CN104940203A - Medicine composition for lung cancer - Google Patents
Medicine composition for lung cancer Download PDFInfo
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- CN104940203A CN104940203A CN201510360703.XA CN201510360703A CN104940203A CN 104940203 A CN104940203 A CN 104940203A CN 201510360703 A CN201510360703 A CN 201510360703A CN 104940203 A CN104940203 A CN 104940203A
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Abstract
The invention provides an active substance for the lung cancer and particularly belongs to the technical field of medicine. The active substance is medicine resistance and is obvious in synergism. The active ingredients of medicine include picropodophyllotoxin and erlotinib, wherein the weight part ratio of the picropodophyllotoxin and the erlotinib is 1:36-1:1.0. It is known through a cell level and nude mouse transplantation tumor experiment that when the picropodophyllotoxin and the erlotinib are combined for use, the growth of medicine resistance cells and medicine resistance nude mouse transplantation tumors can be effectively inhibited, an IGFIR signal path can be inhibited, and therefore the medicine resistance of the erlotinib is prevented or delayed. The invention further provides application of the combined use of the picropodophyllotoxin and the erlotinib in the lung cancer disease of people. After the picropodophyllotoxin and the erlotinib are combined for use, medicine resistance is low, no physiological toxicity exists, and therefore obvious economic value and social benefits are achieved.
Description
Technical field
The application relates to a kind of pharmaceutical composition for pulmonary carcinoma, and relate to picropodophyllotoxin and Erlotinib conbined usage particularly in the application in people's pulmonary carcinoma disease, it belongs to field of pharmaceutical chemistry technology.
Background technology
It is the fastest that pulmonary carcinoma is that M & M increases, to one of population health and the maximum malignant tumor of life threat.The many countries of immediate and mid-term all report that the M & M of pulmonary carcinoma all obviously increases, and male lung cancer M & M all accounts for first of all malignant tumor, and women's sickness rate accounts for second, and mortality rate accounts for second.The cause of disease of pulmonary carcinoma is still not exclusively clear and definite so far, and great mass of data shows, long-term a large amount of smoking and pulmonary carcinoma have very close relationship.Existing research proves: the probability that long-term a large amount of smoker suffers from pulmonary carcinoma is 10 ~ 20 times of non-smoker, and the age starting smoking is less, and the probability of suffering from pulmonary carcinoma is higher.In addition, smoking not only directly affects my healthy, also produces harmful effect to the health of surrounding population, causes involuntary smoker's pulmonary carcinoma prevalence obviously to increase.The sickness rate of urbanite's pulmonary carcinoma is higher than rural area, and this may be relevant containing carcinogen with urban atmospheric pollution and flue dust.Therefore should advocate non-smoking, and strengthen city environmental hygiene work.
Pulmonary carcinoma is one of clinical modal malignant tumor, is also to constitute a threat to maximum malignant tumor to human health and life at present.In many countries, pulmonary carcinoma is the first Cancer death reason, causes considerable distress to patient and family.Pulmonary carcinoma is caused by the factors such as h and E interact, and its development is a multi-step process, relates to the change of lots of genes structure and expression regulation.
PPP (picropodophyllotoxin) is as the micromolecular inhibitor of targeting IGF1R, research discovery can increase lung carcinoma cell radiation sensitivity, II clinical trial phase shows significant prolongation life cycle of the more independent chemotherapy patients of its combined chemotherapy, and wherein the scale cancer of 78% and the adenocarcinoma patients of 57% therefrom benefit.PPP has now entered III clinical trial phase, but at present research is only confined to it whether can increase pulmonary carcinoma Concurrent Chemoradiotherapy Sensitivity aspect, and whether PPP can reverse adenocarcinoma of lung EGFR-TKI drug resistance and have not yet to see report.
Current research finds that EGFR and IGF1R signal path interacts in pulmonary carcinoma, and is realized by Ras/Raf/MAPK approach that it is synergistic.Transitivity colorectal cancer patients is for the curative effect of EGFR monoclonal antibody (Cetuximab), better in IGF1R high expressors.Y. J. Choi etc. find in EGFR-TKI primary drug resistance lung cancer cell line H1650, IGF1R small molecule tyrosine kinase inhibitors α-IR3 and AG1024 can increase gefitinib anti-tumour cell proliferative and apoptosis-promoting effect, and can phosphorylation Akt be lowered, point out its energy antagonism EGFR-TKI primary drug resistance.
