CN105476996B - The purposes of curcumin and Afatinib therapeutic alliance non-small cell lung cancer - Google Patents
The purposes of curcumin and Afatinib therapeutic alliance non-small cell lung cancer Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
Abstract
The present invention relates to field of medicaments, and in particular to curcumin replaces the purposes of the non-small cell lung cancer of Buddhist nun's resistance with Afatinib and its purposes of pharmaceutically acceptable salt therapeutic alliance non-small cell lung cancer, especially therapeutic alliance to Gefitinib and network in distress.
Description
Technical field
The present invention relates to field of medicaments, and in particular to curcumin is combined with Afatinib and its pharmaceutically acceptable salt to be controlled
Treat the purposes of non-small cell lung cancer.
Background technology
Lung cancer be lung tissue inner cell growth it is out of hand caused by a kind of disease.In past over half a century,
The morbidity and mortality of lung cancer increase year by year, have been developed into from a kind of orphan disease of early 20th century current global No.1
Cancer killer.The data periodically announced according to the World Health Organization (WHO), the morbidity and mortality of lung cancer are outstanding in countries in the world
It is that developed country is in obvious ascendant trend, has become the most common tumour of many developed countries, ranks the common evil of male
Property first, tumour and women common cancer second, and as the most common cause of death in malignant tumour.At me
State, the male lung cancer age standardization incidence of disease are 47.51/10 ten thousand, and the female lung cancer age standardization incidence of disease is 22.69/10 ten thousand,
And in increased trend year by year.Expect 2025, China, which is often only, to be died from the number of lung cancer and will just turn into close to 1,000,000
The first in the world lung cancer big country.
Protein tyrosine kinase (Protein Tyrosine Kinases, PTKs) is class protein enzyme, and they can
The phenolic hydroxyl group phosphorylation reaction on the tyrosine residue of a variety of key proteins is catalyzed, thus activates the biology of functional protein
Activity.Occupy highly important status in the signal transduction pathway of this process in the cell, it adjust cell growth in vivo,
A series of plysiochemical processes such as differentiation, death.Protein tyrosine kinase functional disturbance can trigger a series of diseases in organism
Disease.Research shows that the activation of cancer protogene more than half and oncogene is all related to protein tyrosine kinase, albumen junket ammonia
The unconventionality expression of acid kinase can cause cell propagation regulation to get muddled, and then cause tumour.In addition, EGFR-TK
Invasion and attack and transfer of the unconventionality expression also with tumour, tumor neovasculature generation, the chemotherapy resistance to the action of a drug of tumour are closely related.Junket ammonia
Acid kinase has become the critically important target spot of antineoplastic research and development.
EGF-R ELISA (Epidermal Growth Factor Receptor, EGFR) is a kind of acceptor junket ammonia
Pka acid, a kind of transmembrane protein belonged in erbB receptor families.EGFR has regulated and controled the propagation of cell, survival, adhesion, moves
The cells such as shifting and differentiation, its overactivity or continuous activation in kinds of tumor cells, such as lung cancer, breast cancer, prostate cancer
In.EGFR abnormal activation plays critical effect in the conversion and growth of tumour.Block EGFR activation clinical
Prove one of effective targeting therapy on tumor cellular processes.Non- compactness cell lung cancer (non-smalls of the EGFR 50%
Lung cancer, NSCLC) there is expression in case.This causes EGFR and its family member to turn into the main of NSCLC targeted therapies
Candidate.
The tyrosine kinase inhibitor (tyrosine kinase inhibitor, TKI) of small molecule be it is a kind of using EGFR as
The medicine of target spot, it suppresses the phosphorylation in the site to realize by the phosphorylation site in competitive binding EGFR-TK area
Block EGFR signal transductions.Gefitinib (gefitinib) and Tarceva (erlotinib) are EGFR first generation small molecules
Tyrosine kinase inhibitor, be mainly used in treat advanced NSCLC medicine.Clinical effectiveness shows Gefitinib or Tarceva
White man NSCLC and about 35% asian ancestry NSCLC patient to about 10% is effective in cure.
