CN105030777B - Enhancing ALK TKI curative effects, the compound and its preparation for delaying its resistance - Google Patents
Enhancing ALK TKI curative effects, the compound and its preparation for delaying its resistance Download PDFInfo
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- CN105030777B CN105030777B CN201510410323.2A CN201510410323A CN105030777B CN 105030777 B CN105030777 B CN 105030777B CN 201510410323 A CN201510410323 A CN 201510410323A CN 105030777 B CN105030777 B CN 105030777B
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Abstract
The present invention provides a kind of legalon or its salt and ALK TKI compound and application thereof, and the compound can be used for enhancing ALK TKI curative effects, delay its resistance, be effectively improved ALK TKI therapeutic effect.
Description
Technical field
The invention belongs to field of medical application, more particularly to strengthen ALK-TKI curative effects, delay its resistance compound and its
Preparation.
Background technology
Lung cancer is the current mankind because of the main cause of cancer mortality, and its morbidity and mortality constantly rises in recent years.It is non-
ED-SCLC (Non SmaLL CeLL Lung Cancer, NSCLC) has accounted for the 80%-85% of all cases of lung cancer.Mesh
Preceding NSCLC individualized treatment receives much concern.Research shows, the anaplasia lymphom kinase of echinoderm microtubule associated protein 4/
(echinoderm microtubule-associated protein-like 4/anaplastic lymphoma kinase,
EML4/ALK very important effect, the positive patient of EML4/ALK fusions) are played in NSCLC generation evolution
Account for the 3%-7% of all NSCLC patients.For the positive advanced NSCLC patients of EML4/ALK fusions, listing in 2013
Lung cancer molecular targeted agents anaplasia lymphom kinase/tyrosine kinase inhibitor (anaplastic lymphoma kinase/
Tyrosine kinase inhibitor, ALK-TKI) it is that gram azoles replaces Buddhist nun, show significant therapeutic effect, first-line treatment
PFS was brought up to 10 months from 7 months compared with chemotherapy, and it can significantly extend the life cycle of such patient, make part late period
The treatment of NSCLC patient obtains new hope.AKK-TKI is objective effective percentage of the targeted drug to NSCLC patient of representative
Up to 60%, Progression free survival reaches the 8-10 months, total existence significantly extension.Although the positive patient of EML4/ALK fusions benefits aobvious
Write, but often there is the resistance to AKK-TKI in 1-2 in these patients so that AKK-TKI curative effect reduction.Face at present
Not yet occur effectively, ALK-TKI curative effects being strengthened, delay the medicine of its resistance on bed.Thus, it is found that effective enhancing
ALK-TKI curative effects, delay the medicine of its resistance that there is very important scientific meaning and clinical value.
Legalon (siLybin) is extracted from plant milk thistle (SiLybumMarianimL.S.L) fruit effective
Composition, is clinically mainly used in treatment acute, chronic hepatitis, cirrhosis, fatty liver, hepatic injury, metabolism Poisoning liver caused by alcohol
Damage, gall stone and spleen disease etc..Prior art has many researchs to legalon, including it is used to treat the purposes such as lung cancer
Report, but the research for its compound is less；CN103933039 discloses the medicine of a kind of legalon and Sorafenib
Compositions, it is used to treat primary carcinoma of liver, lung cancer and breast cancer.But prior art yet there are no on legalon or
Its salt is with gram azoles for ALK-TKI compounds such as Buddhist nuns and its for the standby report for strengthening ALK-TKI curative effects, delaying its resistance.
The content of the invention
The invention provides a kind of enhancing ALK-TKI curative effects, delay the compound and its preparation of its resistance.
The present invention provides a kind of enhancing ALK-TKI curative effects, delays the compound of its resistance, and the compound includes parts by weight
ALK-TKI and parts by weight for 12.5-50 parts are 7-70 parts of legalon or its salt.
Preferred gram of azoles of ALK-TKI of the present invention replaces Buddhist nun or Ceritinib, and further preferred ALK-TKI is that a gram azoles is replaced
Buddhist nun.