Along with the appearance of the development of molecular biology, genomics, particularly systems biology, there has been proposed the concept of multicomponent pharmaceutical.Multicomponent pharmaceutical is a kind of dosage regimen, difference is the single target drug only comprising a compound, and it comprises the multiple compound with collaborative pharmacotoxicological effect, can disturb multiple target spot simultaneously, make gross effect be greater than each single-action and answer sum, to reach best therapeutic effect.Compared with one pack system cancer therapy drug, multicomponent cancer therapy drug can produce cooperative effect when treating, and makes gross effect be greater than each single-action and answers sum, and then has the advantages that to strengthen drug effect.In addition, multicomponent pharmaceutical also has the advantage reducing drug toxicity and not easily cause drug resistance.
The targeted therapy of pulmonary carcinoma occupies pith in Comprehensive Treatment, Erlotinib as EGFR small molecule tyrosine kinase inhibitors, because of its have oral easy, side effect is little, be easy to be accepted by patient and clinical practice is extensive.The pulmonary carcinoma biological marker of current research is very many, as: EGFR, VEGFR, PDGFR, C-KIT, PI3K, RAS/RAF/MEK/ERK, mTOF, COX, IGF1R or PKC etc.Targeted therapy for these genes shows powerful advantage in clinical treatment, substantially increases quality of life and the Overall survival of patient.Wherein targeting EGFR medicine is as the most successful in adenocarcinoma of lung treatment in gefitinib, Erlotinib etc.But there is acquired drug-resistance in the patients with lung adenocarcinoma of research display 50% after EGFR-TKI treats effective 6-12 month.Its drug resistance reason has a lot, is mainly summarised as following several respects: (1) EGFR genetic mutation or target spot disappearance, usually suddenlys change relevant to the second site T790M; (2) Met amplification; (3) in born of the same parents, EGFR downstream signaling proteins activates; (4) activation of other TK receptors of EGFR path is got around, as IGF1R, VEGFR, PDGFR etc.; (5) angiogenesis of tumor inducing.Part resistance mechanism is wherein had not yet to be fully elucidated.Therefore be necessary to find for these drug resistance reasons to break through, illustrate its mechanism, and actively the new molecular targeted therapy of searching stops or postpones its drug resistance.At this, we select Erlotinib to induce and set up persister, set up its corresponding drug resistance transplanted tumor nude mice model, find the impact that PPP grows Erlotinib drug resistance nude, and then the medicine of the anti-lung tumor providing a kind of good drug efficacy, drug resistance low.
Summary of the invention
The invention provides one and not there is drug resistance, the obvious lung cancer activity material of synergism.
A kind of active substance with active anticancer provided by the present invention, it is made up of PPP and Erlotinib.
Particularly, in above-mentioned anti-lung cancer activity composition, the weight part ratio of PPP and Erlotinib is 1 ︰ 36 ~ 1 ︰ 1.0.
Further, in above-mentioned anti-lung cancer activity composition the weight portion of PPP and Erlotinib preferably than being 1 ︰ 25 ~ 1 ︰ 4.
Particularly, in above-mentioned anti-lung cancer activity composition, the weight part ratio of PPP and Erlotinib is 1 ︰ 16 ~ 1 ︰ 10.
Present invention also offers above-mentioned PPP and the application of Erlotinib in pulmonary carcinoma disease.
Above-mentioned PPP (Picropodophyllotoxin) is picropodophyllotoxin.Picropodophyllotoxin is the rhizome of Berberidaceae plant Radix et Rhizoma Dysosmatis Dysosma versipellis (Hance.) M.Cheng, and its systematic nomenclature is: (5R, 5aS, 8aR, 9R)-5,8,8a, 9-Tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl) furo [3', 4':6,7] naphtho [2,3-d]-1,3-dioxol-6 (5aH)-one.