But clinical research show many patients quickly (12-14 month) just to these EGFR micromolecular inhibitor medicine
Thing generates the resistance to the action of a drug, i.e. acquired resistance, receives the trouble of tyrosine kinase inhibitor (TKI) treatment of first generation small molecule
Person is often due to forming TKI drug resistances and facing the predicament of recurrence.Residue (gatekeeperresidue) T790M that guards the gate is mutated
It is a catastrophe point in EGFR20 extrons, is to cause one of main mechanism of resistance.For the second of these EGFR mutation
Study for inhibitor and be successful recently.Afatinib (Afatinib) is EGFR and human epidermal growth factor receptor
Potent, the irreversible double inhibitor of body 2 (HER2) EGFR-TK.Other similar Mutiple Targets, high activity are irreversible
Inhibitor, for example, Canertinib (canertinib), replaces Buddhist nun (Dacomitinib) also just in later phase clinical experiment up to gram.This
A little new irreversible inhibitor of the second generation have very strong inhibitory action to the L858R and T790M EGFR being mutated, to lucky non-
The patient to have been developed immunity to drugs for Buddhist nun or Tarceva has the effect of notable.But these second generations EGFR mutant suppresses
Agent similarly has extremely strong inhibition to Wild type EGFR (WT-EGFR), and clinical research is verified to Wild type EGFR
Suppression can cause drug toxicity and side effect with most of patient, and fash or diarrhoea are for example shown as in human body.Due to
Second generation TYR kinases and preparation such as Afatinib etc. cause the clinical tolerance agent of medicine to the poor selectivity of EGFR mutant
Measure relatively low.As a result, under maximum tolerated dose, medicine can not reach valid density in vivo, thus to most resistance patients without
Effect.Overcome the Side effect of second generation EGFR inhibitor, must just reduce the suppression to Wild type EGFR (WT-EGFR)
Effect.
In addition, the first generation and second generation TKI are single as Treatment for Non-small Cell Lung drug target and resistance, no easily occur
The multiple genes or albumen of canceration can effectively be suppressed, and the problems such as toxic side effect is big, and make its offer limited effectiveness；Its valency in addition
Lattice are expensive, and huge financial burden is caused to patient and its family.Drug combination in the method for attenuation synergistic increasingly
Obtain people's accreditation and pay attention to, two or more medicines of reasonable employment difference mechanism of action, adverse reaction without superposition not only may be used
To play synergistic sensitization, and single medicine dosage can be reduced, reduce adverse reaction, improve tolerance.But medicine
It is improper to combine, and can pick up anti-, curative effect counteracting, decline, or even cause toxic side effect.Therefore, it is necessary to find effective medication combined
To solve the problems such as non-small cell lung cancer (NSCLC) therapy field resistance and big toxic side effect.
Curcumin is a kind of phenol pigment extracted from Chinese medicine turmeric stem, and research shows that it is a kind of safe and nontoxic
Antineoplastic, US National institute of oncology is more classified as the 3rd generation cancer chemoprevention medicine.The curcumin of broad sense is commonly referred to as
For curcumin, including curcumin, Demethoxycurcumin, Bisdemethoxycurcumin etc., and curcumin is wherein most important
Active component.When not making Special Statement below, sensu lato curcumin is referred to.A large amount of inside and outside experiments prove that curcumin can
To suppress the growth of kinds of tumor cells system, for example leukemia, the cancer of the brain, breast cancer, stomach cancer, liver cancer, cancer of pancreas, colon cancer, skin
Cancer etc..Every clinical data displays that curcumin has to familial form polyposis adenomatous, cancer of pancreas, Huppert's disease
Expected therapeutic action well.In addition, being found in turmeric extract for treating colon cancer, patient is fabulous to its tolerance and in big agent
Also toxicity is not shown during amount.