Gram azoles can reach 60% to the treated effect of non-small cell lung cancer for Buddhist nun, but take gram azoles for Buddhist nun 1-2
Afterwards, also occur that drug resistance causes gram azoles to be reduced for the curative effect of Buddhist nun.But a gram azoles can be overcome by also finding no any medicine at present
For the drug resistance of Buddhist nun, the present invention is drawn by substantial amounts of experiment, and legalon or its salt are replaced after Buddhist nun's composition compound with gram azoles, can
Gram azoles is effectively reversed to replace the drug resistance of Buddhist nun, so that gram azoles strengthens for the curative effect of Buddhist nun.
In further improved scheme, the preferred silibinin meglumine of salt, legalon arginine or the water of legalon
Fly Ji guest's histidine.Further preferably, the salt is selected from silibinin meglumine.
In compound of the present invention, gram azoles is 17 parts for the parts by weight of Buddhist nun, and the parts by weight of legalon are 35
Part.When gram azoles replaces the ratio of weight and number of Buddhist nun and legalon to be 17:It is best for the enhancing effect of Buddhist nun to gram azoles when 35, and prolong
The effect for delaying its resistance is also optimal.
Another aspect of the present invention provides the oral formulations being made up of compound and auxiliary material, preferably tablet.The tablet is
By label and the bilayer tablet that constitutes of release layer of parcel label, the label of legalon or its salt with excipient by being made up
Micro-capsule；The release layer is made up of ALK-TKI and auxiliary material.
In above-mentioned tablet, excipient is selected from Cholesteryl hexadecanoate, propyleneglycoles, stearic acid sodium lactate；Auxiliary material is selected from
Monostearate calcium, maltodextrin, single certain herbaceous plants with big flowers acyl group glycerine and superfine silica gel powder；The parts by weight of each composition of the bilayer tablet are：
Label：
The present invention is made after tablet entrance in vivo, gram azoles is for ALK- such as Buddhist nuns by the way that compound is made after bilayer tablet
TKI first plays a role, afterwards, and legalon or its salt slowly play a role, and both play a part for the treatment of non-small cell lung cancer,
ALK-TKI curative effect can also be strengthened simultaneously, delay its resistance.Gram azoles is mixed for Buddhist nun with monostearate calcium and maltodextrin
Afterwards, gram azoles can be improved and replace the dissolubility of Buddhist nun, and then improve its bioavilability；Simultaneously by legalon or its salt and cholesterine palm fibre
Glycerin monostearate, propyleneglycoles, stearic acid sodium lactate are made after micro-capsule, can slowly play curative effect, make label 1,2,6,12 and 24
The cumulative defaultlogic of hour respectively reaches 30-32%, 65-67%, 80-82%, 85-88% and more than 90%, makes this pair
Synusia has an effect that drug release is steady, slowly release the drug, and can reach that 24h releases the drug to obtain purpose.And it is made after micro-capsule and may be used also
Raising is the water solubility and stability of legalon.
Another aspect of the present invention provides the compound in preparing enhancing ALK-TKI curative effects, delaying the medicine of its resistance
Application.
In addition, additionally providing application of the tablet in preparing enhancing ALK-TKI curative effects, delaying the medicine of its resistance.
Another aspect of the present invention provides the preparation method of sustained release tablets, and this method comprises the following steps：A. by legalon
Or its salt is added in Cholesteryl hexadecanoate and propyleneglycoles, uniform, obtained legalon or its salt abrasive material are ground to；Will
Stearic acid sodium lactate is 1 by volume:3 are added to the water, and the aqueous solution is made；Legalon or its salt abrasive material and the aqueous solution are mixed
Close uniform, in high speed shearing emulsification, legalon or its salt colostrum is made；Legalon or its salt colostrum are placed in high pressure homogenization
Emulsified in machine, legalon or its salt emulsion is made；Legalon or its salt LS are dried, obtained particle size range is
15-25 μm of legalon or its salt micro-capsule, as label；
B. gram azoles is well mixed for Buddhist nun with monostearate calcium and maltodextrin, mixed powder is made；
C. single certain herbaceous plants with big flowers acyl group glycerine is dissolved in absolute ethyl alcohol, adds mixed powder, be well mixed, softwood processed；
D. softwood is uniformly coated on label, wet granular is spray-dried by wet granular processed, whole grain is carried out, with micro mist silicon
Glue is well mixed, tabletting, is made.
Another aspect of the present invention additionally provides the sustained release tablets in the medicine for preparing enhancing ALK-TKI curative effects, delaying its resistance
Application in thing.
