CN108686221A - The antitumor drug of synergy - Google Patents
The antitumor drug of synergy Download PDFInfo
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- CN108686221A CN108686221A CN201810824134.3A CN201810824134A CN108686221A CN 108686221 A CN108686221 A CN 108686221A CN 201810824134 A CN201810824134 A CN 201810824134A CN 108686221 A CN108686221 A CN 108686221A
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/761—Adenovirus
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/766—Rhabdovirus, e.g. vesicular stomatitis virus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to biomedicine field, be related to a kind of synergy antitumor drug more particularly to antitumor drug such as DNA-PK (DNA-dependent protein kinase, DNA-PK) inhibitor and oncolytic virus in the application for preparing antitumor drug.Present invention firstly discovers that the antitumor drug of a variety of target spots such as DNA-PK inhibitor can be used for preparing the antitumor synergist of oncolytic virus.It invents while being related to a kind of pharmaceutical composition comprising antitumor drug and oncolytic virus, including the drug of antitumor drug and oncolytic virus is set with, and purposes of the antitumor drug with oncolytic virus in treatment tumour, tumour especially insensitive to the oncolytic virus.
Description
Technical field
The invention belongs to biomedicine fields, are related to antitumor drug such as DNA-PK protein inhibitors etc. and oncolytic virus
Joint application in preparation of anti-tumor drugs.
Background technology
Oncolytic virus (oncolytic virus) is the infection of a kind of selectivity and killing tumor cell, without damaging just
The replication-competent virus of normal cell.Oncolytic viral therapy (oncolytic virotherapy) is that a kind of cancer target of innovation is controlled
Strategy is treated, it utilizes infected tumor's cell of antiviral selectivity natural or through genetic engineering transformation, and in tumour cell
It replicates, has the function that targeting dissolving, killing tumor cell, but normal cell is not damaged.
Oncolytic virus M1 is a kind of Togaviridae alphavirus lid tower sample virus, is located away from the southern Chinese island of Hainan Culex mosquito
Worm.Our early-stage studies show the high selectivity of viral M1, good security.Its application in terms of preparing antitumor drug is
Through being recorded in Chinese invention patent application 201410425510.3.M1 viruses can selectively cause death of neoplastic cells without influencing
Normal cell is survived, and has extraordinary application prospect in anti-tumor aspect.However, sensibility of the different tumours to M1 viruses
Differ, for certain tumours, when M1 virus independent medications, oncolysis is ideal not enough.Such as Chinese invention patent application
Recorded in 201410425510.3, M1 is as antitumor drug in use, for colorectal cancer, liver cancer, carcinoma of urinary bladder and mammary gland
The effect of cancer is apparent not as good as cancer of pancreas, nasopharyngeal carcinoma, prostate cancer and melanoma;And glioma, cervical carcinoma, lung cancer then more its
It is secondary;And gastric cancer is then least notable.
The compound of screening increase oncolytic virus oncotherapy effect is expected to increase the antitumor spectra of oncolytic virus and anti-tumor is strong
Degree.Before this in Chinese invention patent application 201510990705.7, using Chrysophanol and its derivative as the anti-tumor of oncolytic virus
Synergist, the survival rate of tumour cell can be reduced to 39.6% by the two combination, but there are prodigious progress for its anticancer intensity
Space.In addition, the mechanism of action of this use in conjunction is still not clear, also fail to know not by clearly report can synergy oncolytic virus
Other substances, which having, the amplitude of synergistic effect and synergy can be generated with it.
Invention content
One of the objects of the present invention is to provide a kind of synergist of the anti-tumor of oncolytic virus.
It is another object of the present invention to provide can selectively enhance killing work of the oncolytic virus to tumour cell
With the anticancer synergist without influencing normal cell.
It is another object of the present invention to provide a kind of antitumor drugs in terms of preparing the anti-tumor synergist of Alphavirus
Using.
It is another object of the present invention to provide a kind of antitumor medicine compositions or drug to be set with, and can make oncolytic
Virus plays preferably anti-tumor effect.
