CN103316344B - 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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CN103316344B
CN103316344B CN201310118438.5A CN201310118438A CN103316344B CN 103316344 B CN103316344 B CN 103316344B CN 201310118438 A CN201310118438 A CN 201310118438A CN 103316344 B CN103316344 B CN 103316344B
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egfr
tki
metformin
complex
cell
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CN103316344A (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 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 being in progress or refractory non-small cell lung (non-small cell lung cancer, NSCLC) take EGFR as the micromolecule targeted drug of target spot.One of bottleneck that restriction EGFR-TKI applies further is that acquired drug-resistance occurs.The generation of EGFR-TKI acquired drug-resistance is at least relevant with two kinds of mechanism: Secondary cases exon T790M suddenlys change and MET Secondary cases increases.Chinese patent CN102626405A discloses the application of paclitaxel in preparation treatment EGFR-TKI acquired drug-resistance medicine, this invention confirms, paclitaxel can reverse EGFR-TKI acquired drug-resistance based on above-mentioned two kinds of mechanism, for the nonsmall-cell lung cancer patient producing acquired drug-resistance from Erlotinib/treated with gefitinib, after Paclitaxel Chemotherapy, again can consider to use Erlotinib/treated with gefitinib, make Erlotinib/gefitinib continue to play function.
Also disclose following content in prior art, EGFR-TKI drug resistance patient combines Cetuximab with Ah method for Buddhist nun and solves drug resistance; And use EGFR-TKI and EGFR monoclonal antibody to suppress EGFR intracellular region and extracellular region (vertically blocking) may can overcome drug resistance simultaneously.
Based on the amplification of MET Secondary cases, MetMAb is a kind of monoclonal antibody specific, with the MET receptors bind outside born of the same parents.Whole world, random, double blinding II phase clinical studies show are for the nonsmall-cell lung cancer of MET process LAN, and MetMAb+ Erlotinib is comparatively used alone the disease free survival time (HR0.56 that Erlotinib can extend patient; 95%CI0.31 – 1.02; P=0.05), and for without MET process LAN patient, drug combination effect is treated lower than independent Erlotinib.
Also have in addition, HKI-272, rapamycin, BIBW2992(Tovok), p53 inhibitor, tumor necrosis factor α (TNF α) multi-medicament or method be used for EGFR-TKI acquired drug-resistance.
Although the method for the above-mentioned EGFR-TKI of overcoming acquired drug-resistance obtains certain effect, treat expensive, and the effect overcoming drug resistance still need to improve.
Summary of the invention
The invention provides a kind of with low cost the EGFR-TKI complex and the preparation thereof that delay or reverse nonsmall-cell lung cancer acquired drug-resistance.
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, generally comprise the reversible and irreversible inhibition agent of EGFR.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 the class medicine containing, for example following formula (I), comprises one or more in metformin and salt thereof or derivant, phenformin, buformin, proguanil.For the understanding of biguanides, should by the restriction of the original purposes of biguanides.
Most preferred biguanides is metformin hydrochloride (Metformin Hydrochloride is called for short, Metformin), and 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 by biguanides and be the preparation unit that active component is made by EGFR-TKI.Biguanides preparation unit obtained respectively and EGFR-TKI preparation unit, at least comprise two kinds of application modes, first is be positioned in a packing material simultaneously, can take at interval like this, such as in ante cibum with take out certain preparation unit interval after meal respectively take from above-mentioned packing material; The second way is positioned in a capsule, can take so simultaneously.
EGFR-TKI complex of the present invention, it is the second preparation unit that active component is made jointly that described complex comprises by biguanides and EGFR-TKI.Described 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 comprises 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 comprises 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 comprises 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 comprises the metformin of 1000 weight portions and the Erlotinib of 150 weight portions.
Beneficial effect of the present invention is, EGFR-TKI complex is for delaying or reverse the generation of EGFR-TKI acquired drug-resistance, inhibitory action can be played to some extent to the main mechanism of NSCLC patient EGFR-TKI acquired drug-resistance, thus 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.
