CN105476996A - Application of curcumin and afatinib for combined treatment of non-small cell lung cancer - Google Patents
Application of curcumin and afatinib for combined treatment of non-small cell lung cancer Download PDFInfo
- Publication number
- CN105476996A CN105476996A CN201510956936.6A CN201510956936A CN105476996A CN 105476996 A CN105476996 A CN 105476996A CN 201510956936 A CN201510956936 A CN 201510956936A CN 105476996 A CN105476996 A CN 105476996A
- Authority
- CN
- China
- Prior art keywords
- curcumin
- buddhist nun
- pharmaceutically acceptable
- acceptable salt
- lung cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- A61K31/33—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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 invention relates to the field of medicines, particularly relates to an application of curcumin and afatinib as well as a pharmaceutically acceptable salt thereof for combined treatment of non-small cell lung cancer, and more particularly relates to the application for combined treatment of non-small cell lung cancer having drug resistance for gefitinib and erlotinib.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to curcumin and the Ah method purposes for Buddhist nun and pharmaceutically acceptable salt therapeutic alliance nonsmall-cell lung cancer thereof.
Background technology
Pulmonary carcinoma is the out of hand and a kind of disease that causes of lung tissue inner cell growth.In over half a century in the past, the M & M of pulmonary carcinoma increases year by year, develops into the No.1 cancer killer in the current whole world from a kind of orphan disease of 20 beginnings of the century.According to the data that World Health Organization (WHO) (WHO) regularly announces, the M & M of pulmonary carcinoma in countries in the world especially developed country be obvious ascendant trend, become the modal tumor of many developed countries, rank male's common cancer first and women's common cancer second, and become the modal cause of death in malignant tumor.In China, male lung cancer age standardization sickness rate is 47.51/10 ten thousand, and female lung cancer age standardization sickness rate is 22.69/10 ten thousand, and in the trend increased year by year.Expect 2025, the number dying from pulmonary carcinoma is often only by China just close to 1,000,000, will become the first in the world pulmonary carcinoma big country.
Protein tyrosine kinase (ProteinTyrosineKinases, PTKs) is class protein enzyme, and they can the phenolic hydroxyl group phosphorylation reaction of catalysis on the tyrosine residue of multiple key protein, the biological activity of mobilizing function albumen thus.This process occupies very consequence in intracellular signal transduction pathway, and it regulates a series of plysiochemical processes such as cell growth in vivo, differentiation, death.Protein tyrosine kinase functional disorder can cause a series of diseases in organism.Research shows, cancer protogene more than half is all relevant to protein tyrosine kinase with the activation of oncogene, and the unconventionality expression of protein tyrosine kinase can cause cell proliferation adjustment to get muddled, and then causes tumor to occur.In addition, the unconventionality expression of tyrosine kinase also with the Infiltration and metastasis of tumor, tumor neovasculature generation, the chemotherapy Drug resistance of tumor is closely related.Tyrosine kinase has become the very important target spot of antitumor drug research and development.
EGF-R ELISA (EpidermalGrowthFactorReceptor, EGFR) is a kind of receptor tyrosine protein kinase, belongs to a kind of transmembrane protein in erbB receptor family.EGFR has regulated and controled the propagation of cell, survival, adhesion, and migration and differentiation, it is overactivity or continuous activation in kinds of tumor cells, such as pulmonary carcinoma, breast carcinoma, in the cells such as carcinoma of prostate.The abnormal activation of EGFR is in the conversion of tumor and play critical effect in increasing.The activation blocking EGFR has been clinically proven as one of effective targeting therapy on tumor cellular processes.EGFR has expression in non-compactness cell lung cancer (non-smalllungcancer, the NSCLC) case of 50%.This makes EGFR and family member thereof become the leading candidate of NSCLC targeted therapy.
Micromolecular tyrosine kinase inhibitor (tyrosinekinaseinhibitor, the medicine of TKI) to be a class with EGFR be target spot, it suppresses the phosphorylation in this site to realize blocking EGFR intracellular signaling by the phosphorylation site in competitive binding tyrosine kinase district.Gefitinib (gefitinib) and Erlotinib (erlotinib) are the micromolecular tyrosine kinase inhibitors of the first generation of EGFR, are mainly used in the medicine for the treatment of advanced NSCLC.Clinical effectiveness display gefitinib or the asian ancestry NSCLC patient of Erlotinib to the white man NSCLC and about 35% of about 10% effective in cure.
