declines and occurred
Metastatic phenotype etc..
EGFR paths are considered as having played important function in epithelial malignancy evolution and progression, thus can conduct
One potential target spot of systemic treatment and suppressing epidermal growth factor recipient tyrosine kinase then turns into treatment one of tumour
Study hotspot.Common medicine is at present：
1. tyrosine kinase inhibitor.EGFR tyrosine kinase inhibitors can be divided into two major classes：One kind is non-specific junket
Histidine kinase inhibitor, all EGFR-TKs can be suppressed；Another kind of is to use more selective EGFR tyrosine at present
Kinase inhibitor, such as in Gefitinib (Iressa), Tarceva (Erlotinib) and the Conmana (Kai Mei of China's listing
Receive) etc..But it has now been found that nearly all patient is transformed into resistant tumors in receive such drug therapy 10 months
Patient, finally past medical help and lose life, also, such medicine is because targeting deficiency, it may have toxic side effect is significantly asked
Topic.
2, monoclonal antibody.Combined with EGFR, competition and the combination for blocking the parts such as EGF, TGF-α, reach and suppress tumour life
The purpose of length.Occurs the small-molecule drug of many targeting EGFRs in recent years, wherein with Buddhist nun's trastuzumab, Victibix, western appropriate former times
Monoclonal antibody etc. has been successfully applied to the therapeutic trial of clinical tumor for the monoclonal antibody class drug moiety of representative, but such equally has
With the problem of targeting deficiency, toxic side effect is notable.
The content of the invention
In view of this, the present invention provides a kind of antineoplastic combination medicine and its purposes in cancer therapy drug is prepared, this
Invention additionally provides a kind of purposes of chlorogenic acid in cancer therapy drug toxic side effect inhibitor is prepared, the cancer therapy drug be with
EGFR is the medicine of target spot.Technical scheme can solve poor as the drug selectivity of target spot using EGFR, produce each
Kind of toxic side effect, the defects of producing drug resistance, the targeting using EGFR as the medicine of target spot is improved, reduces toxic side effect, is reversed
Its drug resistance, improve patient compliance.
To solve above technical problem, technical solution of the present invention be a kind of antineoplastic combination medicine, including chlorogenic acid with
The first preparation that the carrier of pharmaceutical acceptable is formed, and formed by the medicine of target spot and the carrier of pharmaceutical acceptable of EGFR
The second preparation.
Preferably, described first preparation 10-40 parts, described second preparation 2-40 parts.
Preferably, the medicine using EGFR as target spot is included in EGFR tyrosine kinase inhibitors, anti-EGFR antibody
It is one or more.
Preferably, the EGFR tyrosine kinase inhibitors replace including Gefitinib, Tarceva, Conmana, Ah method
Buddhist nun, Lapatinib.
Preferably, the anti-egfr antibodies include Cetuximab, Herceptin, Buddhist nun's trastuzumab, Victibix.
Preferably, according to above-mentioned combination medicine, the formulation of the preparation is injection or oral formulations.
The present invention also provides a kind of purposes of above-mentioned combination medicine in cancer therapy drug is prepared.
Preferably, the cancer includes non-small cell carcinoma, breast cancer, glioblastoma, nasopharyngeal carcinoma.
The present invention also provides a kind of purposes of chlorogenic acid in cancer therapy drug toxic side effect inhibitor is prepared.
Preferably, the cancer therapy drug is the medicine using EGFR as target spot.
It is main existing for the molecular targeted agents of current entity knurl from the point of view of EGFR molecular targeted agents clinical therapeutic efficacy
Problem is wanted to have:Toxic side effect is more, and independent medication effect is undesirable, and medicament-resistant mutation etc. easily occurs.How malicious pair is preferably reduced
Effect, optimize scheme of combination drug therapy, overcome resistance etc. to turn into molecular targeted agents urgent problem.
At present, substantial amounts of experiment proves that chlorogenic acid has the function that anti-mutagenesis and anticancer.Chlorogenic acid is as G6PT (grapes
Sugar -6- phosphotransferases) inhibitor, neutrophil leucocyte and promyelocyte HL-60 apoptosis can be started, suppression
Metallothionein (MMP) secretion of people Hep3B liver cancer cells processed, suppresses the migration of glioma..Chlorogenic acid to using EGFR as
The sensitization of the medicine of target spot may be relevant with above-mentioned mechanism.Secondly a certain amount of activity hydroxy is contained in chlorogenic acid molecule,
The hydroperoxyl radical with antioxidation can be formed, the activity of the free radicals such as hydroxyl radical free radical and superoxide anion can be eliminated,
Damage of the protective tissue from oxidation.In addition, chlorogenic acid is intrinsic to intraepithelial lymphocyte (IEL) supernatant and enteron aisle
NF- γ and the horizontal influence of TNF-α are larger in layer lymphocyte (LPL) supernatant.In vitro study shows that chlorogenic acid can induce people
Lymphocyte and human peripheral leucocytes generation IFN- γ and IFN-α, these effects may also in this application can with chlorogenic acid
Reduce relevant as the toxic side effect of the medicine of target spot using EGFR.