It being directed to the insensitive tumour of oncolytic virus it is another object of the present invention to provide a kind of, safely and effectively oncolytic
Virus synergy drug.
Invention is achieved through the following technical solutions above-mentioned purpose:
Inventor is by studying, screening discovery, it was found that the antitumor drug of a variety of target spots can enhance oncolytic virus
Oncolytic effect.The target spot can be ATM (ataxia-telangiectasia mutated), ALK (anaplastic
lymphoma kinase),Akt(protein kinase B),Bcr-Abl(breakpoint cluster region
gene-Abelson murine leukemia viral oncogene homolog 1),Chk(checkpoint
kinases),c-MET(hepatocyte growth factor receptor),DNA-PK,DNA synthesis,DHFR
(dihydrofolate reductase),EGFR(epidermal growth factor receptor),FGFR
(fibroblast growth factor receptor),FAK(focal adhesion kinase),GSK-3(glycogen
synthase kinase-3),HDAC(histone deacetylase),Hedgehog,HSP90(heat shock
protein 90),IκB/IKK(inhibitor of kappa B/inhibitor of kappa B kinase),JAK
(Janus kinase),Kinesin,MEK(Mitogen-activated protein kinase kinase),mTOR(the
mammalian target of rapamycin),Microtubule Associated,Mutant pan Raf,Wnt/
beta-catenin,PDGFR(platelet derived growth factor receptor),Proteasome,PI3K
(phosphoinositde 3-kinase),PKC(protein kinase C),p38MAPK(p38mitogen-activated
protein kinases),PLK(polo like kinase),Syk(spleen associated tyrosine
kinase),Topoisomerase,TGF-beta/Smad(transforming growth factor-beta/smad),
VEGFR(vascular endothelial growth factor).The anticancer drug of different target spots, shows varying strength
Oncolytic virus oncolytic enhancing effect.Wherein, it is DNA dependent protein kinase (DNA- that synergistic effect is the most outstanding
dependent protein kinase,DNA-PK).DNA dependent protein kinase (DNA-dependent protein
Kinase, DNA-PK), the protein serine/threonine being made of 3 subunits belongs to phosphatidylinositol 3-kinase correlation and swashs
Enzyme family (phosphatidylinositol3-kinase-related kinases, PIKK), is the key that DNA damage reparation
Enzyme is primarily involved in non-homologous end joining to repair the DNA double chain of fracture, and DNA-PK also takes part in ionization radiation induction in addition
Apoptotic signal Signal Transduction Pathways, the processes such as cell response under immunocyte V (D) J recombinations, immune cell differentiation, insulin stimulating,
Have the function of maintaining Telomere Stability.Have more document report DNA-PK high expression in tumour cell, inhibits DNA-PK
The reparation of DNA can be hindered to inducing death of neoplastic cells.
Inventor reduces the table of corresponding albumen by the expression for inhibiting this gene with DNA-PK interference fragments (Si RNA)
Up to amount, as a result, it has been found that, it individually interferes DNA-PK and does not interfere with and do not cause cellular morphology lesion, while M1 viruses are used alone
Do not cause cellular morphology lesion, only DNA-PK use in conjunction M1 virus groups is interfered to cause notable cellular morphology lesion.
Inventor is further by inhibiting DNA-PK that can significantly increase the oncolytic effect of oncolytic virus.Inventor uses
A series of inhibition DNA-PK reactive compounds (such as NU7441, NU7026, KU-0060648 etc.) collaboration oncolytic virus are especially
M1 virus functions find that these DNA-PK reactive compounds can cooperate with oncolytic virus enhancing anti-in tumour cell, experimental result
Tumor effect.
Present invention firstly discovers that the antitumor drug of a variety of target spots such as DNA-PK inhibitor can be as the anti-of oncolytic virus
Tumor synergist/reversal agent of drug resistance.
The present invention provides application of the antitumor drug in terms of preparing the anti-tumor synergist/reversal agent of drug resistance of oncolytic virus.