But, clinical research shows that many patients very fast (12-14 month) just create Drug resistance to the micromolecular inhibitor medicine of these EGFR, i.e. acquired resistance, accepts patient that the micromolecular tyrosine kinase inhibitor of the first generation (TKI) treats often faces recurrence predicament owing to forming TKI drug resistance.Residue (gatekeeperresidue) T790M that guards the gate sudden change is a catastrophe point in EGFR20 exon, is one of main mechanism causing drug resistance.The second filial generation inhibitor research suddenlyd change for these EGFR is being successful recently.Ah method is potent, the irreversible double inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) tyrosine kinase for Buddhist nun (Afatinib).Other similar Mutiple Targets, high activity, irreversible inhibitor, such as, card, how for Buddhist nun (canertinib), reaches gram for Buddhist nun (Dacomitinib) also just in later phase clinical test.The irreversible inhibitor of these novel second filial generations has very strong inhibitory action to the EGFR that L858R and T790M suddenlys change, and has significant curative effect to the patient that gefitinib or Erlotinib have developed immunity to drugs.These second filial generation EGFR mutant inhibitor have extremely strong inhibition too to Wild type EGFR (WT-EGFR), the verified suppression to Wild type EGFR of clinical research can cause drug toxicity and side effect with it most of patient, such as in human body, show as erythra or diarrhoea.Because second filial generation TYR kinases and preparation are if Ah method is for the poor selectivity to EGFR mutant such as Buddhist nun, cause the clinical tolerance dosage of medicine lower.As a result, under maximum tolerated dose, medicine cannot reach valid density in vivo, thus invalid to most drug resistance patient.Overcome the Side effect of second filial generation EGFR inhibitor, just must reduce the inhibitory action to Wild type EGFR (WT-EGFR).
In addition, the first generation and second filial generation TKI are single and easily occur drug resistance, multiple gene that effectively can not suppress canceration or albumen as Treatment for Non-small Cell Lung drug target, and the problem such as toxic and side effects is large, and make its offer limited effectiveness; It is expensive in addition, causes huge financial burden to patient and family thereof.Drug combination day by day obtains people's accreditation with the method for attenuation synergistic and payes attention to, the different mechanism of action of reasonable employment, untoward reaction not only can play synergistic sensitization without two or more medicines of superposition, and single medicine dosage can be reduced, reduce untoward reaction, improve toleration.But drug regimen is improper, can pick up anti-, curative effect is offset, decline, even cause toxic and side effects.Therefore, be necessary to find and effectively medication combinedly solve the problems such as nonsmall-cell lung cancer (NSCLC) treats field drug resistance and toxic and side effects is large.
Curcumin is a kind of phenol pigment extracted from Chinese medicine turmeric stem, research show that it is a kind of safe, nontoxic antitumor drug, US National institute of oncology be more classified as the 3rd generation cancer chemoprevention medicine.The curcumin of broad sense is commonly referred to curcumin, comprises curcumin, demethoxycurcumin, bisdemethoxycurcumin etc., and curcumin is wherein most important active component.When below not making Special Statement, refer to sensu lato curcumin.A large amount of experiment in vivo and vitro proves that curcumin can suppress the growth of kinds of tumor cells system, such as leukemia, the brain cancer, breast carcinoma, gastric cancer, hepatocarcinoma, cancer of pancreas, colon cancer, skin carcinoma etc.Every clinical data also shows curcumin to be had familial form polyposis adenomatous, cancer of pancreas, multiple myeloma and well expects therapeutical effect.In addition, find when curcumin treatment colon cancer, patient is fabulous and also do not show toxicity when heavy dose to its toleration.
Aggarwal etc. claim the molecular basis of the antitumor action of curcumin to be all kinds of target spots of regulation and control, as transcription factor, growth regulatory gene, adhesion molecule, apoptosis gene, angiogenesis regulator gene and cell signaling molecule.Curcumin can be lowered TNF-a content and suppress the activity of NF-kb and AP-1.The research such as LataG.Menon claims the metalloproteases in curcumin energy inhibition tumor cell substrate, thus the migration of inhibition tumor cell effectively.Current research finds that curcumin can suppress aldose reductase (AR, aldosereductase).Crucial effect is played in the disease that AR causes in inflammation such as septicemia, uveitis, atherosclerosiss, AR overexpression in the tumor cells such as hepatocarcinoma, colon cancer, breast carcinoma, ovarian cancer, AR can start and accelerate to induce NF.KB (Nu-clearfactor-kB by oxidative stress, endotheliocyte transcription factor) path that activates, produce serial inflammatory reaction and tumor cell proliferation, suppressing AR activity to promote apoptosis of tumor cells, is research and development antitumor drug new way.As can be seen here, curcumin is the very potential antitumor drug of one.But curcumin and tyrosine kinase inhibitor (TKI) Ah method there is not yet report for Buddhist nun's therapeutic alliance nonsmall-cell lung cancer (NSCLC).