Resistance on patient to EGFR-TKI (EGF-R ELISA-tyrosine kinase inhibitor), clinic are divided into
Primary drug resistance and secondary resistance.Primary drug resistance is that patient is reactionless to being treated first using TKI, in symptom improvement, disease
Stove control and life span etc. do not obtain obvious benefit.About 25% is invalid to TKI treatments in the tumor patient of EGFR mutation,
This may be related to TKI primary drug resistances.Its reason mainly includes:Dashed forward 1. existing and being mutated other simultaneous EGFR with susceptibility
Become, the factor of the presence, 4. patient itself of other gene mutations, 3. RAS gene mutations for influenceing EGFR downstream signals 2. be present,
Such as immunologic hypofunction, decline of metabolic rapid deactivation, and absorbability etc..EGFR-TKI acquired resistances and two
This 2 kinds of mechanism of the secondary theory of mutation and Met gene magnifications are relevant, and other resistance mechanisms are probably due to the influence of patient itself
Factor (as smoking whether, sex, ethnic group and histological type etc.) it is different caused by.Chlorogenic acid in the present invention, has reversed EGFR
The drug resistance of TYR kinase inhibitor, its mechanism may be related to all kinds of reasons of above-mentioned generation drug resistance, and specific mechanism has
Treat further to study.
Brief description of the drawings
Fig. 1, Proliferation Ability of the chlorogenic acid to PC9 cell lines
Fig. 2, Proliferation Ability of the chlorogenic acid to PC9/ZD cell lines
Embodiment
In order that those skilled in the art more fully understands the technical scheme of invention, with reference to embodiment pair
The present invention is described in further detail.
EGFR is a member of the receptor subfamily of EGFR-TK I, other members of the family include HER2/
Neu, HER3 and HER4.Their acceptor forms by three parts:Extracellular ligand binding domain, by the single-stranded transmembrane region formed with
And the EGFR-TK area of intracellular.EGFR is constructive expression's composition of many normal epithelial tissues (such as skin and hair follicle),
The overexpression for having EGFR is found in many human tumors.The EGFR of activation is mainly relevant with signals below conduction path:Mitogen
Former activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) approach, start DNA replication dna, cause cell propagation and divide
Change, and mediate CLE to adjust the cell cycle；PI3K-Akt approach, suppress Apoptosis；Downstream VEGF is activated, promotes capillary network
Generation；Epithelial growth factor receptor-signal transduction and activating transcription factor 3 (EGFR-STAT3) approach, make STAT3 many swollen
Activated in knurl, adjust the activity of several genes, so as to participate in the generation of tumour, development and Apoptosis.EGFR signal transductions way
Footpath plays an important role in the propagation of tumour cell, injury repair, invasion and attack and new vessels formation etc., in recent years targeting EGFR
Medicine has turned into the focus of oncotherapy.
For EGFR tumor cells targeted drug, two major classes are broadly divided into by its property:One kind is monoclonal antibody, mesh
It is preceding listed in China have Cetuximab (cetuximab, erbitux), Victibix (panitumumab,
Vectibix), Buddhist nun's trastuzumab (nimotuzumab, nimotuzomab) etc.；Another kind of is micromolecular inhibitor (table 2), has been listed
Have Gefitinib (gefitinib, iressa), Tarceva (erlotinib, tarceva) and La Pafeini
(lapatinib, tykerb) etc..The mechanism of action of micromolecular inhibitor is different with monoclonal antibody, is mainly tied by competitiveness
The phosphorylation site of EGFR intracellular section EGFR-TKs is closed, blocks its interaction with ATP, then suppresses EGFR tyrosine
The a series of signal transduction of phosphorylation and downstream, therefore micromolecular inhibitor is not so good as monoclonal antibody in terms of specificity, can produce
A series of raw toxic side effects, wherein common adverse reactions include fash, diarrhoea, hepatic disorder, and rare adverse reaction includes
Interstitial lung lesion.
The mechanism of action of monoclonal antibody against EGFR is that they can be incorporated into EGFR extracellular receptor binding domains, so as to
The combination of natural part and acceptor in organism is prevented, and then prevents the activation of acceptor and the signal transmission of downstream signaling pathway.
