CN103316344A - EGFR-TKI compound for delaying or reversing drug-resistance in lung cancer treatment, and preparation thereof - Google Patents

EGFR-TKI compound for delaying or reversing drug-resistance in lung cancer treatment, and preparation thereof Download PDF

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CN103316344A
CN103316344A CN2013101184385A CN201310118438A CN103316344A CN 103316344 A CN103316344 A CN 103316344A CN 2013101184385 A CN2013101184385 A CN 2013101184385A CN 201310118438 A CN201310118438 A CN 201310118438A CN 103316344 A CN103316344 A CN 103316344A
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tki
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CN103316344B (en
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何勇
李力
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Third Affiliated Hospital of TMMU
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Abstract

The invention relates to an application of a biguanide based medicament in medicaments for delaying or reversing acquired drug-resistance of NSELC treated by EGFR-TKI, wherein the biguanide based medicament and EGFR-TKI are taken simultaneously or intervally. The compound is used to delay or reverse generation of EGFR-TKI acquired drug-resistance, and performs varying-degree inhibition effects on main mechanisms of EGFR-TKI acquired drug-resistance of NSCLC patients, and thus the sensibility of the lung-cancer patients to EGFR-TKI is increased, the disadvantage that EGFR-TKI is easy to resist drugs is overcome, and the curative effect of EGFR-TKI is improved.

Description

Delay or reverse EGFR-TKI complex and the preparation thereof of drug resistance in treatment pulmonary carcinoma
Technical field
The invention belongs to the tumour medicine field, particularly delay or reverse EGFR-TKI complex and the preparation thereof of nonsmall-cell lung cancer acquired drug-resistance.
Background technology
Epidermal growth factor recipient tyrosine kinase inhibitor (tyrosine kinase inhibitor, EGFR-TKI) be at present by multinational approval and be widely used in progress or the micromolecule targeted drug take EGFR as target spot of refractory non-small cell lung (non-small cell lung cancer, NSCLC).One of bottleneck that restriction EGFR-TKI further uses is that acquired drug-resistance occurs.The generation of EGFR-TKI acquired drug-resistance is relevant with two kinds of mechanism at least: Secondary cases exon T790M sudden change and the amplification of MET Secondary cases.Chinese patent CN102626405A discloses the application of paclitaxel in preparation treatment EGFR-TKI acquired drug-resistance medicine, this invents confirmation, paclitaxel can reverse the EGFR-TKI acquired drug-resistance based on above-mentioned two kinds of mechanism, for the nonsmall-cell lung cancer patient who from Erlotinib/treated with gefitinib, produces acquired drug-resistance, behind Paclitaxel Chemotherapy, can again consider to use Erlotinib/treated with gefitinib, so that Erlotinib/gefitinib continues the performance function.
Also disclose following content in the prior art, EGFR-TKI drug resistance patient unites Cetuximab with Ah method for the Buddhist nun and solves drug resistance; And use EGFR-TKI and EGFR monoclonal antibody to suppress simultaneously the EGFR intracellular region and extracellular region (vertical blocking-up) may can overcome drug resistance.
Based on the amplification of MET Secondary cases, MetMAb is a kind of monoclonal antibody specific, with the MET receptors bind outside the born of the same parents.Whole world, random, double blinding II phase clinical studies show are crossed the nonsmall-cell lung cancer of expression for MET, the MetMAb+ Erlotinib uses more separately Erlotinib can prolong patient's disease free survival time (HR0.56; 95%CI0.31 – 1.02; And for crossing the expression patient without MET, the drug combination effect is lower than independent Erlotinib treatment p=0.05).
Also have in addition HKI-272, rapamycin, BIBW2992(Tovok), p53 inhibitor, tumor necrosis factor α (TNF α) multi-medicament or method be used for the EGFR-TKI acquired drug-resistance.
Although the method for the above-mentioned EGFR-TKI of overcoming acquired drug-resistance has obtained certain effect, treat expensively, and the effect that overcomes drug resistance still need be improved.
Summary of the invention
The invention provides a kind of the EGFR-TKI complex and the preparation thereof that delay or reverse the nonsmall-cell lung cancer acquired drug-resistance with low cost.
The active component of complex of the present invention comprises the biguanides of 250-2000 weight portion and the EGFR-TKI of 75-1000 weight portion.