The present inventor is through further investigation, find that curcumin and tyrosine kinase inhibitor (TKI) Ah method can be used for the treatment of EGFR sensitive mutant cancer for Buddhist nun and pharmaceutically acceptable salt use in conjunction thereof, be also applicable to the treatment producing secondary resistance during current EGFR-TKI treats; The using dosage of Ah method for Buddhist nun can be reduced by administering drug combinations simultaneously, thus the toxic and side effects that the Ah method of substantially reducing produces for Buddhist nun, be the ideal scheme that solution NSCLC drug resistance and many side effect are large.
Summary of the invention
A kind of associating for Buddhist nun or its pharmaceutically acceptable salt by curcumin and Ah method is the object of the present invention is to provide to prepare the application in the medicine for the treatment of nonsmall-cell lung cancer.
To achieve these goals, technical scheme of the present invention is:
The curcumin for the treatment of effective dose and the Ah method for the treatment of effective dose combine for Buddhist nun or its pharmaceutically acceptable salt and are preparing the application in the medicine for the treatment of nonsmall-cell lung cancer, described combine comprise curcumin and Ah method for Buddhist nun or its pharmaceutically acceptable salt successively individually dosed regardless of order, or curcumin with Ah method for administration in the lump while of Buddhist nun or its pharmaceutically acceptable salt.
In some embodiments, described curcumin and Ah method combining for composite packaging form for Buddhist nun or its pharmaceutically acceptable salt.In some embodiments, it take curcumin as active component that this composite packaging comprises (1), add preparation that pharmaceutically acceptable adjuvant or complementary composition be prepared into and (2) with Ah method for Buddhist nun or its pharmaceutically acceptable salt for active component, add the preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared into.Wherein, in some embodiments, above-mentioned preparation is oral formulations, and the dosage form being applicable to oral administration comprises tablet, unguentum, powder, decoction, pill, capsule etc.The curcumin comprised in these preparations or Ah method can be pressed powder or granule for Buddhist nun and pharmaceutically acceptable salt thereof; Solution in aqueous or non-aqueous liquid or suspension; Water-In-Oil or oil-in-water Emulsion etc.Above-mentioned dosage form can be made up via general practice of pharmacy for Buddhist nun and pharmaceutically acceptable salt thereof and one or more carriers or adjuvant of curcumin or Ah method.Above-mentioned carrier needs to replace Buddhist nun and pharmaceutically acceptable salt or other adjuvants thereof compatible with curcumin or Ah method.For solid preparation, conventional non-toxic carrier includes but not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose etc.Carrier for liquid preparation comprises water, normal saline, D/W, ethylene glycol and Polyethylene Glycol etc.Curcumin or Ah method can form solution or suspension with above-mentioned carrier for Buddhist nun and pharmaceutically acceptable salt thereof.Preferably, in some embodiments, in this composite packaging, curcumin and A Fa can be respectively the form of capsule and/or tablet for Buddhist nun and pharmaceutically acceptable salt thereof, and/or gross weight is about 50mg to about 1000mg.In some embodiments, in this composite packaging, curcumin and A Fa can be respectively the form of capsule and/or tablet for Buddhist nun and pharmaceutically acceptable salt thereof, and/or have the gross weight being selected from 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg and/or 500mg.In some embodiments, in this composite packaging, curcumin and A Fa can be respectively the form of capsule and/or tablet for Buddhist nun and pharmaceutically acceptable salt thereof, and/or gross weight is about 250mg.In some embodiments, in this composite packaging, curcumin and A Fa can be respectively the form of capsule and/or tablet for Buddhist nun and pharmaceutically acceptable salt thereof, and/or curcumin replaces Buddhist nun and pharmaceutically acceptable salt thereof to have the mass distribution ratio being 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 with Ah method.In some embodiments, in this composite packaging, curcumin and A Fa can be respectively the form of capsule and/or tablet for Buddhist nun and pharmaceutically acceptable salt thereof, and/or curcumin replaces Buddhist nun and pharmaceutically acceptable salt thereof to have the mass distribution ratio being selected from 12.5:1,8:1,4:1,2:1 with Ah method.In some embodiments, in this composite packaging, curcumin and A Fa can be respectively the form of capsule and/or tablet for Buddhist nun and pharmaceutically acceptable salt thereof, and/or curcumin replaces Buddhist nun and pharmaceutically acceptable salt thereof to have the mass distribution ratio of 8:1 with Ah method.