Therefore biological effect caused by shows as Cyclin-dependent kinase, promotes Apoptosis, suppresses Tumor Angiongesis etc..But mesh
Document in terms of preceding existed system evaluation shows, such monoclonal antibody class medicine, shows in the targeted therapy of solid malignant patient
Work adds the occurrence risk of FAEs (mortality risk and adverse events).Toxicity is mainly manifested in skin and mucosa system, angiocarpy
System, hemopoietic system and gastrointestinal system etc..
Lung cancer epidermal growth factor receptor (epidermal growth factor receptor, EGFR) mutation is main
Occur in intracellular section encoding domain (exons 1 8-21), include the deletion mutation (delE746-A750) and outside of exons 19
21 point mutation of aobvious son (L858R), both account for more than the 90% of all EGFR kinase mutants, and to EGF-R ELISA-junket
The sensitiveness of histidine kinase inhibitor (EGFR tyrosine kinase inhibitors, EGFR-TKI) is relevant；In addition, also
There are the point mutation of exons 18 (G719S) and extron 20 insertion mutation, the former belongs to EGFR-TKI sensitizing mutation and the latter
Relevant with EGFR-TKI resistance, incidence is 5% or so.Under normal circumstances, the NSCLC patient of EGFR mutation is to TKI's
Treatment is more sensitive.EGFR-TKIs blocks EGFR molecules by being combined extracellular ligand binding site with ATP or substrate competitive
The activation of the autophosphorylation and EGFR-TK of interior tyrosine, suppresses that EGFR is homologous or formation with ERBB3 heterodimers,
So as to suppress EGFR activation, downstream signal transduction is prevented, suppresses cell cycle progression, accelerates Apoptosis, suppresses angiogenesis
And transfer.But in clinical position, treatment of many patients to EGFR-TKI is simultaneously insensitive, or in treatment a period of time
After produce resistance.Its resistance mechanism mainly includes primary drug resistance and acquired resistance.Primary drug resistance refers to use first
EGFR-TKI produces resistance, and the about resistance of 60%NSCLC patient is TKI primary drug resistances.Wherein, EGFR gene activated mutant
Person has nearly 30% pair of TKI initial drug-resistant.Although in addition, Gefitinib and Tarceva can in the NSCLC patient of EGFR mutation
To play the effect of fine, but most of patient treatment -12 months 6 months in acquired resistance can occur.
In order to solve the drug resistance and toxic side effect of the small analysis TYR kinase inhibitors of above-mentioned EGFR, and anti-EGFR
Monoclonal antibody target deficiency, the defects of producing toxic side effect, shown with reference to chlorogenic acid in the multiple systems of human body beneficial
Effect, the application is creative to combine the two, generates unexpected technique effect.
The invention discloses a kind of antineoplastic combination medicine and its purposes in cancer therapy drug is prepared, the joint is used
Medicine includes the first preparation and the second preparation, and the antineoplastic combination is calculated by weight as the first preparation 10-40 with medicine
Part, preferably 10-30 parts, are more highly preferred to 10-20 parts, preferably second preparation 2-40 parts, 5-30 parts, the 10-20 parts being more highly preferred to.This
Invention also discloses purposes of the chlorogenic acid in cancer therapy drug toxic side effect inhibitor is prepared, the cancer therapy drug be using EGFR as
The medicine of target spot.
Test result indicates that chlorogenic acid can reduce Tarceva, Conmana, Gefitinib, Afatinib, toltrazuril list
Anti-, Lapatinib, Buddhist nun's trastuzumab, Cetuximab to the normal nasal epithelia of people, the normal pulmonary epithelial cells of people and people just
The toxicity of normal mammary glandular cell, improves the targeting of such medicine, can reduce using EGFR as the medicine of target spot to a certain extent
Toxic side effect.
And in testing, chlorogenic acid and Tarceva, Conmana, Gefitinib, Afatinib, Herceptin, La Pa
When being united and applied in tumour cell for Buddhist nun, Buddhist nun's trastuzumab, Cetuximab etc., obvious synergistic function is generated, is reached
The effect of enhanced sensitivity to tumour cell is arrived.
Results of animal is also shown that chlorogenic acid is combined with Afatinib, Tarceva, Victibix, Buddhist nun's trastuzumab
Using when, to G422 glioma BABLC mouse and Lewis lung cancer C57BL/6 mouse, do not only reached synergistic function,
The toxic side effect of Afatinib, Tarceva, Victibix and Buddhist nun's trastuzumab is also reduced simultaneously.
When experimental result of the present invention is also shown that chlorogenic acid is united and applied in people's lung tumors cell with Gefitinib, hence it is evident that
The drug resistance of Gefitinib is reversed.