The present invention also provides application of the oncolytic virus in terms of preparing antitumor drug synergist or reversal agent of drug resistance.
The antitumor drug is selected from ATM inhibitor, ALK inhibitor, Akt inhibitor, Bcr-Abl inhibitor, Chk suppressions
Preparation, inhibitors of c-met, DNA synthesis inhibitor, DHFR inhibitor, EGFR inhibitor, FGFR inhibitor, FAK inhibit
Agent, GSK-3 inhibitor, hdac inhibitor, Hedgehog inhibitor, HSP90 inhibitor, I κ B/IKK inhibitor, JAK inhibitor,
Kinesin inhibitor, mek inhibitor, mTOR inhibitors, Microtubule Associated inhibitor, Mutant pan
Raf inhibitor, Wnt/beta-catenin inhibitor, PDGFR inhibitor, Proteasome inhibitor, PI3K inhibitor, PKC
Inhibitor, p38MAPK inhibitor, PLK inhibitor, Syk inhibitor, Topoisomerase inhibitor, TGF-beta/Smad suppressions
It is one or more in preparation, VEGFR inhibitor and DNA-PK inhibitor.
These above-mentioned antitumor drugs, can be inhibit the generation of above-mentioned cited target spot or inhibit target active or
Person degrade these target spots substance either tool include chemistry biology substance or tool etc..As exemplary implementation
Mode, the ATM inhibitor are selected from KU-60019 or CP-466722;The ALK inhibitor is selected from Crizotinib;Institute
The Akt inhibitor stated is selected from MK-2206;The Bcr-Abl inhibitor is selected from Ponatinib;The Chk inhibitor is selected from
AZD7762;The inhibitors of c-met is selected from SU11274;The DNA synthesis inhibitor is selected from Gemcitabine
Or Oxaliplatin;The DHFR inhibitor is selected from Pemetrexed;The EGFR inhibitor is selected from Lapatinib
Ditosylate or Gefitinib;The FGFR inhibitor is selected from PD173074;The Fak inhibitor is selected from PF-
562271;The GSK-3 inhibitor is selected from CHIR-99021 HCl;The hdac inhibitor is selected from Vorinostat;Institute
The Hedgehog inhibitor stated is selected from Vismodegib;The HSP90 inhibitor is selected from Ganetespib or AUY922;It is described
I κ B/IKK inhibitor be selected from TPCA-1;The JAK inhibitor is selected from Tofacitinib or Cyt387;Described
Kinesin inhibitor is selected from SB 743921;The mek inhibitor is selected from GSK1120212;The mTOR inhibitors are selected from
Rapamycin;The Microtubule Associated inhibitor is selected from Paclitaxel or Docetaxel;Described
Mutant pan Raf inhibitor is selected from Vemurafenib;The Wnt/beta-catenin inhibitor is selected from FH535;Institute
The PDGFR inhibitor stated is selected from Imatinib;The Proteasome inhibitor is selected from Bortezomib;The PI3K suppressions
Preparation is selected from CAL-101 or GDC-0941;The pkc inhibitor is selected from Sotrastaurin;The p38MAPK inhibitor
Selected from BIRB 796;The PLK inhibitor is selected from BI6727;The Syk inhibitor is selected from R935788;Described
Topoisomerase inhibitor is selected from Doxorubicin;The TGF-beta/Smad inhibitor is selected from LY2157299;Institute
The VEGFR inhibitor stated is selected from Axitinib or Vandetanib.
Reversal agent of drug resistance refers to, when being used to treat tumour as antitumor drug using some oncolytic virus, there is
Some tumours are not too much sensitive to oncolytic virus, these tumours are resistant to oncolytic virus in other words, at this point it is possible to using with
The mode of antitumor drug such as DNA-PK inhibitor (as reversal agent of drug resistance) combination oncolytic virus, with reversing tumor to described molten
The resistance of tumor virus;Alternatively, conversely, when some antitumor drugs are for when treating tumour, there is some tumours to medicine
Object is not too much sensitive, these tumours are resistant to the drug in other words, at this point it is possible to (inverse as drug resistance using oncolytic virus
Turn agent) with the modes of these drug combinations, with reversing tumor to the resistance of the drug.