The beneficial effects of the present invention are, the present invention provide a kind of legalon or its salt and ALK-TKI compound and
Its purposes, the compound can be used for enhancing ALK-TKI curative effects, delay its resistance, be effectively improved ALK-TKI therapeutic effect
In addition, being drawn by experiment, legalon replaces the ALK-TKI such as Buddhist nun compound to the therapeutic effect of non-small cell lung cancer with gram azoles
It is substantially better than the curative effect that gram azoles replaces Buddhist nun；And legalon with other kinds of inhibitor such as Sorafenib, Tarceva etc. to non-
The therapeutic effect of ED-SCLC does not improve a lot compared with single inhibitor；And legalon can only delay gram
Azoles will not delay the resistance of other kinds of non-small cell lung carcinostatic agent for the ALK-TKI such as Buddhist nun drug resistance.
Brief description of the drawings
Fig. 1 is sensitivity experiments of EGFR-TKI sensitive strains H1650, EGFR-TKI persister H1650-M3 to Tarceva
As a result；
Fig. 2 is the sensitivity experiments result that ALK-TKI sensitive strains H2228 replaces Buddhist nun to gram azoles；
Fig. 3 is the sensitivity experiments result that ALK-TKI persisters H2228-CR replaces Buddhist nun to gram azoles；
Fig. 4 is sensitivity experiments knots of EGFR-TKI sensitive strains PC-9, EGFR-TKI persister PC-9GR to Sorafenib
Really；
Fig. 5 is the aggressive experimental result that ALK-TKI persisters H2228-CR is attacked；
Fig. 6 is the aggressive experimental result that EGFR-TKI persisters H1650-M3 is attacked；
Fig. 7 is the aggressive experimental result that EGFR-TKI persisters PC-9GR is attacked；
Fig. 8 is each group nude mouse tumor situation of change schematic diagram of experiment in vivo；
Fig. 9 tumor growth curve figures.
Embodiment
Embodiment 1
A kind of enhancing ALK-TKI curative effects, the compound for delaying its resistance：
The compound includes parts by weight and replaces Buddhist nun and 35 parts of legalon for 17 parts of gram azoles.Embodiment 2
A kind of enhancing ALK-TKI curative effects, the compound for delaying its resistance：
The compound includes parts by weight and replaces Buddhist nun and 60 parts of silibinin meglumine for 25 parts of gram azoles.
A kind of legalon tablet of embodiment 3
The parts by weight of each composition of the bilayer tablet are：
Label：
The preparation method of the double-layer tablets is：
A. legalon or its salt are added in Cholesteryl hexadecanoate and propyleneglycoles, is ground to uniform, obtained water
Fly Ji guest or its salt abrasive material；It is 1 by volume by stearic acid sodium lactate:3 are added to the water, and the aqueous solution is made；By legalon
Or its salt abrasive material and the aqueous solution are well mixed,
In high speed shearing emulsification, legalon or its salt colostrum is made；Legalon or its salt colostrum are placed in high pressure even
Emulsified in matter machine, legalon or its salt emulsion is made；Legalon or its salt LS are dried, obtained particle size range is
15-25 μm of legalon or its salt micro-capsule, as label；
B. gram azoles is well mixed for Buddhist nun with monostearate calcium and maltodextrin, mixed powder is made；
C. single certain herbaceous plants with big flowers acyl group glycerine is dissolved in absolute ethyl alcohol, adds mixed powder, be well mixed, softwood processed；
D. softwood is uniformly coated on label, wet granular is spray-dried by wet granular processed, whole grain is carried out, with micro mist silicon
Glue is well mixed, tabletting, is made.