In summary, it is the medicine of target spot in non-small cell carcinoma, mammary gland that technical scheme of the present invention, which can be improved using EGFR,
Cancer, glioblastoma, the targeting of nasopharyngeal carcinoma, its toxic side effect is reduced, and reversed using EGFR as the resistance to of the medicine of target spot
The property of medicine.
It is below the embodiment of the invention above is to the labor of the content of the invention.
The influence of the independent medication of embodiment 1 and drug combination to different normal cell strains
1.1 materials and instrument
Tested medicine：Chlorogenic acid, Tarceva, Gefitinib, Conmana, Afatinib, Herceptin, drawing pa replace
Buddhist nun, Buddhist nun's trastuzumab, Cetuximab.
Subject cell strain：Human lung carcinoma cell line A549, Human breast cancer cell line MDA- MB-453, human nasopharyngeal carcinoma cell line
CNE-1, the normal pulmonary epithelial cells BEAS-2B of people, people's normal breast cell MCF10A, the normal nasal epithelia of people
RPMI2650。
1.2 experimental method
Take the logarithm one bottle of growth period cell, PBS is washed 2 times, 0.25% Trypsin Induced, with containing 10% calf serum
RPMI-1640 nutrient solutions are made into single cell suspension counting.96 well culture plates are inoculated under aseptic condition, inoculating cell number is 5
×l03/ hole.Cell is in 37 DEG C, 5%CO2Culture medium is changed after being incubated 24h respectively in incubator.
Cell is divided into, negative control group, medicine independent medication group, chlorogenic acid group and the drug combination that EGFR is targeting
Group, blank control group not inoculating cell.Each hole nutrient solution and medicine total amount are 200 μ l, and each concentration sets 3 multiple holes, and with
Isometric nutrient solution alternatives to medication is as blank control.Continue to put 5%CO2Continue to cultivate in 37 DEG C of incubators of saturated humidity.48h
Afterwards, it is that the μ l of 5mg/ml MTT 20 continue after cultivating 4h that concentration is added per hole, and careful inhale abandons liquid in hole, adds 150 μ l dimethyl sub-
Maple dissolving precipitation, fully vibrates 10min, dissolving crystallized thing.570nm wavelength is selected, each hole is determined on enzyme-linked immunosorbent assay instrument
Absorbance value, result is recorded, calculate inhibiting rate and association index.Experiment is at least repeated 3 times above.
1.3 data processing
(1) inhibiting rate=(1-OD570 (experimental group-blank group)/OD570 (control group-blank group)) * 100%.
(2) drug combination calculates whether there is synergy with formula Q=E (a+b)/(Ea+Eb-Ea × Eb).Wherein E (a+b)
The inhibiting rate shared for two medicines, i.e. actual measurement merging effect, Ea and the inhibiting rate that Eb was two prescription used times, denominator (Ea+Eb-Ea ×
Eb) it is expected to merge effect, Q is both ratios.For Q values at 0.85~1.15, two medicines merge effect to be added (+), and Q values exist
It is collaboration (++) when 1.15~20, Q values ＞ 20 is substantially cooperates with (+++), and Q values are antagonism at 0.05~0.85, Q values ＜
0.05 is obvious antagonism
1.4 experimental result
1.4.1 the influence of independent medication and drug combination to different normal cell strains
Influence of the independent medication of table 1 to different normal cell strains
Influence of the drug combination of table 2 to different normal cell strains
Experimental result is shown, in the normal pulmonary epithelial cells BEAS-2B of people, people's normal breast cell MCF10A, the normal nose of people
Chamber epithelial cell RPMI2650 suppresses in experiment, and when chlorogenic acid (20 μ g/ml) is used alone, IC50 values are respectively 1238.1ug/
Ml, 1352.6ug/ml, 1054.4ug/ml, illustrate that chlorogenic acid is non-toxic to normal cell line in itself.It is thin in the normal lung epithelial of people
Born of the same parents BEAS-2B suppress experiment in, chlorogenic acid (20 μ g/ml) respectively with Tarceva, Conmana, Gefitinib, Afatinib
IC50 values when drug combination IC50 values are above being used alone, illustrate that chlorogenic acid can reduce Tarceva, Conmana, Ji Fei
For the toxicity of Buddhist nun, Afatinib pulmonary epithelial cells BEAS-2B normal to people, the targeting of such medicine is improved to a certain extent.