Aggarwal etc. claims the molecular basis of the antitumor action of curcumin to be all kinds of target spots of regulation and control, such as transcription factor, life
Long regulatory gene, adhesion molecule, apoptosis gene, angiogenesis regulatory gene and cell signaling molecule.Under curcumin energy
Adjust TNF-a contents and suppress NF-kb and AP-1 activity.The researchs such as Lata G.Menon claim curcumin to suppress tumour cell
Metalloproteinases in matrix, so as to effectively suppress the migration of tumour cell.Current research finds that curcumin can suppress aldose
Reductase (AR, aldosereductase).AR is in disease caused by the inflammation such as septicemia, uveitis, atherosclerosis
The effect of key is played, AR is over-expressed in the tumour cells such as liver cancer, colon cancer, breast cancer, oophoroma, and AR can start and add
Speed is induced the path of NF.KB (Nu-clearfactor-kB, endothelial cell transcription factor) activation by oxidative stress, produces series
Inflammatory reaction and tumor cell proliferation, apoptosis of tumor cells can be promoted by suppressing AR activity, be the new way of research and development antineoplastic
Footpath.As can be seen here, curcumin is a kind of very promising antineoplastic.But curcumin and tyrosine kinase inhibitor
(TKI) Afatinib therapeutic alliance non-small cell lung cancer (NSCLC) is there is not yet report.
The present inventor is by further investigation, it was found that curcumin and tyrosine kinase inhibitor (TKI) Afatinib and its
Pharmaceutically acceptable salt use in conjunction can be used for the treatment of EGFR sensitive mutant cancers, applies also for current EGFR-TKI and controls
The treatment of secondary resistance is produced in treatment；The dosage of Afatinib can be reduced by administering drug combinations simultaneously, so as to significantly
Toxic side effect caused by Afatinib is reduced, is to solve NSCLC resistances and the big ideal scheme of more side effects.
The content of the invention
Combined it is an object of the invention to provide one kind by curcumin with Afatinib or its pharmaceutically acceptable salt
Prepare the application in the medicine for the treatment of non-small cell lung cancer.
To achieve these goals, the technical scheme is that：
The curcumin of therapeutically effective amount is combined with the Afatinib of therapeutically effective amount or its pharmaceutically acceptable salt to be made
Application in the medicine of standby treatment non-small cell lung cancer, the joint includes curcumin and Afatinib or its is pharmaceutically acceptable
Salt be successively administered alone regardless of order, or curcumin and Afatinib or its pharmaceutically acceptable salt while be administered in the lump.
In some embodiments, the curcumin is compound with Afatinib or combining for its pharmaceutically acceptable salt
Packaged form.In some embodiments, the composite packaging includes (1) using curcumin as active component, and addition can pharmaceutically connect
Preparation that the auxiliary material or complementary composition received are prepared into and (2) using Afatinib or its pharmaceutically acceptable salt for it is active into
Point, add the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared into.Wherein, in some embodiments, it is above-mentioned
Preparation is oral formulations, and the formulation for being adapted to be administered orally includes tablet, paste, powder, decoction, pill, capsule etc..These systems
The curcumin or Afatinib and its pharmaceutically acceptable salt included in agent can be solid powder or particle；It is water-based or non-aqueous
Solution or suspension in property liquid；Water-In-Oil or oil-in-water emulsion etc..Above-mentioned formulation can be by curcumin or Afatinib
And its pharmaceutically acceptable salt is made with one or more carriers or auxiliary material via general practice of pharmacy.Above-mentioned carrier
Need compatible with curcumin or Afatinib and its pharmaceutically acceptable salt or other auxiliary materials.It is conventional for solid pharmaceutical preparation
Non-toxic carrier includes but is not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose etc..For liquid system
The carrier of agent includes water, physiological saline, D/W, ethylene glycol and polyethylene glycol etc..Curcumin or Afatinib and its
Pharmaceutically acceptable salt can form solution or suspension with above-mentioned carrier.Preferably, in some embodiments, this is compound
Curcumin and Afatinib and its pharmaceutically acceptable salt can be respectively the form of capsule and/or tablet in packaging, and/or
Gross weight is about 50mg to about 1000mg.In some embodiments, curcumin and Afatinib and its pharmacy in the composite packaging
Upper acceptable salt can be respectively the form of capsule and/or tablet, and/or with selected from 50mg, 75mg, 100mg, 150mg,
200mg, 250mg, 300mg, 350mg, 400mg, 450mg and/or 500mg gross weight.In some embodiments, the compound bag
Curcumin and Afatinib and its pharmaceutically acceptable salt can be respectively the form of capsule and/or tablet in dress, and/or always
Weight is about 250mg.In some embodiments, curcumin and Afatinib and its pharmaceutically acceptable salt in the composite packaging
Can be respectively the form of capsule and/or tablet, and/or curcumin and Afatinib and its pharmaceutically acceptable salt are with choosing
From 5000:1、4000:1、3000:1、2500:1、2000:1、1500:1、1000：1、500:1、250:1、200:1、100:1、
50:1、25:1、12.5:1、8:1、4:1、2:1、1:1、1:2、1:4 mass distribution ratio.In some embodiments, this is compound
Curcumin and Afatinib and its pharmaceutically acceptable salt can be respectively the form of capsule and/or tablet in packaging, and/or
Curcumin has with Afatinib and its pharmaceutically acceptable salt is selected from 12.5:1、8:1、4:1、2:1 mass distribution ratio.