IGF-1 1 (Insulin-like growth factor receptor 1, IGF1R) as the bypass channel of EGFR, it is a member of family tyrosine kinase, current research display in many malignant tumor as pulmonary carcinoma, breast carcinoma, hepatocarcinoma, colorectal cancer, equal up-regulated in the tissue such as carcinoma of prostate, close with the vicious transformation of tumor, propagation, infiltration, transfer system, can also interact with other cytokines and promote the development of tumor.IGF1R is positioned 15q26 chromosome, and DNA total length is about 100kb, 21 exons, is monokaryon gene, and 1367 amino acid precursor albumen of encoding, belong to receptor tyrosine kinase (RTK) member.It is a transmembrane receptor, and all kinds cell all has expression.IGF-IR overall structure comprises 3 parts: extracellular; Cross-film district; Tyrosine protein kinase district (i.e. cytoplasmic domain) is the different tetramer of a kind of glycoprotein, is made up of two а subunits (ligand binding domain, 707 aminoacid) and two β subunits (cross-film and intracellular region, 626 aminoacid).It is by being combined with IGF-II thus playing a role.The change of cross-film β subunit structure is caused after the extracellular domain combination of IGF-II and IGF1R, in β subunit, namely tyrosine kinase is activated generation autophosphorylation, make stream substrates as IRS (Insuline receptor substrates, IRS), the same derived collagen of Src (Src homology collagen, etc. Shc) there is phosphorylation, thus start phosphinositides-3 kinases (Phosphatidylinositol 3 kinase, PI3K)/protein kinase B (Protein kinase B, or Ras/ mitogen-activated protein kinase (Mitogen activated protein kinase PKB), MAPK) signal path, growth and proliferation of cell signal is continued to reach nucleus, make Cycle Regulation out of control, accelerate cell and enter the S phase from the G1 phase, mitosis promoting, cell phenotype vicious transformation, anti-apoptotic and induction of vascular endothelial growth factor (Vascular endothelial growth factor, VEGF) express, promote developing of tumor.
IGF1R, as a member of family tyrosine kinase, has confirmed that it is played an important role in the generation, development of pulmonary carcinoma by its signal transduction pathway at present.Suppress the activity of IGF-IR, effectively can control growth and the transfer of pulmonary carcinoma, strengthen pulmonary carcinoma to the sensitivity of chemotherapy, radiotherapy.Suppress IGF1R signal path can also suppress angiogenic growth by the expression of lowering VEGFR, thus control growth and the transfer of pulmonary carcinoma.IGF1R also becomes the focus target of specific treatment pulmonary carcinoma already.Be at present that the Therapeutic Method of target spot has many with IGF1R, comprise Antisense OligodeoxynucleotideTechnique Technique, RNA interference, monoclonal antibody and small molecule kinase inhibitors etc.Micromolecular inhibitor is that current clinical research is most widely used.
We pass through to build Erlotinib drug resistance human lung adenocarcinoma cell model PC-9/ER at cellular level, observe after alone EGFR tyrosine kinase inhibitor Erlotinib or associating IGF1R tyrosine kinase inhibitor PPP act on this cell, this cell is on the impact of Erlotinib drug resistance.Then by setting up corresponding drug resistance nude model, being divided into matched group, Erlotinib group, PPP group, PPP and Erlotinib to combine group at random, detecting each group of transplanted tumor volume, weight and calculating tumour inhibiting rate.Successfully build human lung adenocarcinoma Erlotinib drug-resistant cell strain PC-9/ER by the experiment condition of detailed description of the invention, obtain at parental generation and medicine-resistant cell line simultaneously, Erlotinib associating PPP group is all organized compared with other more can antiproliferative effect significantly; In addition show that the expression of Akt, ERK of drug combination group EGFR downstream phosphorylated obviously reduces by Western Blot method result, Erlotinib and PPP coupling effectively can suppress the activation of Akt, IGF1R signal path affects Akt phosphorylation in mdr cell, plays even more important effect, and IGF1R inhibitor PPP affects cell proliferation by indirectly suppressing downstream target gene phosphorylation.
Anti-lung cancer activity material provided by the present invention is made up of jointly PPP and Erlotinib, wherein by cell and nude mice model, find its antineoplastic excellent effect, simultaneously do not produce drug resistance.