In some embodiments, the application that curcumin of the present invention is combined for Buddhist nun or its pharmaceutically acceptable salt with Ah method, the form of associating is replace the compound medicament composition of Buddhist nun or its pharmaceutically acceptable salt containing curcumin and A Fa.Described compound medicament composition can be prepared to oral formulations, and the dosage form being applicable to oral administration comprises tablet, unguentum, powder, decoction, pill, capsule etc.Comprising above-mentioned compound medicament composition in these preparations can be pressed powder or granule; Solution in aqueous or non-aqueous liquid or suspension; Water-In-Oil or oil-in-water Emulsion etc.Above-mentioned dosage form can be made up via general practice of pharmacy of above-mentioned compound medicament composition and one or more carriers or adjuvant.Above-mentioned carrier needs and above-mentioned compound medicament composition or other adjuvants compatibility.For solid preparation, conventional non-toxic carrier includes but not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose etc.Carrier for liquid preparation comprises water, normal saline, D/W, ethylene glycol and Polyethylene Glycol etc.Above-mentioned compound medicament composition can form solution or suspension with above-mentioned carrier.Preferably, in some embodiments, above-mentioned compound medicament composition can be prepared as the form of capsule and/or tablet, and/or gross weight is about 50mg to about 1000mg.In some embodiments, above-mentioned compound medicament composition can be prepared as the form of capsule and/or tablet, and/or has the gross weight being selected from 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg and/or 500mg.In some embodiments, above-mentioned compound medicament composition can be prepared as the form of capsule and/or 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 and Ah method have for Buddhist nun and pharmaceutically acceptable salt thereof the mass distribution ratio being 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.In some embodiments, above-mentioned compound medicament composition can be prepared as the form of capsule and/or tablet, and/or curcumin and Ah method have for Buddhist nun and pharmaceutically acceptable salt thereof the mass distribution ratio being selected from 12.5:1,8:1,4:1,2:1.In some embodiments, above-mentioned compound medicament composition can be prepared as the form of capsule and/or tablet, and/or curcumin and Ah method have the mass distribution ratio of 8:1 for Buddhist nun and pharmaceutically acceptable salt thereof.
On the other hand, the application that curcumin of the present invention is combined for Buddhist nun or its pharmaceutically acceptable salt with Ah method, wherein said nonsmall-cell lung cancer is the nonsmall-cell lung cancer of EGF-R ELISA EGFR mediation.
As preferably, described nonsmall-cell lung cancer is the nonsmall-cell lung cancer of tyrosine kinase inhibitor drug resistance.
As preferably, the tyrosine kinase inhibitor of drug resistance is caused to be selected from gefitinib or network in distress for Buddhist nun.
As preferably, described drug resistance is the drug resistance caused by T790 sudden change that is that the T790 sudden change of being encoded by EGFR extron 20 causes or that comprise EGFR extron 20 coding, as T790M.
As preferably, described nonsmall-cell lung cancer is suddenlyd change by EGFR and causes, and comprises containing EGFRL858R sudden change or L858R/T790 double-mutant gene.
For treating, can give Patients with Non-small-cell Lung medicine of the present invention, dosage is enough to prevention, suppresses, or alleviates the progress of pulmonary carcinoma, and such as, the growth of pulmonary carcinoma, invades, transfer and/or recurrence.The amount being enough to reach this purpose is defined as treating effective dose.Effective dose for this purposes depends on the order of severity of disease and the general status of patient's self immune system.Dosage regimen also can change according to the state of disease condition and patient, is administered once usual every day or continuous several times administration (such as, every 4-6 hour), or is determined according to the situation of patient by the doctor in charge.But, it should be noted that and the invention is not restricted to any specific dosage.
Compared with prior art, beneficial effect of the present invention is: curcumin of the present invention and Ah method replace the use in conjunction of Buddhist nun or its pharmaceutically acceptable salt not known to prior art, two kinds of medicines are combined in treatment nonsmall-cell lung cancer under effective dose, especially have synergism during drug resistance nonsmall-cell lung cancer.Two kinds of Drug combination Ah methods that can reduce replace Buddhist nun and pharmaceutically acceptable salt thereof at the using dosage for the treatment of drug resistance nonsmall-cell lung cancer, thus play the side effect heightening the effect of a treatment and reduce it and cause, the treatment for drug resistance nonsmall-cell lung cancer provides new thinking.