People's normal breast cell MCF10A suppress experiment in, chlorogenic acid (20 μ g/ml) respectively with Herceptin, the connection of Lapatinib
IC50 values when medicine IC50 values are above being used alone are shared, illustrate that chlorogenic acid can reduce Herceptin, Lapatinib to people
Normal breast cell MCF10A toxicity, the targeting of two kinds of medicines is improved to a certain extent.It is thin in the normal nasal epithelial of people
Born of the same parents RPMI2650 suppresses in experiment, chlorogenic acid (20 μ g/ml) respectively with Herceptin, Buddhist nun's trastuzumab, Cetuximab
Drug combination IC50 values be above be used alone when IC50 values, illustrate chlorogenic acid can reduce Herceptin, Buddhist nun's trastuzumab,
Cetuximab nasal epithelia RPMI2650 normal to people toxicity, the target of time three kinds of monoclonal antibody medicines is improved to a certain extent
Tropism.Above-mentioned experimental data illustrates that chlorogenic acid can reduce the toxic side effect using EGFR as the medicine of target spot, improves to a certain extent
Its targeting.
1.4.2 the influence of independent medication and drug combination to different tumor cell lines
Influence of the independent medication of table 3 to different tumor cell lines
The EGFR of table 4 is the medicine and chlorogenic acid drug combination targetted to human lung carcinoma cell line A549 inhibitory action
As a result show, human lung carcinoma cell line A549 is suppressed to make with chlorogenic acid drug combination in the medicine using EGFR as target spot
With in experiment, the Q values of 11uM Tarcevas and 10-50 μ g/ml chlorogenic acid drug combinations merge effect in 1.15~20, two medicines and are
Cooperate with (++)；The Q values of 5uM Conmanas and 10-50 μ g/ml chlorogenic acid drug combinations merge effect in 1.15~20, two medicines and are
Cooperate with (++)；The Q values of 20uM Gefitinibs and 10-50 μ g/ml chlorogenic acid drug combinations merge effect in 1.15~20, two medicines and are
Cooperate with (++)；3uM Afatinibs and the Q values of 10-50 μ g/ml chlorogenic acid drug combinations merge effect in 1.15~20, two medicines and are
Cooperate with (++).
Medicine of the table 5 using EGFR as target spot suppresses with chlorogenic acid drug combination to Human breast cancer cell line MDA- MB-453
Effect
As a result show, using medicine and the chlorogenic acid drug combination that EGFR is target spot to Breast cancer lines MDA-MB-
In the experiment of 453 inhibitory action, the Q values of 50uM Herceptins and 10-50 μ g/ml chlorogenic acid drug combinations are 1.15~20, two
Medicine merges effect for collaboration (++)；The Q values of 4uM Lapatinibs and 10-50 μ g/ml chlorogenic acid drug combinations are 1.15~20, two
Medicine merges effect for collaboration (++).
Table 6 is using medicine and the chlorogenic acid drug combination that EGFR is target spot to human nasopharyngeal carcinoma cell line CNE-1 inhibitory action
As a result show, human nasopharyngeal carcinoma cell line CNE-1 is pressed down with chlorogenic acid drug combination in the medicine using EGFR as target spot
In Experiment on Function processed, the Q values of 75uM Herceptins and 10-50 μ g/ml chlorogenic acid drug combinations are closed in 1.15~20, two medicines
And effect is collaboration (++)；The Q values of 100uM Buddhist nun's trastuzumab and 10-50 μ g/ml chlorogenic acid drug combinations are 1.15~20, two
Medicine merges effect for collaboration (++)；The Q values of 55uM Cetuximabs and 10-50 μ g/ml chlorogenic acid drug combinations 1.15~
20, two medicines merge effect for collaboration (++).