The experiment in vitro of experimental example 1
1. experiment purpose：Can legalon improve the sensitiveness of ALK-TKI cell lines and its persister to ALK-TKI；
2. experimental method：The activity of lung carcinoma cell is calculated using MTT methods；
3. experimental procedure：
(1) to ALK-TKI sensitive strain H2228 cells, EGFR-TKI sensitive strain H1650 cells, ALK-TKI persisters
H2228-CR cells, EGFR-TKI persister H1650-M3 cells, EGFR-TKI sensitive strain PC-9 cells, EGFR-TKI persisters
PC-9GR cells are expanded respectively, logarithmic phase human lung carcinoma cell line are collected respectively, with trypsin digestion and cell, centrifuge cell
Suspension, makes cell deposition get off；Cell is resuspended with culture medium, counts；
(2) cell density is diluted to 2 × 10 after counting4/ mL, is added with sample injector in each hole of flat 96 orifice plate
100 μ L cell suspensions, per hole containing 2000 cells；96 plates for being inoculated with cell are put into 5%CO2, in 37 DEG C of cell culture incubators
Incubated overnight；
(3) next day configures 30 μM of legalons (M represents moL/L, μM expression micromole μm oL/L, similarly hereinafter), adds medicine
Concentration gradient, 5 concentration are set altogether, each concentration sets 3 multiple holes；Totally 12 groups of experiment, it is specific as follows：
EGFR-TKI sensitive strain H1650 groups：Give (20 μM, 15 μM, 10 μM, 5 μM, 2.51 μM, 0 μM) Tarceva；
EGFR-TKI sensitive strain H1650+ legalon groups：Give (20 μM, 15 μM, 10 μM, 5 μM, 2.51 μM, 0 μM) strategic points
Replace+30 μM of legalons of Buddhist nun in Lip river；
EGFR-TKI persister H1650-M3 groups：Give (20 μM, 15 μM, 10 μM, 5 μM, 2.51 μM, 0 μM) Tarceva；
EGFR-TKI persister H1650-M3+ legalon groups:Give (20 μM, 15 μM, 10 μM, 5 μM, 2.51 μM, 0 μM)
+ 30 μM of legalons of Tarceva；
ALK-TKI sensitive strain H2228 groups：(10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0 μM) gram azoles is given for Buddhist nun；
ALK-TKI sensitive strain H2228+ legalon groups：Give (10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0 μM)
Gram azoles replaces+30 μM of legalons of Buddhist nun；
ALK-TKI persister H2228-CR groups：(10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0 μM) gram azoles is given to replace
Buddhist nun；
ALK-TKI persister H2228-CR+ legalon groups：Give (10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0
μM) gram azoles replace+30 μM of legalons of Buddhist nun；
EGFR-TKI sensitive strain PC-9 groups：(16 μM, 8 μM, 4 μM, 2 μM, 1 μM) Sorafenib
EGFR-TKI sensitive strain PC-9+ legalon groups：(16 μM, 8 μM, 4 μM, 2 μM, 1 μM)+30 μM of fine grindings of Sorafenib
Ji guest；
EGFR-TKI persister PC-9GR groups：(16 μM, 8 μM, 4 μM, 2 μM, 1 μM) Sorafenib
EGFR-TKI persister PC-9GR+ legalon groups：(16 μM, 8 μM, 4 μM, 2 μM, 1 μM)+30 μM of water of Sorafenib
Fly Ji guest；
(4) after being administered, insert incubator and continue to cultivate 48h；The action effect of medicine is then observed under inverted microscope；
(5) culture medium of dosing is abandoned, the fresh 10%FBS nutrient solutions of 100 μ L are rejoined per hole, contains 10 μ L MTT adding
(5mg/mL, i.e. 0.5%MTT), continues to cultivate 4h；It is to be crystallized to be sufficiently formed, thoroughly remove nutrient solution in hole, 150 μ are added per hole
L dimethyl sulfoxide (DMSO)s, put low-speed oscillation 10min on shaking table, crystal is fully dissolved；At enzyme-linked immunosorbent assay instrument OD490nm
Measure the light absorption value in each hole.And then calculate the survival rate of each group cell or the IC of each group50Value.
4. experimental result
As shown in Figures 2 and 3, add 30 μM of legalons after, be remarkably improved ALK-TKI sensitive strain H2228 cells and
ALK-TKI persister H2228-CR cells replace the sensitiveness of Buddhist nun to gram azoles, and gram azoles for showing as each concentration is replaced under Buddhist nun's effect, water
The survival rate of cell can be significantly reduced by flying the addition of Ji guest；As shown in figure 1, adding after 30 μM of legalons, EGFR-TKI is quick
Feel the IC of strain H1650 cells and EGFR-TKI persister H1650-M3 cells to Tarceva50There is no too much influence；Such as Fig. 4
It is shown, add after 30 μM of legalons, EGFR-TKI sensitive strain PC-9 cells and EGFR-TKI persister PC-9GR cells are to rope
La Feini IC50There is no too much influence
5. conclusion
Legalon can strengthen ALK-TKI curative effect, and can delay ALK-TKI resistance；Legalon can not
Enough strengthen the curative effect of Tarceva and Sorafenib to non-small cell lung cancer, and Tarceva and Suo Lafei can not be delayed
The resistance of Buddhist nun.