Specific embodiments
Following is in conjunction with specific embodiments and experimental example, sets forth the present invention further.But these embodiments are only limitted to the present invention instead of for limiting the scope of the invention is described.The experimental technique of unreceipted specific experiment condition in the following example, usually conveniently condition.
Test example 1: test is suppressed to Wild type EGFR and the kinase whose activity of mutant egf R
One, materials and methods
(1) medicine
Ah method is for Buddhist nun, and curcumin is made products.
(2) cell culture
Human A549 cell lines (express Wild type EGFR gene) is incubated at containing 10% hyclone and penicillin and streptomycin that (final concentration is 100UmL
-1) RPMI-1640 culture fluid, constant temperature 37 DEG C is placed in 5%CO
2in incubator, cell monolayer adherent growth, the good exponential phase cell of growth conditions is got in experiment, and trypsinization goes down to posterity, and collects for subsequent use.
(3) mtt assay detection of drugs is on the impact of H1975 (expressing EGFRL858R/T790 double-mutant gene M) growth
During MTT detects, blank group is when the absorbance of wavelength 492nm is 0.8 ~ 1.2, effect is distinguished better between different suppression group and blank group, and absorbance is relevant to the cell quantity and activity participating in MTT metabolism in experiment, different tumor cell proliferation speed is different, determines that the bed board number of A549 in 96 orifice plates is 5000/hole by said method.
(4) single medicine and administering drug combinations MTT experiment
Get the cell of the good exponential phase of growth conditions, trypsinization counts, and the centrifugal 5min of 1000r/min also abandons supernatant, and complete medium adjustment concentration is 2.5 × 106/mL, 96 orifice plate every hole 200 μ L, 37 DEG C of 5%CO
2hatch 12h in incubator, after cell is completely adherent, inhales and abandon former culture medium.Complete medium dilution Ah method for Buddhist nun and curcumin respectively to 6 variable concentrations, combined crosswise, every hole adds the complete medium totally 200 μ L containing different pharmaceutical concentration.Blank group (only adding complete medium) and matched group (not adding medicine) are set.After cultivating 72h, every hole adds the 5mgmL-1MTT solution 20 μ L of PBS preparation, continues to hatch 4h, and careful suction abandons supernatant, and every hole adds low-speed oscillation 15min on the rearmounted horizontal shaker of 150 μ LDMSO, and with fully dissolving crystallized, each hole absorbance is measured at 492nm wavelength place.Calculate the suppression ratio of each dosing group respectively.All cells proliferation inhibition test all independently repeats at least 3 times.
Average inhibition=(A medication group/A matched group) × 100%,
Cell inhibitory rate=(1 – A medication group/A matched group) × 100%.
(5) association index analysis
The dose-effect curve of cell can be obtained record the suppression ratio of single medicine different pharmaceutical dosage with mtt assay after, adopt CalcuSyn analysis software to calculate association index (CI).CI=(D)
1/ (Dx)
1+ (D)
2/ (Dx)
2, wherein, (D)
1, (D)
2two medicines concentration separately when being respectively drug combination, when Dx reaches fa when being drug combination, single medicine suppression ratio also reaches the drug level required for fa, and Dx=Dm [fa/ (1 – fa)] 1/m, fa represent the suppression ratio that certain density two medicine drug combinations reach.Input the dosage of single medicine by software and suppression ratio can obtain Dm value and m value, more just can obtain the effect of certain scheme of combination drug therapy through above-mentioned association index computing formula, CI value is less than this scheme of 1 expression and has cooperative effect.
(6) date processing
Use SPSS17.0 software to carry out one factor analysis of variance, represent that difference has statistical significance with P<0.05.
Two, experimental result
(1) single medicine impact that A549 is grown
Ah method replaces Buddhist nun and curcumin effect 72h to the IC of A549 cyto-inhibition
50value is respectively (0.017 ± 0.01) μm ol/L and (17.81 ± 0.08) μm ol/L; (0.12 ± 0.01) μm ol/L and (24.12 ± 1.07) μm ol/L is respectively to the IC50 of H1975, and the growth in concentration dependent T suppression cell.