The chlorogenic acid of embodiment 2 reverses drug resistances of the human lung adenocarcinoma cell PC9 to Gefitinib in vitro
2.1 materials and instrument
Tested medicine：Chlorogenic acid；Gefitinib
Subject cell strain：PC9 cells, PC9/ZD are from the sieve cell line of resistance to Gefitinib
2.2 experimental method
2.2.1 the cultivation of drug-resistant cell strain
Lu-csf-1's PC9 cells, PC9 cells are respectively exposed to Gefitinib (200nmol/L) up to 3
Month, picking out the cell clone of resistance to Gefitinib turns into PC9/ZD cell lines.This two kinds of cells have to Gefitinib respectively
The ability of stable resistance.PC9 cells, PC9/ZD cells distinguish adherent growth in 25cm2In blake bottle, with containing 10% tire ox blood
Clear DMEM medium cultures, put 5%CO2, be incubated in 37 DEG C of incubators.Observation cell daily, cell growth covering bottom of bottle
Passed on 1 time by 1: 3 passage, average 3-4d during 70%-80%, ensure that cell viability provides.2.2.2 Gefitinib is detected to thin
Born of the same parents' strain and the IC50 of persister, calculate resistance multiple
Take the logarithm growth period PC9 cell and drug-resistant cell strain, digested and centrifuged with 0.25% trypsase+0.02%EDTA,
It is 5 × 10 to adjust cell concentration4Individual/ml, 96 orifice plates, 5%CO are inoculated in by every μ l/5000 cells of hole 1002, 37 DEG C be incubated
Original fluid is sucked after 24h, the DMEM nutrient solutions of the Gefitinib containing various concentrations is added per the μ l of hole 100, distinguishes its final concentration
For 0,0.1,0.2,0.5,1,5,10 μM, a not celliferous blank well is separately set, is placed in 5%CO2, 37 DEG C of incubators be incubated 48h
5mg/ml MTT20 μ l are added per hole afterwards, continues to be incubated 4h, sucks upper liquid, DMSO150 μ l are added per hole, stand 30min, treat hole
Bottom tan crystals are completely dissolved.With each hole light absorption value OD values at ELIASA detection 570nm, resistance multiple is calculated by formula.Resistance
Multiple=mdr cell IC50 values/sensitive cells IC50 values.
2.2.3 the chlorogenic acid concentration of mtt assay measure acellular poison
PC9 cells and mdr cell culture and processing method are same as above.Experiment is respectively classified into 3 groups：Blank group, control group and reality
Test group.Blank group only adds DMEM culture mediums, without inoculating cell；Control group adds culture medium and inoculating cell；Experimental group is upper
The chlorogenic acid working solution of various concentrations is added on the basis of stating, it is respectively 1,2,4,8,16,32,64,128 μ to make its ultimate density
G/mL, it is placed in after incubator is incubated 48h and 5mg/ml MTT20 μ l is added per hole, continue to be incubated 4h, suck upper liquid, added per hole
DMSO150 μ l, 30min is stood, it is to be crystallized to be completely dissolved.With each hole light absorption value OD values at ELIASA detection 570nm, tumour is calculated
Inhibitory rate of cell growth.Inhibiting rate=(1-OD570 (experimental group-blank group)/OD570 (control group-blank group)) × 100%,
The chlorogenic acid concentration of inhibiting rate concentration below 10% is taken as the reverse concentration of non-toxic.
2.2.4 acellular poison concentration chlorogenic acid reverses human lung adenocarcinoma persister PC9/ZD effect
Cell culture and experimental method are same as above.Experiment packet is as follows：PC9/ZD groups, the μ g/ml of PC9/ZD+ chlorogenic acids 8
Group, the μ g/ml groups of PC9/ZD+ chlorogenic acids 16, experimental group, which is separately added into Gefitinib, makes final concentration of 0.1,0.2,0.5,1,5,10
μm ol/L, each multiple holes of concentration 3, determine the OD values in each hole, observation no cytotoxicity chlorogenic acid (5 μ g/ml, 10 μ g/ml) joint
After Gefitinib acts on PC9/ZD, change of the Gefitinib to PC9/ZD killing functions of immunocytes, Gefitinib is calculated to people's lung
Gland cancer PC9/ZD IC50.IC50 values after IC50 values/reverse before reversal index=reverse.
2.3 experimental result
2.3.1 Gefitinib to PC9 and PC9/ZD IC50 Gefitinibs to human lung adenocarcinoma sensitive cells PC9 and resistance
Cell PC9/ZD IC50 is respectively 0.21 μm of ol/L and 5.45 μm of ol/L.Resistance multiple is calculated as 25.9 by formula.
IC50 and resistance multiple of the Gefitinib of table 7 to human lung adenocarcinoma sensitive cells PC9 and mdr cell PC9/ZD
2.3.2MTT the chlorogenic acid concentration result of method measure acellular poison
Chlorogenic acid has Inhibit proliferaton effect to human lung adenocarcinoma sensitive cells PC9 and mdr cell PC9/ZD, and IC50 is
190ug/ml.It is equal to human lung adenocarcinoma PC9 and mdr cell PC9/ZD inhibiting rate when chlorogenic acid concentration is less than 16 μ g/ml
<10%, without cytotoxicity, as a result as shown in Figures 1 and 2.
2.3.3 reverse effect of the chlorogenic acid to human lung adenocarcinoma mdr cell PC9/ZD
Chlorogenic acid acellular poison concentration (8 μ g/ml, 16 μ g/ml) joint Gefitinib acts on human lung adenocarcinoma mdr cell
After PC9/ZD, Gefitinib reduces to PC9/ZD IC50.When 8 μ g/ml chlorogenic acids are as reversal agent, Gefitinib is to PC9/
ZD IC50 is 3.25, and reversal index 1.67, during using 16 μ g/ml chlorogenic acids as reversal agent, Gefitinib is to PC9/ZD's
IC50 is 2.03, reversal index 2.68.