EGFR-TKI(EGFR tyrosine kinase inhibitor, epidermal growth factor recipient tyrosine kinase inhibitor) be the emerging targeted drug of a class, the saying of summary comprises the reversible and irreversible inhibition agent of EGFR.The EGFR reversible inhibitor comprises: 4-aniline quinazoline class, Pyridopyrimidine class and Pyrrolopyrimidine medicine, 4-aniline quinazoline compounds mainly contains and comprises gefitinib (Gefitinib, Iressa, Iressa), Erlotinib (Erlotinib, Erlotinib), Conmana (Conmana, Kai Meina), Lapatinib (Lapatinib); Azolopyrimidines has PKI-66 (CGP59326); Pyrido-pyrimidines has PD158780 and PD1655572 kind.The agent of EGFR irreversible inhibition has CI-1033 (PD2183805) and EKB-569.Preferred EGFR-TKI is gefitinib (Gefitinib, Iressa, Iressa), Erlotinib (Erlotinib, Erlotinib), Lapatinib pool (Lapatinib).
Biguanides is a class medicine that contains as shown in the formula (I), comprises in metformin and salt thereof or derivant, phenformin, buformin, the proguanil one or more.For the understanding of biguanides, should not be subjected to the restriction of the original purposes of biguanides.
Figure BDA00003015735800031
Most preferred biguanides is that (Metformin Hydrochloride is called for short metformin hydrochloride, and Metformin), main dosage form is plain sheet, slow releasing tablet, slow releasing capsule.
EGFR-TKI complex of the present invention is the preparation unit made of active component and is the preparation unit that active component is made by EGFR-TKI by biguanides.The biguanides preparation unit that makes respectively and EGFR-TKI preparation unit, at least comprise two kinds of application modes, the firstth, be positioned over simultaneously in the packing material, can take at the interval like this, such as in ante cibum with from above-mentioned packing material, take out respectively after meal certain preparation unit interval and take; The second way is to be positioned in the capsule, can take simultaneously like this.
EGFR-TKI complex of the present invention, described complex comprise the second preparation unit of jointly being made for active component by biguanides and EGFR-TKI.Described the second preparation unit comprises oral solid formulation, liquid preparation.Described solid preparation comprises the known all solids preparation of this areas such as tablet, capsule, powder, granule; Described liquid preparation comprises all liquid preparations such as injection, oral liquid, syrup.
EGFR-TKI complex of the present invention, the active component of described complex comprise the metformin of 250-2000 weight portion and the gefitinib of 75-1000 weight portion.
EGFR-TKI complex of the present invention, the active component of its complex comprise the metformin of 1000 weight portions and the gefitinib of 250 weight portions.
EGFR-TKI complex of the present invention, the active component of its complex comprise the metformin of 250-2000 weight portion and the Erlotinib of 75-150 weight portion.
EGFR-TKI complex of the present invention, the active component of its complex comprise the metformin of 1000 weight portions and the Erlotinib of 150 weight portions.
Beneficial effect of the present invention is, the EGFR-TKI complex is used for delaying or reversing the generation of EGFR-TKI acquired drug-resistance, can bring into play to some extent inhibitory action to the main mechanism of NSCLC patient EGFR-TKI acquired drug-resistance, thereby strengthen patients with lung cancer to the sensitivity of EGFR-TKI, overcome the shortcoming of the easy drug resistance of EGFR-TKI, improve the curative effect of EGFR-TKI.
Description of drawings
The sensitivity tests result of the Erlotinib of Fig. 1, embodiment 1;
Wherein, the H1650 of abscissa, M3, H1650-M3+Met represent respectively sensitive strain H1650 cell, persister H1650-M3 cell, persister H1650-M3+ metformin (lower same), the Erlotinib IC of vertical coordinate 50Value(μ M) IC of expression Erlotinib 50Value.
The sensitivity tests result of the Gefitinib of Fig. 2, embodiment 1;
Wherein, the P9 of abscissa, R9, R9+Met represent respectively sensitive strain PC-9 cell, persister PC-9GR cell and persister PC-9GR+ metformin (lower with), the GefitinibIC50value(μ M of vertical coordinate) IC of expression gefitinib 50Value.