As a preferred embodiment, invention particularly provides DNA-PK inhibitor to prepare the anti-tumor of oncolytic virus
Application in terms of synergist/reversal agent of drug resistance.
The DNA-PK inhibitor refers to that can inhibit DNA-PK activity or inhibition wherein any one subunit (example
Such as, DNA-PKcs subunits, KU70 subunits or KU80 subunits) activity or expression or block subunit assembling or degradation of dna-
The substance of PK.
The DNA-PK inhibitor includes disclosed so far DNA-PK inhibitor.Possibly, future might have
Some other studied DNA-PK inhibitor for providing similar inhibition DNA-PK effects, these DNA-PK inhibitor and oncolytic
The combination of virus is also within the scope of the present invention.
As preferred embodiment, the DNA-PK inhibitor includes but not limited to following compound or it has
The derivative of DNA-PK inhibiting effect or its pharmaceutically acceptable salt, solvate, tautomer, isomer:
NU7441(KU-57788),NU7026(LY293646),KU-0060648,LTURM34,CC-115,PIK-90,Wortmannin
(wortmannin), LY302341, M3814 (nedisertib), SF2523, Compound 401.The acquisition modes of compound
It is optional but be not limited to:Oneself Chemical Decomposition or synthesis are bought from commercial channels.
In some embodiments of the invention, DNA-PK protein inhibitors be NU7441 (formula 1), NU7026 (formula 2),
KU0060648 (formula 3) or combination thereof.
Alternatively, DNA-PK protein inhibitors can also be LTURM34 (formula 4), CC-115 (formula 5), PIK-
90 (formulas 6), Wortmannin (wortmannin, formula 7), LY302341 (formula 8), M3814 (nedisertib, formula 9), SF2523
(formula 10), Compound 401 (formula 11) etc..
In some preferred embodiments of the invention, DNA-PK inhibitor further includes being directed to DNA-PK gene expression inhibition works
Tool, including but not limited to tools means or the material such as gene interference, gene editing, gene silencing or gene knockout.
As an alternative embodiment, the DNA-PK gene expression inhibitions tool is selected from DNA, RNA, PNA, DNA-
One or more of RNA heterozygotes.They can be single-stranded or double-strand.
DNA-PK inhibitor may include some small inhibition nucleic acid molecules, such as short interfering rna (siRNA), double-stranded RNA
(dsRNA), microRNA (miRNA), ribozyme and children purpura nephritis (shRNA), these can weaken or eliminate DNA-PK and appoint
The gene expression of one subunit.
In one embodiment of the invention, the DNA-PK inhibitor is selected from gene interfering material.More preferably
Embodiment, the DNA-PK inhibitor be selected from SEQ ID NO:1,SEQ ID NO:2 or SEQ ID NO:It is arbitrary in 3
One.
These small inhibition nucleic acid molecules may include the first, second chain, and the two hybridization forms one or more double each other
Sequence, the length of about 18~28 nucleotide of every chain, the length or 18 of about 18~23 nucleotide, 19,20,21,
The length of 22 nucleotide.In addition, single-stranded may also include the region for capableing of phase mutual cross formation double-strand, such as at shRNA points
In son.
These are small to inhibit nucleic acid molecules in the ability for keeping the expression of this decrease or elimination DNA-PK, may include
Modified nucleotide.Modified nucleotide can be used for improving characteristic in vitro or in vivo, such as stability, activity and/or biological utilisation
Degree.These modified nucleotides may contain deoxynucleotide, 2 '-methyl nucleotides, 2 '-deoxidations -2 '-fluorine nucleotide, 4 '-three
Nucleotide, lock nucleic acid (LNA) nucleotide and/or 2 '-O- methoxyethyl nucleotide etc..Small inhibition nucleic acid molecules, such as short interference
RNA (siRNA), it is also possible to contain 5 '-and/or 3 '-cap structures, prevent exonuclease from degrading to it with this.