In some embodiments, curcumin and Afatinib and its pharmaceutically acceptable salt can be respectively capsule in the composite packaging
And/or the form of tablet, and/or curcumin and Afatinib and its pharmaceutically acceptable salt are with 8:1 mass distribution ratio.
In some embodiments, curcumin of the present invention and Afatinib or its pharmaceutically acceptable salt are united
Using united form is the compound medicament composition containing curcumin and Afatinib or its pharmaceutically acceptable salt.Institute
Oral formulations can be prepared to by stating compound medicament composition, and the formulation for being adapted to be administered orally includes tablet, paste, powder, soup
Agent, pill, capsule etc..It can be solid powder or particle that above-mentioned compound medicament composition is included in these preparations；It is water-based or
Solution or suspension in non-aqueous liquid；Water-In-Oil or oil-in-water emulsion etc..Above-mentioned formulation can be by above-mentioned compound medicine
Composition is made with one or more carriers or auxiliary material via general practice of pharmacy.Above-mentioned carrier needs and above-mentioned compound
Pharmaceutical composition or other auxiliary materials are compatible.For solid pharmaceutical preparation, conventional non-toxic carrier include but is not limited to mannitol, lactose,
Starch, magnesium stearate, cellulose, glucose, sucrose etc..Carrier for liquid preparation includes water, physiological saline, G/W
Solution, ethylene glycol and polyethylene glycol etc..Above-mentioned compound medicament composition can form solution or suspension with above-mentioned carrier.It is preferred that
, in some embodiments, above-mentioned compound medicament composition can be prepared as the form of capsule and/or tablet, and/or always
Weight is about 50mg to about 1000mg.In some embodiments, above-mentioned compound medicament composition can be prepared as capsule and/or
The form of tablet, and/or with selected from 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg,
450mg and/or 500mg gross weight.In some embodiments, above-mentioned compound medicament composition can be prepared as capsule and/
Or the form of tablet, and/or gross weight is about 250mg.In some embodiments, above-mentioned compound medicament composition can be prepared as
The form of capsule and/or tablet, and/or curcumin have selected from 5000 with Afatinib and its pharmaceutically acceptable salt:
1、4000:1、3000:1、2500:1、2000:1、1500:1、1000：1、500:1、250:1、200:1、100:1、50:1、25:
1、12.5:1、8:1、4:1、2:1、1:1、1:2、1:4 mass distribution ratio.In some embodiments, above-mentioned compound medicine group
Compound can be prepared as the form of capsule and/or tablet, and/or curcumin and Afatinib and its pharmaceutically acceptable salt
With selected from 12.5:1、8:1、4:1、2:1 mass distribution ratio.In some embodiments, above-mentioned compound medicament composition can
The form as capsule and/or tablet is prepared, and/or curcumin has 8 with Afatinib and its pharmaceutically acceptable salt:
1 mass distribution ratio.
On the other hand, curcumin of the present invention is applied in combination with Afatinib or its pharmaceutically acceptable salt, its
Described in non-small cell lung cancer be EGF-R ELISA EGFR mediation non-small cell lung cancer.
Preferably, described non-small cell lung cancer is the non-small cell lung cancer of tyrosine kinase inhibitor drug resistance.
Preferably, causing, the tyrosine kinase inhibitor of resistance is selected from Gefitinib or network in distress replaces Buddhist nun.
Preferably, described drug resistance is caused by the T790 mutation encoded by EGFR extron 20s or included
Drug resistance caused by the T790 mutation of EGFR extron 20s coding, such as T790M.