The microphotograph photograph of invasion and attack occurs in the drug-resistant cell strain M3 of Fig. 3, embodiment 2;
The aggressive result of the test of invasion and attack occurs in the drug-resistant cell strain M3 of Fig. 4, embodiment 2;
The microphotograph photograph of invasion and attack occurs in the drug-resistant cell strain R3 of Fig. 5, embodiment 2;
The aggressive result of the test of invasion and attack occurs in the drug-resistant cell strain R9 of Fig. 6, embodiment 2;
The experimental procedure schematic diagram of experiment in the body of Fig. 7, embodiment 3;
Wherein: cells injection represents to inject tumor cell; Drug application and tumor-50mm 3Expression treats that the transplanted tumor volume reaches 50mm 3Give medicine during the left and right sides; TKI alone and TKI and Met represent respectively to use separately gefitinib and use simultaneously gefitinib and metformin; Water represents to answer the blank group of water; Met alone represents the metformin group; Tumor volume measurement and sacirifice(4w) expression drug administration rear execution of 4 week nude mice, measure the tumor final volume.
Experiment respectively organizes nude mice tumor situation of change schematic diagram in the body of Fig. 8, embodiment 3.
The gross tumor volume curve of experiment in the body of Fig. 9, embodiment 3;
Wherein, abscissa weeks post-drug application represents administration Later Zhou Dynasty, one of the Five Dynasties number; Vertical coordinate Tumor volume(mm 3) the expression gross tumor volume.
The present invention is further described below by test example:
Test example 1 experiment in vitro
Experiment purpose: can metformin improve the EGFR-TKI drug-resistant cell strain to the sensitivity tests of EGFR-TKI
Sensitive strain H1650 cell and persister H1650-M3 cell (being so kind as to give by Cold Spring Harbor Laboratory), sensitive strain PC-9 cell and persister PC-9GR cell (professor Xu Jun is so kind as to give by Guangzhou Medical College).
Test method: adopt the MTT method to calculate the activity of lung carcinoma cell.
Experimental procedure is as follows:
(1) sensitive strain H1650 cell, persister 1650-M3 cell, sensitive strain PC-9 cell and persister PC-9GR cell are increased respectively, collect respectively the JEG-3 of logarithmic (log) phase, use trypsin digestion and cell, the centrifuge cell suspension gets off cell deposition.Use the culture medium re-suspended cell, counting;
(2) behind the counting cell density is diluted to 2 * 10 4/ ml adds 100 μ l cell suspension with sample injector in each hole of flat 96 orifice plates, every hole contains 2000 cells; 96 plates of having inoculated cell are put into 5%CO 2, incubated overnight in the cell culture incubator under 37 ℃ and 90% humidity;
(3) configure 10mM Gefitinib(gefitinib next day) (M represents mol/L, mM represents a mM mmol/L, lower same), 20mM Erlotinib(Erlotinib), 2M metformin(metformin), add the Concentraton gradient of medicine, establish altogether 5 concentration, each concentration is established 5 multiple holes; Totally six groups of experiments, specific as follows:
Sensitive strain PC-9:(1.6,0.8,0.4,0.2,0.1,0) μ M Iressa;
Persister PC-9GR:(16,8,4,2,1,0) μ M Iressa;
Persister PC-9GR+10mMol metforin:10mM metformin+ (16,8,4,2,1,0) μ M Gefitinib;
Sensitive strain H1650:(20,15,10,5,2.5,0) μ M Erlotinib;
Persister H1650-M3:(20,15,10,5,2.5,0) μ M Erlotinib;
Persister H1650-M3+10mM metformin:(20,15,10,5,2.5,0) μ MErlotinib+10mMol metforin.
After the cell administration of (4) 96 orifice plates, insert 5%CO 2, cell culture incubator continues to cultivate 48h under 37 ℃ and 90% humidity.
(5) action effect of observation medicine under the inverted microscope.
(6) abandon the culture medium of dosing, every hole adds the fresh 10%FBS culture fluid of 100 μ l again, contains 10ulMTT(5mg/ml in adding, i.e. 0.5%MTT), continue to cultivate 4h.
(7) after MTT added cultivation 4h, crystallization fully formed, and thoroughly removes culture fluid in the hole, and every hole adds 150 μ l dimethyl sulfoxide, puts low-speed oscillation 10min on the shaking table, and crystal is fully dissolved.Measure the light absorption value in each hole at enzyme-linked immunosorbent assay instrument OD490nm place.
Data analysis
It is IC50 concentration that cell inhibitory rate reaches the required drug level of a half, and IC50 calculates by the IC50 software for calculation.
Experimental result
As shown in Figure 1, add after the metformin, drug-resistant cell strain H1650-M3 is to the IC of Erlotinib 50There were significant differences to drop to 4.8 μ M(statistical analysis from 18.3 μ M, p＜0.01); As shown in Figure 2, drug-resistant cell strain PC-9GR is to the IC of Gefitinib 50There were significant differences to drop to 1.25 μ M(statistical analysis from 4.84 μ M, p＜0.01).