Accompanying drawing explanation
The different group PC-9 of Fig. 1 and PC-9/ER cell survival rate;
Akt, ERK, p-Akt and p-ERK protein expression level in Fig. 2 PC-9/ER cell;
After Fig. 3 gives different pharmaceutical, each group transplanted tumor in nude mice form compares;
Fig. 4 is each group transplanted tumor in nude mice growth curve after giving different pharmaceutical.
Detailed description of the invention
Do detailed explanation below by way of the technical scheme of specific embodiment to the application, but described summary of the invention is not limited only to this.
The present invention, by human lung adenocarcinoma cell line PC-9, sets up Erlotinib persister PC-9/ER, observes the cell proliferative conditions of matched group, Erlotinib group, PPP group, Erlotinib associating PPP group; Cell-based assay PPP reverses Erlotinib drug resistance; The expression of p-EGFR, p-IGF1R and downstream AKT, ERK, p-AKT and p-ERK in Western Blot analysis of cells; Inquire into the mechanism reversing Erlotinib drug resistance and occur.Then build Erlotinib drug resistance adenocarcinoma of lung Nude Mouse Model, observe the nude mouse tumor growing state of matched group, Erlotinib group, PPP group, Erlotinib associating PPP group, calculate tumour inhibiting rate, confirm PPP reversing drug resistance further.
With cell culture, build cytology and the molecular biology methods such as persister, Western blot, flow cytometry and CCK8, disclose the relation of IGF1R path and adenocarcinoma of lung EGFR-TKI acquired drug-resistance from molecular level, and then PPP associating Erlotinib is widely used in pulmonary carcinoma disease.
1 cell research (experiment in vitro)
1.1 main agents
1640 culture medium, hyclone (FBS), pancreatin equal purchased from American Gibco company; CCK-8 test kit is purchased from Japanese colleague company; Akt, ERK and phosphorylation Akt, ERK antibody equal purchased from American sigma company; PPP is presented by Hospital Attached to Nantong Univ.'s Clinical Research Center; Erlotinib is purchased from biological company limited of connection section.PPP and Erlotinib are dissolved in DMSO, make the solution that concentration is 10 μm of ol/L, are stored in-20 DEG C of refrigerators for subsequent use after subpackage.Be diluted to aimed concn with culture fluid during experiment, make its DMSO volume fraction <0.005%.
1.2CCK8 method detects cell proliferation
CCK8 method measures each group to the effect of lung adenocarcinoma cell growth inhibited: the mdr cell of trophophase of taking the logarithm is inoculated in 96 well culture plates, after 24 h, each group adds culture fluid respectively, PPP(5 μm of ol/L), Erlotinib 150 μm of ol/L, it is 150 μm of ol/L that Erlotinib adds PPP(Erlotinib, PPP is 5 μm of ol/L), the 48 backward every holes of h add 10 μ L CCK-8 solution, continue to be determined at 450 nm place absorbances by microplate reader after incubator hatches 2 h, analysis result, result represents with survival rate.By following formulae discovery tumor cell survival: tumor cell survival=(dosing cell OD value one blank OD value)/(compared with control cells OD value one blank OD value) × 100%.
in 1.3 Western Blot analysis of cellsp-IGF1R, p-EGFR
, AKT, MEK and p-AKT, the expression of p-MEK
The mdr cell PC-9/ER of trophophase of taking the logarithm is inoculated in 6 well culture plates, after 24 h, each group adds culture fluid respectively, PPP(5 μm of ol/L), Erlotinib 150 μm of ol/L, it be 150 μm of ol/L, PPP is 5 μm of ol/L that Erlotinib adds PPP(Erlotinib), protein extraction and BCA method determination of protein concentration are extracted in dosing after 24 hours: add the RIPA cell pyrolysis liquid containing PMSF in six orifice plates, fully cracking on ice, 4 DEG C of 13000 centrifugal 10 min of rpm, gets supernatant and is total protein of cell.Protein concentration is surveyed according to BCA test kit operating instruction.Western Blot key step comprise wash plate → glue → electrophoresis → transferring film → close → incubate primary antibodie → incubate two anti-→ video picture.
1.4 statistical procedures
All measurement datas represent with mean ± standard deviation, the comparison between sample average t inspection or variance analysis, and variance analysis first carries out homogeneity test of variance, adopts variance analysis when variance is equal; Games-Howell inspection is adopted during heterogeneity of variance.Add up mapping software process, analytical data, graphing with GrapPad Prism5.0, obtain P value with SPSS 17.0 statistical software, represent that difference has significance with P 0.05.