The experiment in vitro of embodiment 2
Experiment purpose：Can legalon reduce the invasion experiment of ALK-TKI mdr cells；
Experimental method：The invasion of lung carcinoma cell is calculated using Transwell methods；
Experimental procedure is as follows：
(1) selection Transwell chamber：24-well 6.5mm Diameter Ineserts8.0μm Pore
Size(Corning Incorporated)。
(2) 100uL serum-free mediums are added to Transwell chamber upper chambers in advance, lower room adds 600 μm of serum
Nutrient solution (10%FBS), and be put into 37 DEG C of incubators and be incubated 2h；
(3) experiment is divided into 9 groups, is specially：ALK-TKI sensitive strain H2228 groups, EGFR-TKI sensitive strain H1650 groups,
ALK-TKI persister H2228-CR groups, EGFR-TKI persister H1650-M3, ALK-TKI persister H2228-CR+ legalons
Group, EGFR-TKI persister H1650-M3+ legalons group, EGFR-TKI sensitive strain PC-9 groups, EGFR-TKI persisters PC-
9GR groups, EGFR-TKI persister PC-9GR+ legalon groups；With trypsin digestion cell, nutrient solution is resuspended after centrifugation, with PBS and
Respectively it washed once before and after serum-free medium；
(4) cell is resuspended with serum free medium, counts, adjustment concentration is 2 × 105/ mL, to Transwell
Chamber upper chambers add 100uL cell suspensions, and 24 orifice plates are continued in 5%CO2, 37 DEG C, train in 90% humidity cell culture incubator
Support 48 hours；
After (5) 48 hours, the nutrient solution of filter membrane upper chamber and lower room is discarded, (upper chamber in equal volume is separately added into room up and down
200uL, lower room 600uL) preheating PBS, gently blow and beat PBS filter membrane lower surface；
(6) room adds the μ L of 4% paraformaldehyde 800 downwards, is immersed in filter membrane lower surface and wherein fixes cell 20min；
(7) fixer is abandoned, with PBS 2 times, transwell cells are inverted, made under filter membrane up, natural air drying.
(8) the crystal violet dye liquor of (upper chamber 200uL, lower room 800uL) is separately added into room up and down, dyes 20min.
(9) a large amount of distilled water are respectively washed 24 orifice plates and transwell cells, and that wipes that upper surface do not migrate with cotton balls is thin
Born of the same parents, (H1650-M3 is adherent in 24 holes through cell film, and counting is added for observation counting under inverted microscope；Randomly select 5
High power field, averages after counting cell number.
Experimental result
Legalon can significantly reduce the invasion of mdr cell：As shown in figure 5, ALK-TKI persisters H2228-CR
The cell number average value attacked be 238, legalon processing it is dropped to 86 (statistical procedures have significance difference
It is different, p<0.01)；As shown in fig. 6, the cell number average value that EGFR-TKI persisters H1650-M3 is attacked is 209, fine grinding
Ji guest makes it drop to 200 (statistical calculations are not significantly different, p ＞ 0.01)；As shown in fig. 7, EGFR-TKI persisters
The cell number average value that PC-9GR is attacked be 288, legalon it is dropped to 276 (statistical calculations do not show
Write difference, p ＞ 0.01).