(2) two medicine scheme for combining are to the inhibitory action of A549/H1975 cell proliferation
Ah method is diluted to 6 kinds of final concentration combined crosswise respectively for Buddhist nun and curcumin, investigates the inhibitory action of on cell proliferation during 72h.Analyze according to drug combination index method the initial data that administering drug combinations model obtains, adopt the CI value of CalcuSyn computed in software drug combination, concrete outcome is in table 1 and table 2.CI>1 illustrates that between medicine be antagonism, and CI=1 illustrates that between medicine be summation action, and CI<1 illustrates that between medicine be synergism.CI value is less, and collaborative effect is stronger.It has been generally acknowledged that, CI<0.3 represents strong synergistic effect, and 0.3<CI<0.7 is moderate cooperative effect, and 0.7<CI<1.0 is more weak cooperative effect.
Table 1 Ah method cooperates with the association index of A549 for Buddhist nun and curcumin
Table 2 Ah method cooperates with the association index of H1975 for Buddhist nun and curcumin
Table 1 and table 2 result display all values are all less than 1, illustrate Ah method to replace Buddhist nun to combine curcumin to act on the equal main manifestations of A549 and H1975 cell be synergism.Result of study shows, curcumin and Ah method significantly can strengthen the inhibitory action to A549/H1975 cell proliferation for Buddhist nun's coupling.
Test case 2: to the pharmacodynamic evaluation of H3255 (expressing EGFRL858R mutated genes) people source nonsmall-cell lung cancer xenograft model
One, test method
(1) cell culture:
By the MEM culture medium of the penicillin of 10% hyclone containing deactivation, 100U/ml and the streptomycin of 100 μ g/ml at 37 DEG C, 5%CO
2incubator in culture of tumor cell.Collect the tumor cell being in exponential phase, and cell is adjusted to proper density, be only injected in nude mice by subcutaneous 0.2ml/, after tumor is formed, the foundation of xenograft model can be used for for more than 3 times through nude mice interior generation.
(2) inoculation of tumor and grouping:
Above-mentioned mice with tumor is taken off neck to put to death, take out the tubercle block that tumor block cuts into 2mm × 2mm × about 2mm under aseptic condition, be inoculated into scapular region on the right side of nude mice with the trocar subcutaneous.When tumor bearing nude mice gross tumor volume grows to about 150 ± 30mm
3time, laboratory animal is divided at random following 10 groups, each group is gastric infusion, administration every day 1 time, successive administration 14 days, and the same day of dividing into groups is the 0th day.
(3) experimental endpoints and date processing:
The computing formula of gross tumor volume is: volume=0.5 × major diameter × minor axis
2.Result according to measuring calculates relative tumour volume (relativetumorvolume, RTV), and computing formula is: RTV=V
t/ V
0, wherein V
0for the gross tumor volume that (d0) during grouping administration measures, V
tgross tumor volume during for measuring at every turn.Calculate Relative tumor rate of increase T/C with relative tumour volume, T is the meansigma methods for the treatment of group relative tumour volume, and C is the meansigma methods of solvent control group (giving 0.5%DMSO) relative tumour volume.Computing formula is as follows: T/C=T
rTV/ C
rTV× 100% (T
rTV: treatment group RTV; C
rTV: solvent control group RTV).The average tumor of tumour inhibiting rate (%)=(solvent control group average tumor weight-treatment group average tumor weight)/solvent control group heavy × 100%.
(4) statistical analysis:
Application SPSS13.0 carries out One-WayAnova inspection, statistical analysis between organizing.
Two, experimental result
Experimental result is in table 3 and table 4.
Table 3 respectively organizes medicine to the impact of H3255 people source nonsmall-cell lung cancer xenograft model gross tumor volume, relative tumour volume and T/C value
Note: * p<0.05, * * p<0.01 for Ah method for compared with Buddhist nun's group;
#p<0.05,
##p<0.01 is for compared with solvent control group.
T/C < 40%, p<0.05 is significantly effectively; T/C > 40% is that non-significant is effective.
Table 4 each group medicine is heavy on H3255 people source nonsmall-cell lung cancer xenograft model tumor, the impact of suppression ratio
Note :--‖ represents and not fill in or without valid data; * p<0.05, * * p<0.01 for Ah method for compared with Buddhist nun's group;
#p<0.05,
##p<0.01 is for compared with solvent control group.Suppression ratio > 40% is effective.