1.5 experimental result
Erlotinib alone or in combination PPP acts on the cell proliferative conditions after cell
PPP (concentration 5 μm of ol/L) after Erlotinib (concentration 150 μm of ol/L) acts on cell alone or in combination, adopts CCK-8 method to analyze the change of each group of cell proliferation after 48h.As shown in Figure 1, Erlotinib associating PPP group PC-9/ER cell survival rate is obviously respectively organized low compared with other, difference have statistical significance (
p< 0.05).* ratio is organized with other,
p< 0.05; * organizes ratio with other,
p< 0.05.
In Figure of description 1, Untreated is experiment contrast group; PPP is the cell experiment group of adding PPP component; Erlotinib is the cell experiment group of Erlotinib; Erlotinib+PPP is the symphyogenetic cell experiment group of Erlotinib and PPP.
erlotinib alone or in combination PPP acts on the expression of Akt, ERK and p-Akt, p-ERK in cell after PC-9/ER
Western Blot result shows, PPP acts solely on PC-9/ER cell, its p-Akt and p-ERK protein expression level decline comparatively, and Erlotinib independent role is obvious, when both synergy, inhibitory action is more obvious, as shown in Figure of description 2, p-Akt and the p-ERK protein expression level of PC-9/ER cell obviously declines compared with other three groups.And Akt and ERK at each group without significant change.
In addition, we devise after PPP and Erlotinib variable concentrations proportioning act on cell, administration simultaneously, 48h post analysis, and its result is as shown in table 3 below; Wherein test concrete operations as 2.1,2.2 consistent with 2.3.
The result after cell is acted under the different PPP of table 1 and Erlotinib concentration proportioning
2 nude mices (experiment in vivo)
2.1 experiment reagent
(its main component is that erlotinid hydrochloride, chemistry are by name to Erlotinib: two (2-the methoxyethoxy)-4-quinolinamine hydrochlorates of N-(3-acetylene phenyl)-6,7-, chemical formula is: C
22h
23n
3o
4hCl; Purchased from biological company limited of connection section.
PPP (Picropodophyllotoxin) is picropodophyllotoxin.Picropodophyllotoxin is the rhizome of Berberidaceae plant Radix et Rhizoma Dysosmatis Dysosma versipellis (Hance.) M.Cheng, and its systematic nomenclature is: (5R, 5aS, 8aR, 9R)-5,8,8a, 9-Tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl) furo [3', 4':6,7] naphtho [2,3-d]-1,3-dioxol-6 (5aH)-one, is presented by Hospital Attached to Nantong Univ.'s Clinical Research Center.
PPP and Erlotinib are dissolved in DMSO, make the solution that concentration is 10 μm of ol/L, are stored in-20 DEG C of refrigerators for subsequent use after subpackage; Be diluted to aimed concn with culture fluid during experiment, make its DMSO volume fraction <0.005%.
PC-9/ER cell is provided by tumor radiotherapy section of Hospital Attached to Nantong Univ. experimental center.
4 ~ 6 week age, BALB/c nude mice was provided by Nantong University's Experimental Animal Center, and only, male and female half and half, raise quality 18 ~ 20g/ under SPF condition.
2.2 the foundation of PC-9/ER cell transplanted tumor in nude mice and experiment grouping
PC-9/ER cell attachment is grown on the RPMI-1640 complete medium containing 10% hyclone, at 37 DEG C, 5%CO
2, cellar culture in saturated humidity incubator, within 2 ~ 3 days, change liquid and go down to posterity once.Collecting cell makes concentrating cells suspension, by 0.2mL concentrating cells suspension (2 × 10
6/ L) inject nude mice shoulder dorsal sc, form the subcutaneous protuberance of diameter 3 about mm, absorb gradually subsequently, observe one week, when being about 8-10 mm size to tumor body major diameter, nude mice is divided into 4 groups at random, often organize 5, namely matched group, Erlotinib group, PPP group, PPP and Erlotinib combine group.Matched group: do not carry out any treatment; Erlotinib group: give Erlotinib 5mg/kg, gastric infusion, once a day; PPP group: give PPP 3mg/kg, gastric infusion, once a day; Associating group: PPP and Erlotinib dosage and administrated method are with above two groups.The survival condition of nude mice is observed in therapeutic process.