The experiment in vivo of experimental example 3
Experiment purpose：Can legalon improve sensitiveness and suppression of the ALK-TKI sensitive strain H2228 cells to ALK-TKI
Tumour growth experiment processed
ALK-TKI sensitive strain H2228 cells, (Beijing magnificent experimental animal technology of dimension tonneau is limited from nude mice for experimental animal
Company, female mice, 3 groups of experiment point (control group and 1 group of experiment, 2 groups of experiment), every group of 6 animals, totally 18)
Experimental procedure is as follows：
(1) choose before the week old of nude mice 6, inoculated tumour cell, need to be fed 1 week raising place；
(2) to oxter inoculated tumour cell H2228 on the right side of every nude mice：2×106, reconstruct and build Nude Mouse Model；
(3) carry out that nude mice body weight is weighed (electronic scale measurement) and gross tumor volume is measured from inoculated tumour cell the 10th day
(vernier caliper measurement).Knurl body most major diameter (a) and most minor axis (b) are measured, and calculates tumour relative volume V (mm3)=ab2/ 2, often
Week measurement 2 times；
(4) treat that transplantable tumor volume reaches 50mm3During left and right, animal is randomly divided into 3 groups and to give relative medicine oral：
Control group：Gram azoles is given for Buddhist nun (170mg/L)；
Test 1 group：Gram azoles is given for Buddhist nun (170mg/L)+legalon (350mg/L)；
Test 2 groups：Give Sorafenib (170mg/L)+legalon (350mg/L)；
(5) three groups of equal daily administrations, continue 4 weeks；Nude mice is put to death after 4 weeks, tumour final volume is measured, tumour inhibiting rate is calculated；
Tumour inhibiting rate=(control group relative volume-experimental group relative volume)/control group relative volume × 100%；Take tumor tissue, one
Divide and fixed in neutral formalin, a part is saved backup in liquid nitrogen.Draw tumor growth curve.
Experimental result
As shown in figure 8, the gross tumor volume of 1 group of experiment is reduced significantly relative to 2 groups of control group and experiment, and there is statistics to show
Write difference.As shown in figure 9, in treatment starting, 3 groups of tumor average volumes are consistent, respectively 10.53mm3, 11.41mm3,
11.62mm3；Treat after 4 weeks, control group tumor average volume is 2254.5mm3, testing 1 group of tumor average volume is
1512.3mm3, 2 groups of group tumor average volumes of experiment are 2056.4mm3；Test 1 group with control group and experiment 2 groups compared with tumour have
Reduce, with statistically-significant difference, and test 2 groups compared with control group, gross tumor volume is not changed much, and no statistics is poor
It is different.
Experiment conclusion
Compared with gram azoles is used alone for Buddhist nun, gram azoles can be obviously reduced the growth of transplantable tumor for Buddhist nun's joint legalon.Table
Bright legalon and gram azoles can significantly increase its curative effect to non-small cell lung cancer for nylon 6 complex；With Sorafenib+milk thistle
Guest's group is compared, and gram azoles can also be obviously reduced the growth of transplantable tumor for Buddhist nun's joint legalon.
Claims (5)
1. a kind of enhancing ALK-TKI curative effects, the compound for delaying its resistance, it is characterised in that the compound includes parts by weight
Number is 12.5-50 parts of ALK-TKI and parts by weight are 7-70 parts legalon or its salt, the ALK-TKI are that a gram azoles is replaced
Buddhist nun.
2. compound as claimed in claim 1, it is characterised in that the salt is silibinin meglumine, the smart ammonia of legalon
Acid or legalon histidine.
3. compound as claimed in claim 1, it is characterised in that described gram of azoles is 17 parts, the water for the parts by weight of Buddhist nun
The parts by weight for flying Ji guest are 35 parts.
4. the tablet being made containing any described compounds of claim 1-3 and auxiliary material, it is characterised in that the tablet is served as reasons
The bilayer tablet of the release layer composition of label and parcel label, the label is made up of legalon or its salt with excipient
Micro-capsule；The release layer is made up of ALK-TKI and auxiliary material.
5. tablet as claimed in claim 4, it is characterised in that the excipient is selected from Cholesteryl hexadecanoate, propylene second two
Alcohol, stearic acid sodium lactate；The auxiliary material is selected from monostearate calcium, maltodextrin, capric monoglyceride and superfine silica gel powder；It is described
The parts by weight of each composition of bilayer tablet are：
Label：
Release layer
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| CN103316344A (en) * | 2013-04-07 | 2013-09-25 | 中国人民解放军第三军医大学第三附属医院 | EGFR-TKI compound for delaying or reversing drug-resistance in lung cancer treatment, and preparation thereof |
| CN103316343A (en) * | 2013-04-07 | 2013-09-25 | 中国人民解放军第三军医大学第三附属医院 | Application of biguanide based medicament in medicaments for delaying or reversing acquired drug-resistance of NSELC treated by EGFR-TKI |
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