Test example 2 experiment in vitro
Experiment purpose: can metformin reduce the aggressive test of EGFR-TKI mdr cell
Sensitive strain H1650 cell, persister H1650-M3 cell, sensitive strain PC-9 cell and persister PC-9GR cell (cell derived is the same)
Test method: adopt the Transwell method to calculate the aggressive of lung carcinoma cell
Experimental procedure is as follows:
(1) selects Transwell chamber:24-well6.5mm Diameter Ineserts8.0 μ m Pore Size(Corning Incorporated);
(2) in advance to the upper chamber adding of Transwell chamber 100ul serum-free medium, lower chamber adds 600 μ m serum free culture system liquid (10%FBS), and puts into 37 ℃ of incubators and hatch 2h;
(3) to be divided into be six groups in experiment, is specially: H1650 groups of cells, H1650-M3 group, H1650-M3+ metformin group, PC-9 group, PC-9GR group, PC-9GR+ metformin group.Use trypsin digestion cell, centrifugal rear culture fluid is resuspended, with each washing before and after PBS and the serum-free medium once;
(4) use the serum-free medium re-suspended cell, counting, adjusting concentration is 2 * 10 4/ ml, the chamber adds 100ul cell suspension on the Transwell chamber, and 24 orifice plates are continued at 5%CO 2, cultivated 48 hours in 37 ℃, 90% humidity cell culture incubator;
After (5) 48 hours, discard the culture fluid of chamber and lower chamber on the filter membrane, add respectively the preheating PBS of equal-volume (upper chamber 200ul, lower chamber 600ul) in chamber up and down, wash 2 times, at every turn 3min;
(6) chamber adds 4% paraformaldehyde, 800 μ l downwards, makes the filter membrane lower surface be immersed in wherein fixed cell 30min;
(7) abandon fixative, clean 2 times with PBS, be inverted the transwell cell, make under the filter membrane to face up natural air drying;
(8) add respectively the crystal violet dye liquor of (upper chamber 200ul, lower chamber 800ul), dyeing 30min in chamber up and down;
(9) a large amount of distilled water clean respectively 24 orifice plates and transwell cell, wipe the cell that upper surface does not move with cotton balls, observe counting and take a picture (it is adherent in 24 holes that H1650-M3 passes the cell film, and counting adds) under inverted microscope.Choose at random 5 high power fields, average behind the counting cells number.
Experimental result
Metformin can significantly reduce the aggressive of mdr cell: shown in Fig. 3,4, the cell number meansigma methods that invasion and attack occur drug-resistant cell strain M3 is 209, and metformin is processed and made it drop to 101 (there were significant differences for statistical procedures, p＜0.01); Shown in Fig. 5,6, the cell number meansigma methods that invasion and attack occur drug-resistant cell strain R9 is 289, and metformin makes it drop to 92 (there were significant differences for statistical calculations, p＜0.01)
Experiment in test example 3 bodies
Experiment purpose: can metformin improve the EGFR-TKI mdr cell to the sensitivity of EGFR-TKI and suppress the tumor growth test
Drug-resistant cell strain PC-9GR, laboratory animal is selected nude mice (Beijing Vital River Experimental Animals Technology Co., Ltd., female Mus, experiment minute 4 groups (blank group, metformin group, Iressa group, Iressa+metformin group), every group of 8 animals, totally 32)
In conjunction with shown in Figure 7, experimental procedure is as follows:
(1) chooses ages in nude mice 6 week, before the inoculated tumour cell, need raising local the nursing for 1 week;
(2) give oxter, every nude mice right side inoculated tumour cell PC9-GR:2 * 10 6, be resuspended among the 100 μ lPBS;
(3) carry out nude mice body weight (electronic scale measurement) and gross tumor volume (vernier caliper measurement) from inoculated tumour the 5th day.Measure the major diameter (a) of tumor body and minor axis (b), and calculate tumor relative volume V (mm 3)=(a * b 2)/2.Weekly twice until experiment finish.
(4) treat that the transplanted tumor volume reaches 30mm 3During the left and right sides, drink water by nude mice, give blank group common drinking water oral, metformin group metformin (1mg/ml) is oral, Iressa group nude mice Iressa (Iressa:250mg/L) aqueous solution is oral, give Iressa+metformin group nude mice Iressa Iressa(250mg/L)+Metformin(1mg/ml) aqueous solution is oral, uninterrupted administration.