In some embodiments, small that the double-strandednucleic acid of nucleic acid molecules composition is inhibited to contain the nucleotide that both ends are blunt or dangle.
Other nucleotide may include that can lead to dislocation, raised, cycle or wobble base pair nucleotide.Small inhibition nucleic acid molecules can
With component design to apply, for example, by liposome, or mix other carrier (such as biodegradable polymers water-settings
Glue or cyclodextrin).
In other preferred embodiments of the invention, the DNA-PK inhibitor further includes antibody, antibody functional
One or more of segment, peptides and peptidomimetic class.For example, be bound to the arbitrary functional domain of the arbitrary subunits of DNA-PK
Antibody, antibody functional segment, peptides or peptidomimetic.For example, the combined areas DNA of DNA-PK, catalysis area or Ku protein bindings
Area.Wherein, the antibody may be monoclonal antibody, polyclonal antibody, multivalent antibody, multi-specificity antibody (such as:Double spies
Heterogenetic antibody), and/or the antibody fragment that is connected on DNA-PK.The antibody can be chimeric antibody, humanized antibody, CDR shiftings
Plant antibody or human-like antibody.Antibody fragment can be, for example, Fab, Fab ', F (ab ') 2, Fv, Fd, scFv (scFv), tool two
The FV (sdFv) or VL, VH structural domain of sulfide linkage.Antibody may be one conjugation form, for example, in conjunction with a label, one
Detectable label or a kind of cytotoxic agent.Antibody may be homotype IgG (such as:IgG1,IgG2,IgG3,IgG4),IgA,
IgM, IgE or IgD.
In another preferred embodiment of the present invention, DNA-PK protein inhibitors are the RNA interfering segment of DNA-PK.As
Preferred embodiment, the DNA-PK inhibitor are selected from SEQ ID NO:1,SEQ ID NO:2 or SEQ ID NO:In 3
Any one.
The oncolytic virus is selected from Alphavirus, getah virus, adenovirus, vaccinia virus, measles virus, bubble stomatitis disease
It is one or more in poison and herpes simplex virus;Preferably Alphavirus, it is highly preferred that selected from M1 virus, getah virus or
Person's combination thereof.
Single oncolytic virus strain can also be applied.In other embodiments, it is possible to use a variety of strains and/or type
Oncolytic virus.
In some embodiments, M1 viruses are that deposit number CCTCC V201423 (are preserved in China typical culture collection
Center, preservation date on July 17th, 2014) M1 viruses.China of the virus of the preservation in application number 201410425510.3
It is also on the books in patent application.As the virus for likely originating from same strain, Genbank Accession
No.EF011023 has recorded the sequence of one plant of M1.Getah virus has up to 97.8% (Wen et as with M1 viruses
al.Virus Genes.2007;35(3):597-603) the virus of homology, the two have very high homogeneity, M1 viruses
It is classified as class getah virus by some documents.Alphavirus of the present invention includes being up to the M1 strains sequence identity
97.8% or more M1 or getah virus.
Oncolytic virus described in the present invention can existing oncolytic virus before feeling the pulse with the finger-tip in particular, but be also not excluded for some natures
Make a variation or carried out the virus of mutation, modification, sequence increase, reduction etc..These variations, mutation, modification, sequence increasing add deduct
Few virus is possible to have the function of similar oncolysis or even slightly reduce or enhance etc..These situations
With within protection scope of the present invention.Described inhibition DNA-PK inhibitor be can play strike it is low or influence DNA-PK it is arbitrarily sub-
Either any protein subunit amount or protein active either block the assembling of subunit or the object of degradation of dna-PK for base gene expression
Matter (such as compound or amino acid sequence, nucleotide sequence etc.) or tool etc..Those skilled in the art can be to its inhibition
It closes object or Genetic tools is modified, replaced, changed, alternatively, these situations also belong to the guarantor of the present invention
Protect range.