2.3 growth of xenografted measure
Every day tumor growth situation and tumor size, gross tumor volume V (mm
3)=0.5 × a × b
2(a=major diameter, b=highly), draw growth curve chart according to gross tumor volume.After injection cell suspension 5 weeks, draw neck to put to death nude mice, peel off tumor, and claim tumor weight, calculating tumour inhibiting rate (tumor inhibition rate, TIR).TIR (%)=(matched group tumor weight-experimental group tumor weight)/matched group tumor heavy × 100%.
2.4 statistical procedures
All measurement datas represent with mean ± standard deviation, add up mapping software process, analytical data, graphing, obtain P value with SPSS17.0 statistical software with GrapPad Prism5.0, with
p0.05 represents that difference has significance.
the situation of 2.5 nude mices and one-tenth tumor time
PC-9/ER cell inoculation nude mice is after 7 days, and tumor nodule is all touched in all nude inoculation positions, lung cancer in nude mice transplanted tumor tumor formation rate 100%.Experimental group and nude mice of control group all survive, and upgrowth situation is good, take food, urinate and defecation all normal, without inappetence, the situation such as lose weight.
2.6 each group nude mice tumor bulk-growth situations and gross tumor volume compare
Injection cell, after 5 weeks, is put to death nude mice, is isolated transplanted tumor, and be circular or oval by the visible transplanted tumor of Figure of description 3, surface irregularity, irregular, toner is red, in matter.PPP and Erlotinib are combined and are organized comparatively matched group, Erlotinib group, PPP group and compare, and transplanted tumor volume is obviously little, can be learnt by foregoing, combines group transplanted tumor volume growth rate and is starkly lower than other each group, difference have statistical significance (
p<0.05), as Figure of description 4.
2.7 respectively organize tumor weight and tumour inhibiting rate
Isolated transplanted tumor weighed, each group tumor is heavily in table 2, and PPP and Erlotinib combine group comparatively other three groups of ratios, and tumor weight obviously reduces, difference have statistical significance (
p<0.05).Erlotinib group, PPP group, PPP and Erlotinib are combined group tumour inhibiting rate and are respectively 10.4%, 42.3% and 67.8%.
Table 2 is group nude mice model tumor weight and tumour inhibiting rate respectively
* with other two groups of ratios,
p< 0.05.
PC-9/ER cell inoculation nude mice is after 7 days, and tumor nodule is all touched in all nude inoculation positions, lung cancer in nude mice transplanted tumor tumor formation rate 100%.Nude mice is divided into 4 groups at random, namely matched group, Erlotinib group, PPP group, PPP and Erlotinib combine group, and combine group and compare compared with other groups, transplanted tumor volume is obviously little, and transplanted tumor volume growth rate is starkly lower than other each group, difference have statistical significance (
p<0.05).Isolated transplanted tumor weighed, PPP and Erlotinib combine group comparatively other three groups of ratios, and tumor is heavy obviously low, difference have statistical significance (
p<0.05).Erlotinib group, PPP group, PPP and Erlotinib are combined group tumour inhibiting rate and are respectively 10.4%, 42.3% and 67.8%.
Meanwhile, we have done the experiment of nude mouse of several groups of different PPP and Erlotinib different proportion, and wherein experiment condition as above, and the nude mice 5 of different group, concrete result of the test is as table 2.Matched group is still blank experiment, subcutaneous injection culture fluid.PPP 2mg/kg, Erlotinib 2mg/kg in example 1; PPP 2mg/kg, Erlotinib 8mg/kg in example 2; PPP 2mg/kg, Erlotinib 10mg/kg in example 3; PPP 2mg/kg, Erlotinib 15mg/kg in example 4; PPP 2mg/kg, Erlotinib 20mg/kg in example 5; PPP 2mg/kg, Erlotinib 50mg/kg in example 6.