Three, experiment conclusion
Curcumin and Ah method replace the T/C of Buddhist nun's administering drug combinations dosage group to be respectively 28.8%, 22.5%, 15.6% and 11.2%, present good amount-result relation.Curcumin and Ah method replace the tumour inhibiting rate of Buddhist nun's administering drug combinations dosage group to be respectively 71.9%, 78.5%, 86.0% and 90.2%.The above results prompting curcumin and Ah method possess good anti-tumor activity for Buddhist nun's administering drug combinations to the nonsmall-cell lung cancer that EGFRL858R mutated genes causes, and are preferred clinical application selections.
Test case 3: to the pharmacodynamic evaluation of NCI-H1975 (expressing EGFRL858R/T790M double-mutant gene) people source nonsmall-cell lung cancer xenograft model
One, test method
With test case 2
Two, experimental result
Experimental result is in table 5 and table 6.
Table 5 respectively organizes medicine to the impact of NCI-H1975 people source nonsmall-cell lung cancer xenograft model gross tumor volume, relative tumour volume and T/C value
Note: * p<0.05, * * p<0.01 for Ah method for compared with Buddhist nun's group;
#p<0.05,
##p<0.01 is for compared with solvent control group.
T/C < 40%, p<0.05 is significantly effectively; T/C > 40% is that non-significant is effective.
Table 6 each group medicine is heavy on NCI-H1975 people source nonsmall-cell lung cancer xenograft model tumor, the impact of suppression ratio
Note :--‖ represents and not fill in or without valid data; * p<0.05, * * p<0.01 for Ah method for compared with Buddhist nun's group;
#p<0.05,
##p<0.01 is for compared with solvent control group.Suppression ratio > 40% is effective.
Three, experiment conclusion
Curcumin and Ah method replace the T/C of Buddhist nun's administering drug combinations dosage group to be respectively 39.2%, 26.9%, 20.1% and 19.0%, present good amount-result relation.Curcumin and Ah method replace the tumour inhibiting rate of Buddhist nun's administering drug combinations dosage group to be respectively 58.0%, 72.9%, 79.1% and 80.4%.The above results prompting curcumin and Ah method possess good anti-tumor activity for Buddhist nun's administering drug combinations for the nonsmall-cell lung cancer caused by EGFRL858R/T790M double-mutant gene, are preferred clinical application selections.
Should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. the Ah method of the curcumin and treatment effective dose for the treatment of effective dose combines for Buddhist nun or its pharmaceutically acceptable salt and is preparing the application in the medicine for the treatment of nonsmall-cell lung cancer, described combine comprise curcumin and Ah method for Buddhist nun or its pharmaceutically acceptable salt successively individually dosed regardless of order, or curcumin with Ah method for administration in the lump while of Buddhist nun or its pharmaceutically acceptable salt.
2. application according to claim 1, is characterized in that described curcumin and Ah method combining for composite packaging form for Buddhist nun or its pharmaceutically acceptable salt.
3. application according to claim 2, it is characterized in that described composite packaging form, it take curcumin as active component that this composite packaging comprises (1), add preparation that pharmaceutically acceptable adjuvant or complementary composition be prepared into and (2) with Ah method for Buddhist nun or its pharmaceutically acceptable salt for active component, add the preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared into.
4. application according to claim 3, is characterized in that described preparation is oral formulations, and wherein, the dosage form of described oral formulations is tablet, unguentum, powder, decoction, pill, capsule.
5. application according to claim 3, is characterized in that described composite packaging form, and in this composite packaging, curcumin and A Fa can be respectively the form of capsule and/or tablet for Buddhist nun and pharmaceutically acceptable salt thereof.
6. application according to claim 1, described curcumin is combined for Buddhist nun or its pharmaceutically acceptable salt with Ah method, and the form of associating is replace the compound medicament composition of Buddhist nun or its pharmaceutically acceptable salt containing curcumin and A Fa.
7. the application according to claim 1 ~ 6 any one, wherein said nonsmall-cell lung cancer is the nonsmall-cell lung cancer of EGF-R ELISA EGFR mediation.
8. the application according to claim 7 any one, wherein said nonsmall-cell lung cancer is the nonsmall-cell lung cancer of tyrosine kinase inhibitor drug resistance.
9. application according to claim 8, wherein said tyrosine kinase inhibitor is selected from gefitinib or network in distress replaces Buddhist nun.