The present invention also provides application of the combination of antitumor drug and oncolytic virus in preparing tumor.
The present invention also provides a kind of for treating the pharmaceutical composition of tumour, it includes antitumor drug as described above with
And oncolytic virus, especially include DNA-PK inhibitor and oncolytic virus.
The present invention also provides the drug suits for treating tumour, and it includes antitumor drug as described above and oncolytics
Virus especially includes DNA-PK inhibitor and oncolytic virus.
The place that drug suit is different from composition is that antitumor drug such as DNA-PK inhibitor is different from oncolytic virus
Dosage form, but independent packaging (such as:Pill or capsule or tablet or peace are cutd open in bottle, and antitumor drug such as DNA-PK is contained
Inhibitor;Other pill or capsule or tablet or peace are cutd open in bottle, and oncolytic virus is contained).In some embodiments, oncolytic disease
The combination of poison, antitumor drug such as DNA-PK inhibitor and oncolytic virus and antitumor drug such as DNA-PK inhibitor, also may be used
Containing one or more adjuvants.The adjuvant refer to drug composition in, can ancillary drug curative effect ingredient.Drug suit also may be used
With the antitumor drug comprising independent packaging such as DNA-PK inhibitor and the oncolytic virus of independent packaging.Drug is set with moderate resistance
The application of tumour medicine such as DNA-PK inhibitor and oncolytic virus can be administered simultaneously either with arbitrary front and back suitable
Sequence is applied, such as antitumor drug such as DNA-PK inhibitor is applied before oncolytic virus, or is applied after oncolytic virus
Antitumor drug such as DNA-PK inhibitor, or both is administered simultaneously.In various embodiments, patient can be mammal.
In some embodiments, mammal can be people.
As an implementation, the pharmaceutical composition or drug suit can also include pharmaceutically acceptable load
Body.
As an implementation, the pharmaceutical composition or the dosage form of drug suit include but not limited to freeze-dried powder
The dosage forms such as needle, injection, tablet, capsule or patch;Preferably injection type;More preferably intravenous injection.
As preferred embodiment, the drug is set with the antitumor drug such as DNA-PK albumen for including independent packaging
Inhibitor or derivatives thereof or combination thereof and the oncolytic virus of independent packaging.
As a preferred embodiment, the antitumor drug includes but not limited to KU-60019, CP-
466722,Crizotinib,MK-2206,Ponatinib,AZD7762,SU11274,Gemcitabine,Oxaliplatin,
Pemetrexed,Lapatinib Ditosylate,Gefitinib,PD173074,PF-562271,CHIR-99021HCl,
Vorinostat,Vismodegib,Ganetespib,AUY922,TPCA-1,Tofacitinib,Cyt387,SB 743921,
GSK1120212,Rapamycin,Paclitaxel,Docetaxel,Vemurafenib,FH535,Imatinib,
Bortezomib,CAL-101,GDC-0941,Sotrastaurin,BIRB 796,BI6727,R935788,Doxorubicin,
LY2157299,Axitinib,Vandetanib,NU7441,NU7026,KU-0060648,LTURM34,CC-115,PIK-90,
It is one or more in Wortmannin, LY302341, M3814, SF2523, Compound 401, and or they pharmaceutically
Acceptable salt, solvate, tautomer, isomer.
As preferred embodiment, the antitumor drug includes but not limited to NU7441 (formula 1), NU7026 (formulas
2), KU0060648 (formula 3), LTURM34 (formula 4), CC-115 (formula 5), PIK-90 (formula 6), Wortmannin (wortmannin,
Formula 7), LY302341 (formula 8), M3814 (nedisertib, formula 9), SF2523 (formula 10), the suppressions such as Compound 401 (formula 11)
The compound of DNA-PK protein actives processed.Or be directed to DNA-PK gene expression inhibition tools, including but not limited to gene interference,
The tools such as gene silencing and gene editing or knockout means or material.The preferable NU7441 of DNA-PK inhibitor,
KU0060648, NU7026 or combinations thereof.