Accompanying drawing explanation
The sensitivity tests result of the Erlotinib of Fig. 1, embodiment 1;
Wherein, H1650, M3, H1650-M3+Met of abscissa represent sensitive strain H1650 cell, persister H1650-M3 cell, persister H1650-M3+ metformin (lower same), the Erlotinib IC of vertical coordinate respectively 50value(μM) represent the IC of Erlotinib 50value.
The sensitivity tests result of the Gefitinib of Fig. 2, embodiment 1;
Wherein, P9, R9, R9+Met of abscissa represent sensitive strain PC-9 cell, persister PC-9GR cell and persister PC-9GR+ metformin (lower with) respectively, the Gefitinib IC50value(μM of vertical coordinate) represent the IC of gefitinib 50value.
There is the microphotograph photograph of invasion and attack in the drug-resistant cell strain M3 of Fig. 3, embodiment 2;
There is the aggressive result of the test of invasion and attack in the drug-resistant cell strain M3 of Fig. 4, embodiment 2;
There is the microphotograph photograph of invasion and attack in the drug-resistant cell strain R3 of Fig. 5, embodiment 2;
There is the aggressive result of the test of invasion and attack in the drug-resistant cell strain R9 of Fig. 6, embodiment 2;
The experimental procedure schematic diagram of the experiment in vivo of Fig. 7, embodiment 3;
Wherein: cells injection represents injection tumor cell; Drug application and tumor-50mm 3represent and treat that transplanted tumor volume reaches 50mm 3medicine is given during left and right; TKI alone and TKI and Met represents application gefitinib and simultaneously application gefitinib and metformin separately respectively; Water represents the blank group of application water; Met alone represents metformin group; Tumor volume measurement and sacirifice(4w) represent that drug administration put to death nude mice after 4 weeks, measure tumor final volume.
Each group of nude mouse tumor situation of change schematic diagram of the experiment in vivo of Fig. 8, embodiment 3.
The gross tumor volume curve of the experiment in vivo 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) represent gross tumor volume.
Below by test example, the present invention is further described:
Test example 1 experiment in vitro
Experiment purpose: can metformin improve the sensitivity tests of EGFR-TKI drug-resistant cell strain to 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 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 the JEG-3 of logarithmic (log) phase respectively, with trypsin digestion and cell, centrifuge cell suspension, makes cell deposition get off.Use culture medium re-suspended cell, counting;
(2) after 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, and every hole is containing 2000 cells; 96 plates having inoculated cell are put into 5%CO 2, incubated overnight in cell culture incubator under 37 DEG C and 90% humidity;
(3) 10mM Gefitinib(gefitinib is configured 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 5 concentration altogether, each concentration establishes 5 multiple holes; Experiment totally six groups, specific as follows:
Sensitive strain PC-9:(1.6,0.8,0.4,0.2,0.1,0) μM Iressa;
Persister PC-9GR:(16,8,4,2,1,0) μM Iressa;
Persister PC-9GR+10mMol metforin:10mM metformin+ (16,8,4,2,1,0) μM Gefitinib;
Sensitive strain H1650:(20,15,10,5,2.5,0) μM Erlotinib;
Persister H1650-M3:(20,15,10,5,2.5,0) μM Erlotinib;
Persister H1650-M3+10mM metformin:(20,15,10,5,2.5,0) μM Erlotinib+10mMol metforin.
After the cell administration of (4) 96 orifice plates, insert 5%CO 2, under 37 DEG C and 90% humidity, cell culture incubator continues to cultivate 48h.
(5) action effect of medicine is observed under inverted microscope.
(6) abandon the culture medium of dosing, every hole rejoins the fresh 10%FBS culture fluid of 100 μ l, is adding containing 10ulMTT(5mg/ml, i.e. 0.5%MTT), continue to cultivate 4h.
(7) after MTT adds cultivation 4h, crystallization is fully formed, and thoroughly removes culture fluid in hole, and every hole adds 150 μ l dimethyl sulfoxide, puts low-speed oscillation 10min on shaking table, crystal is fully dissolved.The light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument OD490nm place.
Data analysis
The cell inhibitory rate drug level reached needed for a half is IC50 concentration, and IC50 is calculated by IC50 software for calculation.