(5) respectively organize equal administration every day and lasting 4 weeks, draw the gross tumor volume curve.
Experimental result
Shown in Fig. 8,9, the gross tumor volume of Iressa+metformin group significantly dwindles with respect to other groups, and initial in treatment, 4 groups of tumor average volumes are consistent, are respectively 29.917mm 3, 29.141mm 3, 27.75mm 3, 28.73254mm 3After treating for 4 weeks, the matched group tumor average volume is 2468.4mm 3, metformin group tumor average volume is 1678.1, and Iressa group tumor average volume is 1685.9, and Iressa+metformin group is 1027.9mm 3(metformin group and Iressa group are compared tumor to be had and dwindles with matched group, but without statistically-significant difference, the p value is respectively 0.05 and 0.052), Iressa+metformin group is compared gross tumor volume with its excess-three group and is obviously dwindled, and statistically-significant difference is arranged all, compare the p value all less than 0.01 with matched group with the metformin group, compare the p value less than 0.05 with the Iressa group).
The specific embodiment
Embodiment 1 assembly packaging
Assembly packaging comprises 1 metformin hydrochloride tablet (every contains the 250mg metformin hydrochloride) and 1 Erlotinib sheet (every contains Erlotinib 25mg)
Embodiment 2 assembly packagings
Assembly packaging comprises 1 metformin hydrochloride tablet (every contains the 250mg metformin hydrochloride) and 1 Erlotinib sheet (every contains Erlotinib 100mg)
Embodiment 3 assembly packagings
Assembly packaging comprises 1 metformin hydrochloride tablet (every contains the 250mg metformin hydrochloride) and 1 Erlotinib sheet (every contains Erlotinib 150mg)
Embodiment 4 assembly packagings
Assembly packaging comprises 1 metformin hydrochloride tablet (every contains the 250mg metformin hydrochloride) and 1 gefitinib sheet (every contains gefitinib 250mg)
Embodiment 5 assembly packagings
Assembly packaging comprises 2 metformin hydrochloride tablets (every contains the 1000mg metformin hydrochloride) and 2 gefitinib sheets (every contains gefitinib 500mg)
Embodiment 6 assembly packagings
Assembly packaging comprises 4 metformin hydrochloride tablets (every contains the 250mg metformin hydrochloride) and 1 gefitinib sheet (every contains gefitinib 250mg)
Embodiment 7 compositionss
Every contains 250mg metformin hydrochloride and 25mg Erlotinib
Method for making: metformin hydrochloride, Erlotinib, water soluble starch, medical starch, dextrin, hydroxypropyl cellulose, silicon dioxide are sieved according to given ratio mix homogeneously, then add binding agent and be made into soft material, granulation, oven dry, granulate, compacting are in flakes.
Embodiment 8 compositionss
Every contains 250mg metformin hydrochloride and 100mg Erlotinib
Method for making is with embodiment 7.
Embodiment 9 compositionss
Every contains 250mg metformin hydrochloride, 150mg Erlotinib
Method for making is with embodiment 7.
Embodiment 10 compositionss
Every contains 250mg metformin hydrochloride, 250mg gefitinib.
Method for making is with embodiment 7.
The above embodiment only is that preferred implementation of the present invention is described; be not that scope of the present invention is limited; design under the prerequisite of spirit not breaking away from the present invention; various distortion and improvement that those of ordinary skills make technical scheme of the present invention all should fall in the definite protection domain of claims of the present invention.

Claims (10)

1. an EGFR-TKI complex that delays or reverse the nonsmall-cell lung cancer drug resistance is characterized in that, the active component of described complex comprises the biguanides of 250-2000 weight portion and the EGFR-TKI of 75-1000 weight portion.
2. EGFR-TKI complex as claimed in claim 1 is characterized in that, described complex comprises by biguanides and is the preparation unit made of active component and is the preparation unit that active component is made by EGFR-TKI.
3. EGFR-TKI complex as claimed in claim 1 is characterized in that, described complex comprises the second preparation unit of jointly being made for active component by biguanides and EGFR-TKI.
4. arbitrary EGFR-TKI complex as claimed in claim 3 is characterized in that, described the second preparation unit comprises oral solid formulation, liquid preparation.
5. such as the described arbitrary EGFR-TKI complex of claim 1-3, it is characterized in that, described biguanides comprises in metformin and salt thereof or derivant, phenformin, buformin, the proguanil one or more.