Reverse effect of the chlorogenic acid of table 8 to human lung adenocarcinoma mdr cell PC9/ZD
Embodiment 2 shows, when chlorogenic acid joint Gefitinib is applied to human lung adenocarcinoma mdr cell PC9/ZD, can reverse
The drug resistance of Gefitinib.
The chlorogenic acid of embodiment 3 and the Synergy and attenuation of the medication combined tumor suppression in vivo with EGFR target spots act on
3.1 materials and instrument
Tested medicine：Chlorogenic acid；Afatinib, Tarceva, Victibix, Buddhist nun's trastuzumab
Subject cell strain:G422 cells, Lewis murine lung cancer cell strains
Animal subject：BABLc mouse, C57BL/6 mouse
3.2 experimental method
3.2.1 the foundation of experimental animal tumor models
Exponential phase cell is collected, 1000rpm centrifugation 5min, cell is heavy to be washed 2 times with PBS, and serum-free is used after counting
Nutrient solution adjustment cell concentration is 1x107/ m1, animal housing is sent under aseptic condition.Under the conditions of aseptic experiment, right side of mice armpit
1x10 is subcutaneously injected in nest7There is obvious skin mound in/m1 cell, every 0.1ml, injection site, go out after 1 week on the left of nude mice at armpit
Existing grain of rice major tubercle, illustrates that transplantation model is successfully established, is now divided into 6 groups according to randomized blocks.
BABLc mouse G422 glioma transplantable tumors are grouped into：1st, physiological saline group (NS groups)；2nd, Buddhist nun's trastuzumab group；
3rd, chlorogenic acid group；4th, Victibix group；5th, chlorogenic acid+Buddhist nun's trastuzumab group；6th, chlorogenic acid+Victibix group, every group each 5.
C57BL/6 Mice Bearing Lewis Lung Cancers are grouped into：7th, physiological saline group (NS groups)；8th, Afatinib group；9th, chlorogenic acid
Group；10th, Tarceva group；11st, chlorogenic acid+Afatinib group；12nd, chlorogenic acid+Tarceva group, every group 5
3.2.2 medication
Treat that tumor average diameter reaches 100mm3After start to treat, daily intraperitoneal injection once, saline control group is given
0.2ml sterile salines.
3.2.3 antitumor action is evaluated
The weight of animals is surveyed daily after observation administration；Treat that negative group knurl volume is about 0.5cm3When stop experiment, eyeball excise
Hematometry WBC, HBC and HGB content is taken, de- cervical vertebra is put to death mouse and weighed, and strips tumour and weighs.
Tumour inhibiting rate=(control group knurl weight-experimental group knurl weight)/control group knurl weight x 100%.
Two medicines merge Q=E (a+b)/(Ea+Eb-Ea × Eb), and wherein E (a+b) is the inhibiting rate that two medicines share, that is, is surveyed
Merge effect, Ea and the inhibiting rate that Eb was two prescription used times, for denominator (Ea+Eb-Ea × Eb) it is expected to merge effect, Q is both
Ratio.For Q values at 0.85~1.15, two medicines merge effect to be added (+), and Q values are collaboration (++), Q values ＞ at 1.15~20
20 be obvious collaboration (+++), and Q values are antagonism at 0.05~0.85, and Q values ＜ 0.05 is obvious antagonism.
3.2.4 statistical analysis
Experimental data is handled with the statistical softwares of SPSS 17.0, all data with mean scholar standard deviation (mean ±
SD) represent.Compare between group and statistical procedures, P are carried out using one-way analysis of variance<0.05 thinks variant, P<0.01 thinks
There is significant difference.
3.3 experimental result
Tumour inhibiting rate of the chlorogenic acid of table 9 to G422 glioma BABLC mice-transplanted tumors
Note：* the P ＜ 0.01 compared with chlorogenic acid group, ## the , ＆＆ of P ＜ 0.01 P ＜ compared with pa Buddhist nun's group compared with the appropriate pearl group of Buddhist nun
0.01
As shown in table 9, chlorogenic acid 10mg/kg, Buddhist nun trastuzumab 20mg/kg, and Victibix 20mg/kg is to G422
Glioma transplantable tumor has weaker inhibitory action, and there was no significant difference compared with physiological saline group.But chlorogenic acid and the appropriate pearl of Buddhist nun
Monoclonal antibody, and chlorogenic acid have preferable tumour inhibiting rate with Victibix combination, there is significant difference compared with alone.Drug combination Q
Value result of calculation shows that chlorogenic acid has cooperative effect with Victibix and the combination of Buddhist nun's trastuzumab.