Composition or drug suit in, antitumor drug (such as NU7441, KU0060648, NU7026, LTURM34,
CC-115, PIK-90, Wortmannin, LY302341, M3814, SF2523 or Compound 401 etc.) match with oncolytic virus
Than being optionally:0.01~200mg:103~109PFU;It is preferred that 0.1~200mg:104~109PFU;Further preferred 0.1~
100mg:105~109PFU;
It is preferable to use dosage to be:Antitumor drug (such as NU7441, KU0060648, NU7026, LTURM34, CC-115,
PIK-90, Wortmannin, LY302341, M3814, SF2523 or Compound 401 etc.) use scope be 0.01mg/kg extremely
200mg/kg, while oncolytic virus is MOI from 10 using titre3To 109(PFU/kg);More preferable DNA-PK inhibitor (such as
NU7441,KU0060648,NU7026,LTURM34,CC-115,PIK-90,Wortmannin,LY302341,M3814,
SF2523 or Compound 401 etc.) use scope is 0.1mg/kg to 200mg/kg, while oncolytic virus is MOI using titre
From 104To 109(PFU/kg);Even more preferably from DNA-PK inhibitor (such as NU7441, KU0060648, NU7026, LTURM34,
CC-115, PIK-90, Wortmannin, LY302341, M3814, SF2523 and Compound 401 etc.) use scope is
0.1mg/kg to 100mg/kg, while oncolytic virus is MOI from 10 using titre5To 109(PFU/kg)。
In one embodiment, the oncolytic virus is selected from Alphavirus, getah virus, adenovirus, vaccinia virus, measles
One or more of virus, vesicular stomatitis virus and herpes simplex virus.Preferably, the oncolytic virus is Alphavirus,
More preferable M1 viruses, getah virus or combination thereof.
In one embodiment, the tumour is solid tumor or blood tumor.In one embodiment, the solid tumor
For liver cancer, colorectal cancer, carcinoma of urinary bladder, breast cancer, cervical carcinoma, prostate cancer, glioma, melanoma, cancer of pancreas, nasopharyngeal carcinoma,
Lung cancer or gastric cancer.In a preferred embodiment, the tumour is the tumour insensitive to oncolytic virus.Preferred real
It applies in mode, the tumour is the tumour insensitive to M1 oncolytic virus.
Compared with prior art, the invention has the advantages that:
Present invention finds antitumor drug such as DNA-PK inhibitor (such as NU7441 or KU0060648 or NU7026 etc.)
The anti-tumor effect that oncolytic virus can be increased, to improve treatment validity of the oncolytic virus as antitumor drug when.Cell
It learns experiments have shown that oncolytic virus is respectively with DNA-PK inhibitor, (such as NU7441 or KU0060648 or NU7026 etc.) combines and answer
With can significantly cause the morphology lesion of tumour cell, to significantly increase the inhibiting effect to tumour cell.
And unexpectedly, NU7441, KU0060648 or NU7026 etc. are used as antiviral compound, with oncolytic virus
When combination, instead can enhanced virus oncolytic.For example, in embodiment 3, antiviral compound NU7441 or
The viral combined applications of KU0060648 or NU7026 and M1 act on HCT116 plants of people's Colon and rectum cell cancer, and it is thin to significantly reduce tumour
Born of the same parents' survival rate.In embodiment 2 and 3, when M1 viral (MOI=1) individually processing colorectal cancer cells, tumor cell survival
It is 93.8%;When handling colorectal cancer cell with 1 μM of NU7441, tumor cell survival 76.7%;And when with 1 μM
When NU7441 and the M1 viruses of same titre are combined, the tumour cell of cellular morphology lesion obviously increases, tumor cell survival
It declines to a great extent to 23.1%.Compared with the antitumous effect that M1 viruses are applied alone, when NU7441 and M1 is combined, oncolytic effect significantly carries
It rises.As it can be seen that the oncolytic effect that NU7441 and M1 is substantially improved when being combined, is the concertedness having benefited between NU7441 and M1 viruses
Mechanism plays a role not by the antitumor mechanism of NU7441.