Experimental result
As shown in Figure 1, after adding metformin, drug-resistant cell strain H1650-M3 is to the IC of Erlotinib 50drop to 4.8 μMs (there were significant differences for statistical analysis, p<0.01) from 18.3 μMs;
As shown in Figure 2, drug-resistant cell strain PC-9GR is to the IC of Gefitinib 50drop to 1.25 μMs (there were significant differences for statistical analysis, p<0.01) from 4.84 μMs.
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 Transwell method to calculate the aggressive of lung carcinoma cell
Experimental procedure is as follows:
(1) Transwell chamber:24-well6.5mm Diameter Ineserts8.0 μm of Pore Size(Corning Incorporated is selected);
(2) add 100ul serum-free medium to room on Transwell chamber in advance, lower room adds 600 μm of serum free culture system liquid (10%FBS), and puts into 37 DEG C of incubators and hatch 2h;
(3) experiment is divided into six groups, is specially: H1650 groups of cells, H1650-M3 group, H1650-M3+ metformin group, PC-9 group, PC-9GR group, PC-9GR+ metformin group.With trypsin digestion cell, centrifugal rear culture fluid is resuspended, washs once with each before and after PBS and serum-free medium;
(4) use serum-free medium re-suspended cell, counting, adjustment concentration is 2 × 10 4/ ml, on Transwell chamber, room adds 100ul cell suspension, continues 24 orifice plates at 5%CO 2, 37 DEG C, cultivate 48 hours in 90% humidity cell culture incubator;
After (5) 48 hours, discard the culture fluid of room and lower room on filter membrane, add the preheating PBS of equal-volume (upper room 200ul, lower room 600ul) in upper and lower room respectively, wash 2 times, each 3min;
(6) room adds 4% paraformaldehyde 800 μ l downwards, makes filter membrane lower surface be immersed in wherein fixed cell 30min;
(7) abandon fixative, clean 2 times with PBS, be inverted transwell cell, face up under making filter membrane, natural air drying;
(8) the crystal violet dye liquor of (upper room 200ul, lower room 800ul) is added respectively in upper and lower room, dyeing 30min;
(9) a large amount of distilled water cleans 24 orifice plates and transwell cell respectively, wipes the cell that upper surface do not move, observe and count and take a picture (H1650-M3 is adherent in 24 holes through cell film, counts and adds) under inverted microscope with cotton balls.Random selecting 5 high power fields, average after counting cells number.
Experimental result
Metformin significantly can reduce the aggressive of mdr cell: as shown in Figure 3,4, the cell number meansigma methods that invasion and attack occur drug-resistant cell strain M3 is 209, metformin process makes it drop to 101 (there were significant differences for statistical procedures, p<0.01); As shown in Figure 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)
Test example 3 experiment in vivo
Experiment purpose: can metformin improve EGFR-TKI mdr cell to the sensitivity of EGFR-TKI and Tumor suppression growth test
Drug-resistant cell strain PC-9GR, laboratory animal selects nude mice (experiment point 4 groups (blank group, metformin group, Iressa group, Iressa+metformin group), often organizes 8 animals, totally 32 for Beijing Vital River Experimental Animals Technology Co., Ltd., female Mus)
Shown in composition graphs 7, experimental procedure is as follows:
(1) choose 6 week age of nude mice, before inoculated tumour cell, need feed 1 week raising is local;
(2) to inoculated tumour cell PC9-GR:2 × 10, oxter on the right side of every nude mice 6, be resuspended in 100 μ lPBS;
(3) nude mice body weight (electronic scale measurement) and gross tumor volume (vernier caliper measurement) is carried out from inoculated tumour the 5th day.Measure the most major diameter (a) of tumor body and most minor axis (b), and calculate tumor relative volume V (mm 3)=(a × b 2)/2.Weekly twice until experiment terminate.
(4) treat that transplanted tumor volume reaches 30mm 3during left and right, drunk 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 continue 4 weeks, drawing gross tumor volume curve.