Preferably, the non-small cell lung cancer is as caused by being mutated EGFR, including the mutation of L858R containing EGFR or
L858R/T790 double-mutant genes.
To be treated, Patients with Non-small-cell Lung can be given the medicine of the present invention, dosage is enough to prevent, and suppresses,
Or mitigate the progress of lung cancer, for example, the growth of lung cancer, intrusion, transfer and/or recurrence.The amount for sufficiently achieving this purpose is determined
Justice is therapeutically effective amount.For this purposes effective dose depend on disease the order of severity and patient's self immune system one
As situation.Dosage regimen can also change according to the state of disease condition and patient, generally be administered once a day or continuous several times
It is administered (for example, every 4-6 hours), or is determined by the doctor in charge according to the situation of patient.It should be noted, however, that the present invention is not
It is limited to any specific dosage.
Compared with prior art, beneficial effect of the present invention is：Curcumin of the present invention and Afatinib or its medicine
For the use in conjunction of acceptable salt not known to prior art, combination of two kinds of medicines under effective dose is non-small in treatment on
There is synergy during cell lung cancer, especially drug resistance non-small cell lung cancer.Two kinds of Drug combinations can reduce Ah method
For Buddhist nun and its pharmaceutically acceptable salt treatment drug resistance non-small cell lung cancer dosage, heighten the effect of a treatment so as to playing and
Its caused side effect is reduced, new thinking is provided for the treatment of drug resistance non-small cell lung cancer.
Specific embodiment
Following is in conjunction with specific embodiments and experimental example, the present invention to be expanded on further.But these embodiments are only limitted to illustrate
The present invention rather than for limiting the scope of the present invention.The experimental method of unreceipted specific experiment condition in the following example, lead to
Often according to normal condition.
Test example 1：The activity suppression of Wild type EGFR and mutant egf R kinases is tested
First, materials and methods
(1) medicine
Afatinib, curcumin are made products.
(2) cell culture
Human A549 cell lines (expression Wild type EGFR gene) are incubated at containing 10% hyclone and penicillin and chain
Mycin (final concentration of 100UmL-1) RPMI-1640 nutrient solutions, 37 DEG C of constant temperature is placed in 5%CO2In incubator, cell monolayer
Adherent growth, experiment take the good exponential phase cell of growth conditions, Trypsin Induced passage, collected standby.
(3) shadow of the mtt assay detection medicine to H1975 (expression EGFR L858R/T790 double-mutants gene M) growth
Ring
In MTT detections, blank control group is when wavelength 492nm absorbance is 0.8~1.2, different suppression groups and blank
It is preferable that effect is distinguished between group, and absorbance is related to the cell quantity and activity that MTT metabolism is participated in experiment, different tumours is thin
Born of the same parents' growth rate is different, determines that bed board numbers of the A549 in 96 orifice plates is 5000/hole by the above method.
(4) single medicine and administering drug combinations MTT experiment
The cell of the good exponential phase of growth conditions is taken, pancreatin digestion is counted, and 1000r/min centrifugation 5min are simultaneously abandoned
Clearly, complete medium adjustment concentration is 2.5 × 106/mL, and 96 orifice plates are per hole 200 μ L, 37 DEG C of 5%CO2It is incubated in incubator
12h, after cell is completely adherent, former culture medium is abandoned in suction.Complete medium dilutes Afatinib with curcumin respectively to 6 differences
Concentration, combined crosswise, the complete medium totally 200 μ L of the concentration containing different pharmaceutical are added per hole.Blank group is set (only to add full training
Support base) and control group (being not added with medicine).The μ L of 5mgmL-1MTT solution 20 that PBS is prepared are added per hole after cultivating 72h, continue to incubate
4h is educated, careful inhale abandons supernatant, adds low-speed oscillation 15min on the 150 rearmounted horizontal shakers of μ L DMSO per hole, with fully dissolving crystallized,
Each hole absorbance is measured at 492nm wavelength.The inhibiting rate of each dosing group is calculated respectively.All cell growth inhibition assays are independent
Repeat at least 3 times.
Average inhibition=(A medications group/A control groups) × 100%,
Cell inhibitory rate=(1-A medications group/A control groups) × 100%.