6. EGFR-TKI complex as claimed in claim 5 is characterized in that, described EGFR-TKI medicine comprises one or more in gefitinib, Erlotinib, Conmana, the Lapatinib pool.
7. EGFR-TKI complex as claimed in claim 6 is characterized in that, the active component of described complex comprises the metformin of 250-2000 weight portion and the gefitinib of 75-1000 weight portion.
8. EGFR-TKI complex as claimed in claim 7 is characterized in that, the active component of described complex comprises the metformin of 1000 weight portions and the gefitinib of 250 weight portions.
9. EGFR-TKI complex as claimed in claim 6 is characterized in that, the active component of described complex comprises the metformin of 250-2000 weight portion and the Erlotinib of 75-150 weight portion.
10. EGFR-TKI complex as claimed in claim 9 is characterized in that, the active component of described complex comprises the metformin of 1000 weight portions and the Erlotinib of 150 weight portions.
CN201310118438.5A 2013-04-07 2013-04-07 EGFR-TKI compound for delaying or reversing drug-resistance in lung cancer treatment, and preparation thereof Expired - Fee Related CN103316344B (en)

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
CN103784453A (en) * 2014-01-15 2014-05-14 青岛市肿瘤医院 Medicine composition fort treating tumor diseases and preparation method thereof
CN103784412A (en) * 2014-01-15 2014-05-14 青岛市肿瘤医院 Icotinib hydrochloride dispersible tablet and preparation method thereof
CN105030777A (en) * 2015-07-14 2015-11-11 中国人民解放军第三军医大学第三附属医院 Compound capable of enhancing curative effect of ALK-TKI and delaying drug resistance of same and preparation of compound
CN103784459B (en) * 2014-01-15 2015-12-09 青岛市肿瘤医院 Pharmaceutical composition for the treatment of tumor disease and its production and use
CN106138061A (en) * 2015-04-03 2016-11-23 中国人民解放军第三军医大学第三附属医院 Prevention or weaken the complex of pulmonary fibrosis and preparation thereof and purposes
CN108096257A (en) * 2017-12-28 2018-06-01 中国人民解放军陆军军医大学第三附属医院（野战外科研究所） Aspirin is preparing the application in treating NSCLC drugs
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Publication number Priority date Publication date Assignee Title
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ALEJANDRO VÁZQUEZ-MARTÍN ET AL.: "mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb®)", 《CLIN TRANSL ONCOL》 *
ALEJANDRO VÁZQUEZ-MARTÍN ET AL.: "mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb®)", 《CLIN TRANSL ONCOL》, 31 December 2009 (2009-12-31) *

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CN103784453A (en) * 2014-01-15 2014-05-14 青岛市肿瘤医院 Medicine composition fort treating tumor diseases and preparation method thereof
CN103784412A (en) * 2014-01-15 2014-05-14 青岛市肿瘤医院 Icotinib hydrochloride dispersible tablet and preparation method thereof
CN103784459B (en) * 2014-01-15 2015-12-09 青岛市肿瘤医院 Pharmaceutical composition for the treatment of tumor disease and its production and use
CN103784453B (en) * 2014-01-15 2016-03-30 青岛市肿瘤医院 Pharmaceutical composition for the treatment of tumor disease and preparation method thereof
CN106138061A (en) * 2015-04-03 2016-11-23 中国人民解放军第三军医大学第三附属医院 Prevention or weaken the complex of pulmonary fibrosis and preparation thereof and purposes
CN106138061B (en) * 2015-04-03 2019-06-04 中国人民解放军第三军医大学第三附属医院 The compound and its preparation and purposes of prevention or decrease pulmonary fibrosis
CN105030777A (en) * 2015-07-14 2015-11-11 中国人民解放军第三军医大学第三附属医院 Compound capable of enhancing curative effect of ALK-TKI and delaying drug resistance of same and preparation of compound
CN105030777B (en) * 2015-07-14 2017-07-21 中国人民解放军第三军医大学第三附属医院 Enhancing ALK TKI curative effects, the compound and its preparation for delaying its resistance
CN108096257A (en) * 2017-12-28 2018-06-01 中国人民解放军陆军军医大学第三附属医院（野战外科研究所） Aspirin is preparing the application in treating NSCLC drugs
CN108939081A (en) * 2018-10-26 2018-12-07 黄泳华 Composition containing kinases inhibitor and melbine

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