Tumour inhibiting rate of the chlorogenic acid of table 10 to Lewis lung cancer C57BL/6 mice-transplanted tumors
Note：* the P ＜ 0.01 compared with chlorogenic acid group, ## the , ＆＆ of P ＜ 0.01 and Tarceva group ratio compared with Afatinib group
Compared with P ＜ 0.01
As shown in table 10, chlorogenic acid and Afatinib, and chlorogenic acid have preferable tumour inhibiting rate with Tarceva combination, with
Alone compare has significant difference.Drug combination Q value result of calculations show that chlorogenic acid is combined with Afatinib and Tarceva
There is cooperative effect.
The influence to mouse blood routine of 3.4 drug combinations
Influence of the drug combination of table 11 to G422 glioma BABLC mouse blood routines
The * p ＜ 0.05 compared with negative group, * * p ＜ 0.01；The △ p ＜ 0.05 compared with positive group, △ △ p ＜ 0.01
Influence of the drug combination of table 12 to Lewis lung cancer C57BL/6 mouse blood routines
The * p ＜ 0.05 compared with negative group, * * p ＜ 0.01；The △ p ＜ 0.05 compared with positive group, △ △ p ＜ 0.01
As a result show：Chlorogenic acid (10mg/kg), can significantly improve G422 gliomas mouse using Buddhist nun's trastuzumab,
After Victibix in blood routine WBC, RBC, HGB reduction phenomenon；In addition, Afatinib, E Luo are used to Lewis lung cancer in mice
For in blood routine after Buddhist nun WBC, RBC, HGB reduce phenomenon also be improved significantly, leucocyte numeration increase, illustrate chlorogenic acid
Bone marrow inhibition caused by VEGF pathway inhibitors can be alleviated, the increase of blood platelet counts can reduce hemorrhagic adverse reaction
Occur, while hemoglobin increase can prevent the generation of anaemia and anaemia correlation adverse reaction, show chlorogenic acid from all multi-party
Face reduces the toxic side effect using EGFR as the medicine of target spot.
It the above is only the preferred embodiment of the present invention, it is noted that above-mentioned preferred embodiment is not construed as pair
The limitation of the present invention, protection scope of the present invention should be defined by claim limited range.For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, some improvements and modifications can also be made, these change
Enter and retouch and also should be regarded as protection scope of the present invention.
Claims (10)
- A kind of 1. antineoplastic combination medicine, it is characterised in that the formed including the carrier of chlorogenic acid and pharmaceutical acceptable One preparation, and the second preparation formed using EGFR as the medicine of target spot and the carrier of pharmaceutical acceptable.
- 2. combination medicine according to claim 1, it is characterised in that described first preparation 10-40 parts, second system Agent 2-40 parts.
- 3. combination medicine according to claim 2, it is characterised in that the medicine using EGFR as target spot includes EGFR One or more in tyrosine kinase inhibitor, anti-egfr antibodies.
- 4. combination medicine according to claim 3, it is characterised in that the EGFR tyrosine kinase inhibitors include Ji It is non-to replace Buddhist nun, Tarceva, Conmana, Afatinib, Lapatinib.
- 5. combination medicine according to claim 4, it is characterised in that the anti-egfr antibodies include Cetuximab, Herceptin, Buddhist nun's trastuzumab, Victibix.
- 6. according to the combination medicine described in claim 1-5 any one, it is characterised in that the formulation of the preparation is injection Agent or oral formulations.
- A kind of 7. purposes of the combination medicine described in claim 1 in cancer therapy drug is prepared.
- 8. purposes according to claim 7, it is characterised in that the cancer includes non-small cell carcinoma, breast cancer, pernicious god Through glioma, nasopharyngeal carcinoma.
- A kind of 9. purposes of chlorogenic acid in cancer therapy drug toxic side effect inhibitor is prepared.
- 10. purposes according to claim 9, it is characterised in that the cancer therapy drug is the medicine using EGFR as target spot.
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| WO2015070038A1 (en) * | 2013-11-11 | 2015-05-14 | University Hospitals Cleveland Medical Center | Targeted treatment of anerobic cancer |
| CN104758277A (en) * | 2015-03-06 | 2015-07-08 | 刘晓梅 | Uses of chlorogenic acid in preparation of drugs treating multidrug resistance of cancer |
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| CN104758277A (en) * | 2015-03-06 | 2015-07-08 | 刘晓梅 | Uses of chlorogenic acid in preparation of drugs treating multidrug resistance of cancer |
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