(5) association index is analyzed
The dose-effect curve of cell can be obtained after the inhibiting rate of single medicine different pharmaceutical dosage by being measured with mtt assay, be used
CalcuSyn analysis softwares calculate association index (CI).CI=(D)1/(Dx)1+(D)2/(Dx)2, wherein, (D)1、(D)2Respectively
Two medicines respective concentration during drug combination, when fa is reached when Dx is drug combination, single medicine inhibiting rate also reaches the medicine required for fa
Concentration, Dx=Dm [fa/ (1-fa)] 1/m, fa represent the inhibiting rate that certain density two medicines drug combination reaches.It is defeated by software
Enter the dosage of single medicine and inhibiting rate can obtain Dm values and m values, then certain joint is just can obtain through above-mentioned association index calculation formula
The effect of therapeutic regimen, CI values are less than 1 and represent that this scheme has cooperative effect.
(6) data processing
One-way analysis of variance is carried out using SPSS17.0 softwares, with P<0.05 expression difference has statistical significance.
2nd, experimental result
(1) influence that single medicine grows to A549
Afatinib and curcumin act on ICs of the 72h to A549 cyto-inhibitions50Value is respectively (0.017 ± 0.01) μ
Mol/L and (17.81 ± 0.08) μm ol/L；Be respectively to H1975 IC50 (0.12 ± 0.01) μm ol/L and (24.12 ±
1.07) μm ol/L, and in the growth of concentration dependent suppression cell.
The inhibitory action that (2) two medicine scheme for combining are bred to A549/H1975 cells
Afatinib is diluted to 6 kinds of final concentration combined crosswises respectively with curcumin, the suppression of cell proliferation when investigating 72h
Effect.The initial data that administering drug combinations model obtains is analyzed according to drug combination index method, using CalcuSyn softwares
The CI values of drug combination are calculated, concrete outcome is shown in Tables 1 and 2.CI>It is antagonism between 1 explanation medicine, CI=1 illustrates medicine
Between be summation action, CI<It is synergy between 1 explanation medicine.CI values are smaller, and the effect of collaboration is stronger.Generally, it is considered that CI<
0.3 expression strong synergistic effect, 0.3<CI<0.7 is moderate cooperative effect, 0.7<CI<1.0 be weaker cooperative effect.
The Afatinib of table 1 cooperates with A549 association index with curcumin
The Afatinib of table 2 cooperates with H1975 association index with curcumin
Tables 1 and 2 result shows that all values are respectively less than 1, illustrates that Afatinib joint curcumin acts on A549 and H1975
Cell is mainly shown as synergy.Result of study shows that curcumin can significantly be strengthened to A549/ with Afatinib combination
The inhibitory action of H1975 cells propagation.
Test case 2：To H3255 (expression EGFR L858R mutated genes) people source non-small cell lung cancer xenograft model
Pharmacodynamic evaluation
First, test method
(1) cell culture：
With the MEM culture mediums of the streptomysin of 10% hyclone containing inactivation, 100U/ml penicillin and 100 μ g/ml
In 37 DEG C, 5%CO2Incubator in cultivate tumour cell.The tumour cell in exponential phase is collected, and cell is adjusted
To proper density, nude mice by subcutaneous 0.2ml/ is injected in only, after tumour is formed, can be used for for more than 3 times through nude mice interior generation
The foundation of xenograft model.
(2) inoculation and packet of tumour：
Above-mentioned mice with tumor is taken off into neck to put to death, the tubercle that tumor mass cuts into 2mm × 2mm × 2mm or so is taken out under aseptic condition
Block, it is subcutaneous to be inoculated into scapular region on the right side of nude mice with trochar.When tumor bearing nude mice gross tumor volume grows to about 150 ± 30mm3When, will be real
Test animal and be randomly divided into following 10 groups, each group is gastric infusion, is administered once daily, successive administration 14 days, and the packet same day is the
0 day.