10. application according to claim 8, wherein said nonsmall-cell lung cancer is suddenlyd change by EGFR and causes, and comprises EGFRL858R sudden change or L858R/T790 double-mutant gene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510956936.6A CN105476996B (en) | 2015-12-21 | 2015-12-21 | The purposes of curcumin and Afatinib therapeutic alliance non-small cell lung cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510956936.6A CN105476996B (en) | 2015-12-21 | 2015-12-21 | The purposes of curcumin and Afatinib therapeutic alliance non-small cell lung cancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105476996A true CN105476996A (en) | 2016-04-13 |
| CN105476996B CN105476996B (en) | 2017-12-26 |
Family
ID=55664514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510956936.6A Active CN105476996B (en) | 2015-12-21 | 2015-12-21 | The purposes of curcumin and Afatinib therapeutic alliance non-small cell lung cancer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105476996B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109674990A (en) * | 2019-01-30 | 2019-04-26 | 中国人民解放军西部战区总医院 | With the composition and preparation method thereof for adjusting EGFR effect |
| 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 |
| 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 |
| TWI798994B (en) * | 2020-12-17 | 2023-04-11 | 中國醫藥大學 | Use of medicinal composition for treating lung cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2015
- 2015-12-21 CN CN201510956936.6A patent/CN105476996B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 盛琦 等: "姜黄素逆转非小细胞肺癌吉非替尼耐药的研究", 《中国现代应用药学》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109674990A (en) * | 2019-01-30 | 2019-04-26 | 中国人民解放军西部战区总医院 | With the composition and preparation method thereof for adjusting EGFR effect |
| 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 |
| TWI798994B (en) * | 2020-12-17 | 2023-04-11 | 中國醫藥大學 | Use of medicinal 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105476996B (en) | 2017-12-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105476996A (en) | Application of curcumin and afatinib for combined treatment of non-small cell lung cancer | |
| CN104758277A (en) | Uses of chlorogenic acid in preparation of drugs treating multidrug resistance of cancer | |
| CN103179967A (en) | Anti-tumor pharmaceutical composition | |
| CN104398526A (en) | Application of triptolide and tripterine in preparation of antitumor drugs | |
| CN104434939B (en) | Antitumor medicament composition of panax notoginseng saponins R7 and oridonin with capabilities of reducing toxicity and enhancing efficacy and application of antitumor medicament composition | |
| CN110123809A (en) | 5- methyl-dihydro benzofuran-application of the imidazole salt compound in pharmacy | |
| CN106822904B (en) | The pharmaceutical composition and its application of inhibitor containing AKT and IRE1 inhibitor | |
| CN109481454B (en) | Anti-tumor composition, application of anti-tumor composition in preparation of anti-tumor or cancer cell inhibiting medicine, and anti-tumor medicine | |
| CN109453176B (en) | Anti-tumor composition, application of anti-tumor composition in preparation of anti-tumor or cancer cell inhibiting medicine, and anti-tumor medicine | |
| CN101485665B (en) | Novel medical use of cucurbitacin | |
| CN101229175A (en) | Medical applications of couple protopanoxadiol derivatives and compound body thereof | |
| CN105232527A (en) | Application of medicine containing catechin to preparation of medicines for prevention and/or treatment of cancers | |
| CN110613716B (en) | Pharmaceutical composition for treating cancer and application thereof | |
| CN111494385B (en) | Medicine for treating ovarian cancer and preparation method and application thereof | |
| CN103933035B (en) | A kind of pharmaceutical composition for the treatment of cerebral glioma | |
| CN102018690B (en) | Anti-tumor medicament and application thereof | |
| CN113893256A (en) | Application of compound or pharmaceutically acceptable salt, dimer or trimer thereof in preparation of medicine for treating cancer | |
| CN114642665A (en) | Pharmaceutical composition containing palbociclib and 10-hydroxycamptothecin and application | |
| CN104055786A (en) | Medicagenic acid-3-O-beta-D-glucopyranoside and medicagenic acid and application of salt of medicagenic acid-3-O-beta-D-glucopyranoside and medicagenic acid to preparation of medicine for preventing and treating tumor | |
| CN101856393B (en) | Application of compound Yiganling composition in aspect of auxiliary treatment of chemotherapy of tumors | |
| CN110893192A (en) | Pharmaceutical composition for treating nasopharyngeal carcinoma | |
| CN108324707A (en) | Fenofibrate list medicine and combined chemotherapy medicine application in preparation of anti-tumor drugs | |
| CN115381954B (en) | Combined medicine for treating osteosarcoma | |
| CN108096239A (en) | A kind of pharmaceutical composition for treating glioma and liver cancer | |
| CN102727867A (en) | Antineoplastic pharmaceutical composition and application thereof, kit and package |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |