CN103990126A - Synergic pharmaceutical composition treating tumors - Google Patents
Synergic pharmaceutical composition treating tumors Download PDFInfo
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- CN103990126A CN103990126A CN201310051944.7A CN201310051944A CN103990126A CN 103990126 A CN103990126 A CN 103990126A CN 201310051944 A CN201310051944 A CN 201310051944A CN 103990126 A CN103990126 A CN 103990126A
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Abstract
The invention belongs to the technical field of medicines and biology, relates to a synergic pharmaceutical composition treating tumors, and especially relates to a compound medicine or a pharmaceutical composition prepared from one or a plurality of cell autophagy inhibitors and beta interferon. The cell autophagy inhibitor(s) and beta interferon of the synergic pharmaceutical composition are administrated in a combined administration manner or in a sequential administration manner. By inhibiting autophagy of tumor cells induced by beta interferon, the antagonistic action, caused by cell autophagy, of tumor on treatment of beta interferon is offset, and therefore the killing effect of individually-used beta interferon on tumors is enhanced, and the treatment effect of beta interferon on tumors is substantially enhanced. The synergic medicine is applicable to glioma, pancreas cancer, lung cancer, liver tumor, vascular cancer and myeloma, and the treatment effect of individually-used beta interferon on tumors is substantially enhanced.
Description
Technical field
The invention belongs to medicine, biological technical field, relate to antitumor drug, be specifically related to
a kind of synergism medicine compositions for the treatment of tumor, relate in particular to compound medicine or the pharmaceutical composition by one or more cell autophagy inhibitor and interferon-β, made, should
synergism medicine compositions is passed throughadministering drug combinations or sequential occupation mode can be used for treating glioma, cancer of pancreas, pulmonary carcinoma, liver tumor, vascular cancer and myeloma.
Background technology
Glioblastoma is the most common in central nervous system, and the malignant tumor that sickness rate is the highest accounts for 30% of Brain Tumor in Adults.In the past 30 years, the multiple treatment means such as operative treatment, radiation and chemotherapy obtains to be improved, and brought into play certain effect, but patient's survival rate does not significantly increase in gliomatous treatment.Practice shows, because glioblastoma is easy to be diffused into normal structure, by the very difficult tumor of thoroughly removing of method of operation, the high relapse rate that has caused glioblastoma, studies show that, from making a definite diagnosis death, glioblastoma patient's meta survival period only has 14.5 months.
Interferon-β is a kind of I type interferon, mainly by fibroblast, produced, belong to the protein that term single gene coding produces, can suppress viral growth by viral interference RNA or DNA replication dna, and can significantly strengthen the killing activity of NK cell, by promoting MHC I quasi-molecule to express, enhanced CT L, to the identification of virus infected cell and lethal effect, has antiviral, antitumor, immunomodulating isoreactivity.In clinical practice, interferon-β is widely used in the treatment of various diseases, especially good to the therapeutic effect of multiple sclerosis, is the unique biological drug for MS treatment of current FDA approval.
Cell autophagy (autophagy) claims again II type programmed death (type II programmed cell death), it is the phenomenon of common " self-digestion " (cellular degradation) in most eukaryotes, conventionally according to substrate in cell, be transported to the difference of lysosome intracavity mode, mammalian cell autophagy can be divided into three kinds of modes: the autophagy (chaperone-mediated autophagy, CMA) of large autophagy (macroautophagy), little autophagy (microautophagy) and molecular chaperones mediation.In recent years along with development and the deep understanding to cell autophagy of molecular biology and gene technology, find that the development of itself and various diseases, especially tumor is in close relations.
In general, because cell autophagy is conducive to the survival of cell, therefore no matter in normal cell or tumor cell, autophagy all is generally retained, and is all maintaining basic autophagy in the ordinary course of things.Actually but or autophagy suppresses to promote the generation development of tumor cell still not come to a conclusion at present.Studies show that, the autophagy initial stage can be used as tumorigenic a kind of inhibition factor, the tumor-inhibiting factor that some are known, for example PTEN, TSC1 and TSC2 can activate autophagy, and can make protein degradation reduce to the inhibition of autophagy, anabolism increases, finally cause former cancerous cell to continue propagation.Most of tumor cells (as liver, pancreas, breast carcinoma etc.) are although autophagy ability is had nothing in common with each other before canceration, and after canceration, its autophagy ability all weakens.Because autophagy role in tumor occurs and develops is still not clear; therefore its role in antitumor drug killing tumor cell process is also not quite similar; roughly may be summarized to be two kinds: a kind of is protection to tumor cell, another kind of be killing and wounding tumor cell.Research shows chemotherapeutics 5-FU Induces Autophagy significantly; and the cell autophagy that suppresses to be produced by these 3 kinds of medicines can significantly increase sensitivity [the Li J of tumor cell to treatment; Hou N; Faried A; Tsutsumi S, et al. Inhibition of Autophagy by 3-MA Enhances the Effect of 5-FU-Induced Apoptosis in Colon Cancer Cells. Ann Surg Oncol .2009; 16 (3): 761 – 771.].At present the adjusting class medicine of cell autophagy can be divided into two classes by it to the effect of autophagy, a class be autophagy derivant as; Rapamycin (Rapamycin), lithium salts (lithium) and trehalose (trehalose) etc., to also have a class be autophagy inhibitor as: 3-MA(3-Methyladenine), wortmannin (wortmannin), LY294002 etc., and NH
4cl, chloroquine (Chloroquine) and hydroxychloroquine (hydroxychloroquine) etc.
So far, there is not yet cell autophagy inhibitor and interferon-β and make the relevant report that compound medicine, compositions carry out administering drug combinations or sequential administration treatment tumor.
Summary of the invention
The object of this invention is to provide a kind of
treatmentthe synergism medicine compositions of tumor, relates in particular to a kind of synergism medicine compositions being comprised of cell autophagy inhibitor and β interference.This synergism medicine compositions, one or more cell autophagy inhibitor wherein, himself is without obvious cytotoxicity but can strengthen by suppressing cell autophagy the curative effect of interferon-β, thereby reduces the consumption of interferon-β when treatment tumor, reduces the generation of its side effect.
Concrete, the invention provides a kind of
treatmentthe synergism medicine compositions of tumor, is characterized in that, this synergism medicine compositions by one or more cell autophagy inhibitor and
interferon-β formspharmaceutical composition; One or several autophagy inhibitors of this synergism medicine compositions with
interferon-βby using administering drug combinations or the mode of sequential administration, can offset the antagonism to interferon-β treatment that tumor causes due to cell autophagy by suppressing the cell autophagy of the tumor cell of interferon-β induction, thereby significantly strengthen, use separately the lethal effect of interferon-β to tumor, strengthen the therapeutic effect of interferon-β to tumor.
In the present invention, described cell autophagy inhibitor comprises (but being not limited to): 3-MA(3-Methyladenine), wortmannin (Wortmannin), LY294002, cycloheximide, Bava Lip river mycin A1(Bafilomycin A1), ammonium chloride, chloroquine (Chloroquine) and hydroxychloroquine (Hydroxychloroquine) etc.; In embodiments of the invention, preferred 3-MA(3-Methyladenine), chloroquine (Chloroquine) and hydroxychloroquine (Hydroxychloroquine).
Interferon-β described in the present invention includes, but is not limited to: recombinant human interferon-β 1b (Ser 17), recombinant human interferon-β 1a, human beta interferon.
In the present invention, the tumor that described synergism medicine compositions can be used for treatment comprises glioma, cancer of pancreas, pulmonary carcinoma, liver tumor, vascular cancer and myeloma.
In the present invention, described synergism medicine compositions preferred therapeutic glioma; Described glioma comprises ependymoma, astrocytoma, oligodendroglioma, glioblastoma multiforme and medulloblastoma.
It is a kind of that the present invention also provides
treatmentthe Synergistic compound medicine of tumor, described
form with interferon-βcompound medicine refer to in autophagy inhibitor one or more for example: 3-MA(3-Methyladenine), wortmannin (Wortmannin), LY294002, cycloheximide, Ba Faluo mycin A1(Bafilomycin A1), NH
4cl, chloroquine (Chloroquine) and hydroxychloroquine (hydroxychloroquine), form compound medicine with interferon-β, sequential use treatment tumor.
The present invention has carried out cell in vitro test, and result shows: cell autophagy has resistant function to interferon-β in interferon-β in to gliomatous therapeutic process; And use cell autophagy inhibitor can strengthen interferon-β to glioma, cancer of pancreas, pulmonary carcinoma, liver tumor, vascular cancer and myeloma, especially gliomatous curative effect.
Result of the test of the present invention also shows, described interferon-β is made Nano medication can further strengthen the therapeutic effect of interferon-β to neuroglial cytoma.
Accompanying drawing explanation
Fig. 1: interferon-β can cause that human glioma cell's autophagosome forms,
Wherein, A is U251MG negative control; B gives 2000IU/ml interferon-β to process the U251MG after 48h; C is that the part of B figure is amplified; D is U87MG negative control; E gives 2000IU/ml interferon-β to process the U87MG after 48h; F is that the part of E figure is amplified.
Fig. 2: interferon-β can be induced the generation of human glioma cell's autophagy signal,
Wherein, left figure is U251MG cell; Right figure is U87MG cell, Hoechst 33342 dyes nucleus, and Cyto-ID Green Dye dyes autophagy signal.
Fig. 3: interferon-β can cause the increase of autophagy associated protein LC3-II,
Wherein, the negative contrast of Ctrl, IFN β gives the cell that 2000IU/ml interferon-β is processed 48h.
Fig. 4: 3-MA suppresses cell autophagy and strengthens human glioma cell's growth inhibited that interferon-β causes.
Fig. 5: CQ suppresses cell autophagy and strengthens human glioma cell's growth inhibited that interferon-β causes.
Fig. 6: 3-MA suppresses cell autophagy can strengthen human glioma cell's apoptosis that interferon-β causes.
Fig. 7: chloroquine suppresses cell autophagy can strengthen human glioma cell's apoptosis that interferon-β causes.
Fig. 8: interferon-β is made Nano medication and further strengthened tumor suppression effect.
The specific embodiment
embodiment 1: preparation interferon-β and autophagy suppress medicine
preparation interferon-β medicine:take 0.25mg recombinant human interferon beta-1b, be dissolved in the aseptic sodium chloride solution of 1ml0.54%, fully stir 30 minutes and filter by 0.1 μ m sterile filters, be distributed into 10 pipes and preserve, every pipe 100 μ l.The activity of interferon-β is 8.0MIU/ml;
preparation autophagy suppresses medicine:
(1) preparation of chloroquine: get appropriate chloroquine and be dissolved in the storage liquid that pure water is made into 10mmol/L, be stored in 4 ℃ after the filter filtration sterilization with 0.1 μ m, experiment in vitro chamber dilution 500-1000 is doubly for suppressing cell autophagy;
(2) preparation of ammonium chloride: get the storage liquid of the water-soluble 0.4mol/L of being made into of appropriate ammonium chloride, be stored in 4 ℃ after the filter filtration sterilization with 0.1 μ m.During experiment in vitro, dilute 50-80 doubly for suppressing cell autophagy;
(3) preparation of hydroxychloroquine: get appropriate hydroxychloroquine and be dissolved in the storage liquid that pure water is made into 10mmol/L, be stored in 4 ℃ after the filter filtration sterilization with 0.1 μ m, experiment in vitro chamber dilution 500-1000 is doubly for suppressing cell autophagy;
(4) preparation of 3-MA: get the storage liquid that appropriate 3-MA dry powder is mixed with 0.2mol/L, be stored in-20 ℃ after the filter filtration sterilization with 0.1 μ m.During experiment in vitro, dilute 50-200 doubly for suppressing cell autophagy;
(5) preparation of LY294002: get the storage liquid that appropriate LY294002 dry powder is mixed with 0.2mol/L, be stored in-20 ℃ after the filter filtration sterilization with 0.1 μ m.During experiment in vitro, dilute 50-100 doubly for suppressing cell autophagy;
(6) preparation of Bava Lip river mycin A1: get the storage liquid that appropriate Bava Lip river mycin A1 dry powder is mixed with 0.5 μ g/ml, be stored in-20 ℃ after the filter filtration sterilization with 0.1 μ m, dilute 1000 times during experiment in vitro for suppressing cell autophagy.
embodiment 2: interferon-β can cause that human glioma cell's autophagosome forms
Human glioma cell U251MG and U87MG cell adopt respectively the interferon-β of 2000IU/ml to process 48h, collecting cell is fixed, carry out electron microscopic sample preparation, do not give the cell of interferon-β as negative control, adopt transmission electron microscope to observe, result demonstration, the electron micrograph after amplification can be observed clearly has the double-deck autophagosome structure (as shown in Figure 1) to multilayer film.
embodiment 3: interferon-β can cause that human glioma cell's autophagy signal produces
Human glioma U251MG and U87MG cell adopt respectively 2000IU/ml interferon-β to process 48h, adopt the cell of 500nM rapamycin treatment 12h as positive control, the cell of not administration is as negative control, cell is used confocal laser scanning microscope after adopting the green autophagy dyestuff of Cyto-ID to dye, result negative control does not have the green fluorescence that autophagy is relevant to occur, interferon-β all has the green fluorescence that autophagy is relevant (as shown in Figure 2) with the positive control of rapamycin treatment.
embodiment 4: interferon-β can cause that human glioma cell's autophagy associated protein LC3-II increases
Human glioma U251MG and U87MG cell adopt the interferon-β of 0IU/ml and 2000IU/ml to process 48h, collecting cell, with 0.01M PBS washing 2 times, adopt RIPA lysate cracking 30min on ice, the centrifugal 5-10min of 13000rpm, collect supernatant, adopt BCA protein quantification test kit to carry out protein quantification, by every swimming lane 20ug albumen loading, undertaken after SDS-PAGE electrophoresis, go to pvdf membrane, with 5% skim milk room temperature sealing 1h, add respectively anti-LC3B and β-actin primary antibodie, hatch 12h for 4 ℃, after adopting TBST to wash film, add two anti-incubated at room 2h, adopt ECL chemical luminescence reagent kit to develop the color, result of the test shows, compared with the control, the expression that gives the neuroglial cytoma LC3-II of 2000IU/ml interferon-β obviously increases (as shown in Figure 3).
embodiment 5: interferon-β and cell autophagy suppress medicine 3-MA administering drug combinations can obviously strengthen the growth inhibited of interferon-β to human glioma cell
Human glioma U251MG and U87MG cell attachment give respectively 2000IU/ml interferon-β after cultivating 24h, administering drug combinations group gives to add 2000IU/ml interferon-β after 1mM 3-MA effect 1h, after administration, continue to cultivate 48h, cell growth inhibition adopts MTT to detect at 570nm, result of the test, add the autophagy inhibitor 3-MA to suppress after cell autophagy, obviously strengthened the human glioma cell's that interferon-β causes growth inhibited (as shown in Figure 4).
embodiment 6: interferon-β and cell autophagy suppress medicine chloroquine administering drug combinations can obviously strengthen the growth inhibited of interferon-β to human glioma cell
Human glioma U251MG and U87MG cell attachment give respectively 2000IU/ml interferon-β after cultivating 24h, administering drug combinations group gives to add 2000IU/ml interferon-β after 5uM CQ effect 1h, after administration, continue to cultivate 48h, cell growth inhibition adopts MTT to detect at 570nm, result of the test shows, add the autophagy inhibitor CQ to suppress after cell autophagy, obviously strengthened the human glioma cell's that interferon-β causes growth inhibited 9 as shown in Figure 5).
embodiment 7: interferon-β and cell autophagy suppress medicine 3-MA administering drug combinations can obviously strengthen human glioma cell's apoptosis that interferon-β causes
Human glioma U251MG and U87MG cell attachment give 2000IU/ml interferon-β after cultivating 24h, administering drug combinations group gives to add 2000IU/ml interferon-β after 1mM 3-MA effect 1h, after administration, continue to cultivate 48h, apoptosis adopts flow cytometer to analyze, result shows, interferon-β can cause that apoptosis occurs for human glioma cell U251MG and U87MG, use separately autophagy inhibitor 3-MA not have a significant effect to U251MG and U87MG, the apoptosis degree higher (as shown in Figure 6) that interferon-β associating autophagy inhibitor 3-MA causes than alone interferon-β, show that autophagy inhibitor 3-MA and interferon-β coupling can significantly strengthen the therapeutic effect of interferon-β to neuroglial cytoma.
embodiment 8: interferon-β and cell autophagy suppress medicine chloroquine administering drug combinations can obviously strengthen human glioma cell's apoptosis that interferon-β causes
Human glioma U251MG and U87MG cell attachment give 2000IU/ml interferon-β after cultivating 24h, administering drug combinations group gives to add 2000IU/ml interferon-β after 5 μ M CQ effect 1h, after administration, continue to cultivate 48h, apoptosis adopts flow cytometer to analyze, result shows, interferon-β can cause that apoptosis occurs for human glioma cell U251MG and U87MG, use separately autophagy inhibitor CQ not have a significant effect to U251MG and U87MG, the apoptosis degree higher (as shown in Figure 7) that interferon-β associating autophagy inhibitor CQ causes than alone interferon-β, show that autophagy inhibitor CQ and interferon-β coupling can significantly strengthen the therapeutic effect of interferon-β to neuroglial cytoma.
embodiment 9: interferon-β is made nano controlled-release medicine can further strengthen oncotherapy effect
After human glioma U87MG cell attachment cultivation 24h, give respectively the Nano medication that 2000IU/ml interferon-β and nano medicament carrying system PAMAM-interferon-β are made, continuous culture 96h after administration, cell growth inhibition adopts MTT to analyze, result shows, compare with common interferon-β, the cell growth inhibition degree higher (as shown in Figure 8) that nano medicament carrying system PAMAM-interferon-β causes, shows that interferon-β makes Nano medication and can further strengthen the therapeutic effect of interferon-β to neuroglial cytoma.
Claims (10)
1. a synergism medicine compositions for the treatment of tumor, is characterized in that, this synergism medicine compositions forms pharmaceutical composition or combination drug by one or more cell autophagy inhibitor and interferon-β.
2. by the synergism medicine compositions for the treatment of tumor claimed in claim 1, it is characterized in that, described cell autophagy inhibitor is selected from 3-MA(3-Methyladenine), wortmannin (Wortmannin), LY294002, cycloheximide, Bava Lip river mycin A1(Bafilomycin A1), ammonium chloride, chloroquine (Chloroquine) or hydroxychloroquine (Hydroxychloroquine).
3. by the synergism medicine compositions for the treatment of tumor claimed in claim 1, it is characterized in that, described cell autophagy inhibitor is selected from 3-MA(3-Methyladenine), chloroquine (Chloroquine) and hydroxychloroquine (Hydroxychloroquine).
4. by the synergism medicine compositions for the treatment of tumor claimed in claim 1, it is characterized in that, described interferon-β is selected from recombinant human interferon-β 1b (Ser 17), recombinant human interferon-β 1a or human beta interferon.
5. by the synergism medicine compositions for the treatment of tumor claimed in claim 1, it is characterized in that, described compound medicine is that one or more and the interferon-β in cell autophagy inhibitor forms compound medicine, the sequential use of this compound medicine.
6. by the synergism medicine compositions for the treatment of tumor claimed in claim 1, it is characterized in that, in described compound medicine, cell autophagy inhibitor is selected from 3-MA(3-Methyladenine), wortmannin (Wortmannin), LY294002, cycloheximide, Ba Faluo mycin A1(Bafilomycin A1), NH
4one or more in Cl, chloroquine (Chloroquine) and hydroxychloroquine (hydroxychloroquine).
7. by the synergism medicine compositions of the arbitrary described treatment tumor of claim 1-6, it is characterized in that, described tumor comprises glioma, cancer of pancreas, pulmonary carcinoma, liver tumor, vascular cancer and myeloma.
8. by the synergism medicine compositions of the arbitrary described treatment tumor of claim 1-6, it is characterized in that, described tumor is glioma.
9. by the synergism medicine compositions for the treatment of tumor claimed in claim 8, it is characterized in that, described glioma is ependymoma, astrocytoma, oligodendroglioma, glioblastoma multiforme or medulloblastoma.
10. by the synergism medicine compositions for the treatment of tumor claimed in claim 1, it is characterized in that, described interferon-β is made Nano medication.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104353074A (en) * | 2014-10-15 | 2015-02-18 | 中国科学技术大学 | Method for killing tumor cells through combination of gold-mediated near-infrared light heat effect and autophagy inhibitor |
| CN105250296A (en) * | 2015-10-19 | 2016-01-20 | 中国科学院近代物理研究所 | Method for improving tumor treatment effect of ion beams through chloroquine autophagy inhibitor |
| CN112089841A (en) * | 2020-04-05 | 2020-12-18 | 徐静 | Pharmaceutical composition for treating diseases caused by virus infection of epithelial tissues |
Citations (1)
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| CN102639700A (en) * | 2009-09-30 | 2012-08-15 | 哈佛大学校长及研究员协会 | Methods for modulation of autophagy through the modulation of autophagy-enhancing gene products |
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2013
- 2013-02-17 CN CN201310051944.7A patent/CN103990126A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102639700A (en) * | 2009-09-30 | 2012-08-15 | 哈佛大学校长及研究员协会 | Methods for modulation of autophagy through the modulation of autophagy-enhancing gene products |
Non-Patent Citations (1)
| Title |
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| LI Y B,ET AL.: "Suppression of Autophagy Enhanced Growth Inhibition and Apoptosis of Interferon-β in Human Glioma Cells", 《MOLECULAR NEUROBIOLOGY》, vol. 47, 18 January 2013 (2013-01-18) * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104353074A (en) * | 2014-10-15 | 2015-02-18 | 中国科学技术大学 | Method for killing tumor cells through combination of gold-mediated near-infrared light heat effect and autophagy inhibitor |
| CN104353074B (en) * | 2014-10-15 | 2017-11-07 | 中国科学技术大学 | A kind of near infrared light fuel factor of gold mediation combines the method for killing tumor cell with autophagy inhibitor |
| CN105250296A (en) * | 2015-10-19 | 2016-01-20 | 中国科学院近代物理研究所 | Method for improving tumor treatment effect of ion beams through chloroquine autophagy inhibitor |
| CN112089841A (en) * | 2020-04-05 | 2020-12-18 | 徐静 | Pharmaceutical composition for treating diseases caused by virus infection of epithelial tissues |
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Application publication date: 20140820 |