(3) experimental endpoints and data processing：
The calculation formula of gross tumor volume is：Volume=0.5 × major diameter × minor axis2.Calculated relatively according to the result of measurement
Gross tumor volume (relative tumor volume, RTV), calculation formula is：RTV=Vt/V0, wherein V0When being administered for packet
The gross tumor volume of (i.e. d0) measurement, VtGross tumor volume during to measure every time.Relative tumor propagation is calculated with relative tumour volume
Rate T/C, T are the average value for the treatment of group's relative tumour volume, and C is solvent control group (giving 0.5%DMSO) relative tumour volume
Average value.Calculation formula is as follows：T/C=TRTV/CRTV× 100% (TRTV：Treatment group RTV；CRTV：Solvent control group RTV).Suppression
Ratio of outflow (%)=(the average knurl weight of the average knurl weight-treatment group of solvent control group) average knurl weight × 100% of/solvent control group.
(4) statistical analysis：
One-Way Anova inspections are carried out using SPSS13.0, carry out statistical analysis between group.
2nd, experimental result
Experimental result is shown in Table 3 and table 4.
The each group medicine of table 3 to H3255 people source non-small cell lung cancer xenograft model gross tumor volume, relative tumour volume and
The influence of T/C values
Note：*p<0.05、**p<0.01 is compared with Afatinib group；#p<0.05、##p<0.01 is and solvent control group phase
Than.
T/C ＜ 40%, p<0.05 is significantly effectively；T/C ＞ 40% are non-significant effective.
Influence of each group medicine of table 4 to H3255 people source non-small cell lung cancer xenograft model knurl weight, inhibiting rate
Note：--‖ represents not fill in or without valid data；*p<0.05、**p<0.01 is compared with Afatinib group；#p<
0.05、##p<0.01 is compared with solvent control group.Inhibiting rate ＞ 40% is effective.
3rd, experiment conclusion
The T/C of curcumin and Afatinib administering drug combinations dosage group be respectively 28.8%, 22.5%, 15.6% and
11.2%, show preferable amount-result relation.Curcumin and the tumour inhibiting rate of Afatinib administering drug combinations dosage group are respectively
71.9%th, 78.5%, 86.0% and 90.2%.The above results prompt curcumin with Afatinib administering drug combinations to EGFR L858R
Non-small cell lung cancer caused by mutated genes possesses good antitumor activity, is preferred clinical application selection.
Test case 3：To NCI-H1975 (expression EGFR L858R/T790M double-mutants gene) people source non-small cell lung cancer
The pharmacodynamic evaluation of xenograft model
First, test method
With test case 2
2nd, experimental result
Experimental result is shown in Table 5 and table 6.
The each group medicine of table 5 is to NCI-H1975 people source non-small cell lung cancer xenograft model gross tumor volume, Relative tumor body
The influence of product and T/C values
Note：*p<0.05、**p<0.01 is compared with Afatinib group；#p<0.05、##p<0.01 is and solvent control group phase
Than.
T/C ＜ 40%, p<0.05 is significantly effectively；T/C ＞ 40% are non-significant effective.
Influence of each group medicine of table 6 to NCI-H1975 people source non-small cell lung cancer xenograft model knurl weight, inhibiting rate
Note：--‖ represents not fill in or without valid data；*p<0.05、**p<0.01 is compared with Afatinib group；#p<
0.05、##p<0.01 is compared with solvent control group.Inhibiting rate ＞ 40% is effective.
3rd, experiment conclusion
The T/C of curcumin and Afatinib administering drug combinations dosage group be respectively 39.2%, 26.9%, 20.1% and
19.0%, show preferable amount-result relation.Curcumin and the tumour inhibiting rate of Afatinib administering drug combinations dosage group are respectively
58.0%th, 72.9%, 79.1% and 80.4%.The above results prompt curcumin with Afatinib administering drug combinations for by EGFR
Non-small cell lung cancer caused by L858R/T790M double-mutant genes possesses good antitumor activity, is more preferably to face
Bed medication selection.
It should be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can make to the present invention
Various changes or modification, these equivalent form of values equally fall within the application appended claims limited range.
Claims (15)
- Prepared 1. the curcumin of therapeutically effective amount is combined with the Afatinib of therapeutically effective amount or its pharmaceutically acceptable salt The application in the medicine of non-small cell lung cancer is treated, the joint includes curcumin and Afatinib or its is pharmaceutically acceptable Salt is successively administered alone regardless of order, or curcumin is administered in the lump simultaneously with Afatinib or its pharmaceutically acceptable salt, its It is characterised by, curcumin has with Afatinib and its pharmaceutically acceptable salt is selected from 5000:1-1:4 mass distribution ratio.