The nude mice model tumor weight of the active medicine that the different PPP of table 3 and Erlotinib ratio form and tumour inhibiting rate
EGFR (epidermal growth factor receptor, referred to as EGFR, ErbB-1 or HER1) is one of EGF-R ELISA (HER) family member.This family comprises HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3) and HER4 (erbB4).HER family plays important regulating action in cellular physiological processes.EGFR be distributed widely in mammalian epithelial cell, fibroblast,
glial cell, horn cell etc.
cell surface, EGFR
signal paththe growth of cell, the physiological process such as propagation and differentiation are played an important role.The reason of EGFR acquired drug-resistance has a lot, except common second site T790M suddenlys change and Met amplification, gets around activation of other TK receptors of EGFR path etc. in addition.Wherein IGF1R path may be a major reason of current clinical Erlotinib drug resistance to the activation of downstream gene.The patients with lung cancer prognosis of both IGF1R and EGFR high expressed is obviously worse than low expression patient, and IGF1R monoclonal antibody IMC-A12 coupling Erlotinib can increase the sensitivity of mdr cell to Erlotinib.The present invention selects the small molecule tyrosine kinase inhibitors PPP of IGF1R to study.Result display PPP and Erlotinib are combined group transplanted tumor growth rate and are starkly lower than other each group, tumor volume and weight obviously little (
p<0.05).Erlotinib group, PPP group, PPP and Erlotinib are combined group tumour inhibiting rate and are respectively 10.4%, 42.3% and 67.8%, clearly can show that PPP and Erlotinib coupling effectively can suppress the growth of drug resistance nude by foregoing.Suppress IGF1R signal path, and then stop or postpone the drug resistance of Erlotinib.
The pharmaceutical composition of anti-pulmonary carcinoma provided by the present invention, has inhibitory action clearly to human lung cancer in vitro.
Claims (4)
1. for a pharmaceutical composition for pulmonary carcinoma, it is characterized in that: the active component of pharmaceutical composition is PPP and Erlotinib.
2. a kind of pharmaceutical composition for pulmonary carcinoma according to claim 1, is characterized in that: the weight part ratio of the active component of pharmaceutical composition is PPP ︰ Erlotinib=1 ︰ 36 ~ 1 ︰ 1.0.
3. a kind of pharmaceutical composition for pulmonary carcinoma according to claim 1, is characterized in that: the weight part ratio of the active component of pharmaceutical composition is PPP ︰ Erlotinib=1 ︰ 25 ~ 1 ︰ 4.
4. a kind of pharmaceutical composition for pulmonary carcinoma according to claim 1, is characterized in that: the weight part ratio of the active component of pharmaceutical composition is PPP ︰ Erlotinib=1 ︰ 16 ~ 1 ︰ 10.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105998033A (en) * | 2016-07-05 | 2016-10-12 | 福州大学 | Pharmaceutical composition containing erlotinib hydrochloride and ursolic acid and application thereof for preparing antitumor drugs |
| CN106727586A (en) * | 2016-12-06 | 2017-05-31 | 遵义医学院附属医院 | A kind of new opplication of Artesunate |
-
2015
- 2015-06-26 CN CN201510360703.XA patent/CN104940203A/en active Pending
Non-Patent Citations (4)
| Title |
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| CHOI Y. J.等: "Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors", 《CANCER CHEMOTHER PHARMACOL》 * |
| KENICHI SUDA等: "The insulin-like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild-type epidermal growth factor receptor", 《INTERNATIONAL JOURNAL OF CANCER》 * |
| LUDOVINI V.等: "High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients", 《ANNALS OF ONCOLOGY》 * |
| QI ZHANG等: "Targeting the Insulin-Like Growth Factor-1 Receptor by Picropodophyllin for Lung Cancer Chemoprevention", 《MOLECULAR CARCINOGENESIS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105998033A (en) * | 2016-07-05 | 2016-10-12 | 福州大学 | Pharmaceutical composition containing erlotinib hydrochloride and ursolic acid and application thereof for preparing antitumor drugs |
| CN105998033B (en) * | 2016-07-05 | 2018-11-27 | 福州大学 | A kind of pharmaceutical composition and its application in preparation of anti-tumor drugs containing Tarceva and ursolic acid |
| CN106727586A (en) * | 2016-12-06 | 2017-05-31 | 遵义医学院附属医院 | A kind of new opplication of Artesunate |
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