Experimental result
As shown in Figure 8,9, the gross tumor volume of Iressa+metformin group significantly reduces relative to other groups, initial in treatment, and 4 groups of tumor average volumes are consistent, are respectively 29.917mm 3, 29.141mm 3, 27.75mm 3, 28.73254mm 3; After treating 4 weeks, 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 has with Iressa group tumor compared with matched group and reduces, but without statistically-significant difference, p value is respectively 0.05 and 0.052), Iressa+metformin group gross tumor volume compared with its excess-three group obviously reduces, and all have statistically-significant difference, compare p value with matched group with metformin group and be all less than 0.01, p value is less than 0.05 compared with Iressa group).
Detailed description of the invention
Embodiment 1 assembly packaging
Assembly packaging comprises 1 metformin hydrochloride tablet (every sheet is containing 250mg metformin hydrochloride) and 1 Erlotinib sheet (every sheet is containing Erlotinib 25mg)
Embodiment 2 assembly packaging
Assembly packaging comprises 1 metformin hydrochloride tablet (every sheet is containing 250mg metformin hydrochloride) and 1 Erlotinib sheet (every sheet is containing Erlotinib 100mg)
Embodiment 3 assembly packaging
Assembly packaging comprises 1 metformin hydrochloride tablet (every sheet is containing 250mg metformin hydrochloride) and 1 Erlotinib sheet (every sheet is containing Erlotinib 150mg)
Embodiment 4 assembly packaging
Assembly packaging comprises 1 metformin hydrochloride tablet (every sheet is containing 250mg metformin hydrochloride) and 1 gefitinib sheet (every sheet is containing gefitinib 250mg)
Embodiment 5 assembly packaging
Assembly packaging comprises 2 metformin hydrochloride tablets (every sheet is containing 1000mg metformin hydrochloride) and 2 gefitinib sheets (every sheet is containing gefitinib 500mg)
Embodiment 6 assembly packaging
Assembly packaging comprises 4 metformin hydrochloride tablets (every sheet is containing 250mg metformin hydrochloride) and 1 gefitinib sheet (every sheet is containing gefitinib 250mg)
Embodiment 7 compositions
Every sheet is containing 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, tabletted.
Embodiment 8 compositions
Every sheet is containing 250mg metformin hydrochloride and 100mg Erlotinib
Method for making is with embodiment 7.
Embodiment 9 compositions
Every sheet is containing 250mg metformin hydrochloride, 150mg Erlotinib
Method for making is with embodiment 7.
Embodiment 10 compositions
Every sheet is containing 250mg metformin hydrochloride, 250mg gefitinib.
Method for making is with embodiment 7.
The above embodiment is only that the preferred embodiment of the present invention is described; not scope of the present invention is limited; under not departing from the present invention and designing the prerequisite of spirit; the various distortion that those of ordinary skill in the art make technical scheme of the present invention and improvement, all should fall in protection domain that claims of the present invention determine.

Claims (8)

1. delay or reverse an EGFR-TKI complex for nonsmall-cell lung cancer drug resistance, it is characterized in that, the active component of described complex is selected from the biguanides of 250-2000 weight portion and the EGFR-TKI of 75-1000 weight portion; Described biguanides is selected from metformin and salt thereof; Described EGFR-TKI medicine be selected from gefitinib, Erlotinib one or more.
2. EGFR-TKI complex as claimed in claim 1, is characterized in that, described complex is selected from by biguanides to be the preparation unit made of active component and to be the preparation unit that active component is made by EGFR-TKI.
3. EGFR-TKI complex as claimed in claim 1, is characterized in that, it is the second preparation unit that active component is made jointly that described complex is selected from by biguanides and EGFR-TKI.
4. EGFR-TKI complex as claimed in claim 3, it is characterized in that, described second preparation unit is selected from oral solid formulation, liquid preparation.
5. EGFR-TKI complex as claimed in claim 1, it is characterized in that, the active component of described complex is selected from the metformin of 250-2000 weight portion and the gefitinib of 75-1000 weight portion.
6. EGFR-TKI complex as claimed in claim 6, it is characterized in that, the active component of described complex is selected from the metformin of 1000 weight portions and the gefitinib of 250 weight portions.
7. EGFR-TKI complex as claimed in claim 1, it is characterized in that, the active component of described complex is selected from the metformin of 250-2000 weight portion and the Erlotinib of 75-150 weight portion.
8. EGFR-TKI complex as claimed in claim 7, it is characterized in that, the active component of described complex is selected from 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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