- 2. application according to claim 1, it is characterised in that curcumin and Afatinib and its pharmaceutically acceptable salt With selected from 5000:1、4000:1、3000:1、2500:1、2000:1、1500:1、1000:1、500:1、250:1、200:1、 100:1、50:1、25:1、12.5:1、8:1、4:1、2:1、1:1、1:2、1:4 mass distribution ratio.
- 3. application according to claim 2, it is characterised in that curcumin and Afatinib and its pharmaceutically acceptable salt With selected from 12.5:1、8:1、4:1、2:1 mass distribution ratio.
- 4. application according to claim 3, it is characterised in that curcumin and Afatinib and its pharmaceutically acceptable salt With 8:1 mass distribution ratio.
- 5. according to any described applications of claim 1-4, it is characterised in that curcumin can connect with Afatinib and its pharmaceutically The salt received have selected from 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg and/or 500mg gross weight.
- 6. application according to claim 5, it is characterised in that curcumin and Afatinib and its pharmaceutically acceptable salt Gross weight with 250mg.
- 7. according to claim 1-4,6 any described applications, it is characterised in that the curcumin and Afatinib or its pharmacy The joint of upper acceptable salt is composite packaging form.
- 8. application according to claim 7, it is characterised in that the composite packaging form, the composite packaging include（1）With Curcumin is active component, add preparation that pharmaceutically acceptable auxiliary material is prepared into and（2）With Afatinib or its pharmaceutically Acceptable salt is active component, adds the preparation that pharmaceutically acceptable auxiliary material is prepared into.
- 9. application according to claim 8, it is characterised in that described preparation is oral formulations, wherein, the oral system The formulation of agent is tablet, paste, powder, decoction, pill, capsule.
- 10. application according to claim 9, it is characterised in that the composite packaging form, curcumin in the composite packaging Can be respectively the form of capsule and/or tablet with Afatinib and its pharmaceutically acceptable salt.
- 11. according to claim 1-4,6 any described applications, it is characterised in that the curcumin and Afatinib or its medicine Acceptable salt joint on, united form is the compound containing curcumin and Afatinib or its pharmaceutically acceptable salt Pharmaceutical composition.
- 12. according to claim 1-4,6, any described applications of 8-10, it is characterised in that described non-small cell lung cancer is table The non-small cell lung cancer of skin growth factor Receptor EGFR mediation.
- 13. application according to claim 12, wherein described non-small cell lung cancer is tyrosine kinase inhibitor resistance The non-small cell lung cancer of property.
- 14. application according to claim 13, wherein described tyrosine kinase inhibitor is selected from Gefitinib or network in distress For Buddhist nun.
- 15. application according to claim 13, wherein described non-small cell lung cancer is as caused by being mutated EGFR, comprising EGFR L858R are mutated or L858R/T790 double-mutant genes.
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| CN109771436A (en) * | 2019-03-06 | 2019-05-21 | 康赋葆(深圳)生物医药科技有限公司 | The application of tetrahydro curcumin and capecitabine combination therapy colorectal cancer |
| CA3205490A1 (en) * | 2020-12-17 | 2022-06-23 | Chang-Hai TSAI | Use of pharmaceutical composition for treating lung cancer |
| CN115381836A (en) * | 2022-09-30 | 2022-11-25 | 上海纳米技术及应用国家工程研究中心有限公司 | Combination drug for treating lung cancer |
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| CN104163915A (en) * | 2013-05-16 | 2014-11-26 | 沈阳药科大学 | Cholesterol-poloxamer-cholesterol triblock copolymer, preparation method and application thereof |
| CN104797267A (en) * | 2012-06-26 | 2015-07-22 | 德玛医药 | Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof |
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| CN104797267A (en) * | 2012-06-26 | 2015-07-22 | 德玛医药 | Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof |
| CN104163915A (en) * | 2013-05-16 | 2014-11-26 | 沈阳药科大学 | Cholesterol-poloxamer-cholesterol triblock copolymer, preparation method and application thereof |
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