Inventor before this using Chrysophanol and its derivative as the anticancer synergist of M1 viruses, it is found through experiment that, 50 μM
For Chrysophanol with after the combination of M1 viruses, the survival rate of tumour cell drops to 39.6%, and it is a discovery of the invention that by 1 μM of NU7441
After M1 (MOI=1) virus combinations, the survival rate of tumour cell is remarkably decreased to 23.1%.With Chrysophanol and its derivative phase
Than, the antitumor synergist of M1 of the invention significantly improves the killing rate of tumour, meanwhile, NU7441 on medicine effective dose only
It is 1st/50th of Chrysophanol, and acts on quickly, the used time is 2/3rds (Chrysophanol processing 72h, NU7441 of Chrysophanol
Handle 48h), have notable superiority.
In addition, inventor is also using mTOR inhibitors everolimus as the anticancer synergist references object of M1 viruses, through examination
It issues after examination and approval now, for 10 μM of everolimus with after the combination of (MOI=1) M1 viruses, the survival rate of tumour cell drops to 36.7%, and originally
Invention finds that after 1 μM of NU7441 and M1 viral (MOI=1) combination, the survival rate of tumour cell is remarkably decreased to 23.1%
(see embodiment 3).Compared with everolimus, the antitumor synergist of M1 of the invention significantly improves the killing rate of tumour, meanwhile,
NU7441 is only 1/10th of everolimus on medicine effective dose, has notable superiority.
Description of the drawings
Fig. 1 multiple target points screen oncolytic virus M1 synergist NU7441;
A. drug screening flow chart;For HCT116 cells kind on 96 orifice plates, cell is divided into two groups:Single dosing group:With difference
The compound of dosage is handled;Combination group:Add virus to be jointly processed by with the compound of various dose, cell is detected with mtt assay after 72h
Survival rate;
B. area under comparison curves;Cells survival curve is drawn using cells survival rate, area under calculated curve;
C. area under the curve is utilized to draw scatter plot, the compound that makes number one is NU7441.
Fig. 2 DNA-PK inhibitor NU7441 increases oncolysis of the oncolytic virus M1 in kinds of tumor cells, and to just
Normal cell is without influence.
The oncolytic effect of a variety of DNA-PK inhibitor collaboration M1 oncolytic virus of Fig. 3.
Fig. 4 strikes the oncolytic effect of low DNA-PKcs subunits enhancing M1 viruses;
A. inhibit the oncolytic effect of DNA-PKcs enhanced viruses on Colon and rectum cell HCT116;
B. inhibit the oncolytic effect of DNA-PKcs enhanced viruses in cancer of pancreas BxPC-3.
The viral combined processing of Fig. 5 NU7441 and M1 significantly inhibits people's growth of transplanted human;
A. the administration time arrangement on colorectal cancer HCT116 animal models;
The viral combined processing of B.NU7441 and M1 significantly inhibits Human colorectal carcinoma strain growth of transplanted human;
The viral combined processing of C.NU7441 and M1 has no significant effect lotus knurl (HCT116) nude mice weight;
D. the administration time arrangement on cancer of pancreas BxPC-3 animals administration model;
The viral combined processing of E.NU7441 and M1 significantly inhibits human pancreas cancer strain growth of transplanted human;
The viral combined processing of F.NU7441 and M1 has no significant effect lotus knurl (BxPC-3) nude mice weight;
Rectal neoplasm volume size when G. comparing terminal knot;
Pancreatic tumor volume size when H. comparing terminal knot.
Specific implementation mode
Following implementation is that the invention will be further described, but embodiments of the present invention are not limited to reality below
Example introduction is applied, it is all according to variation equivalent made by the principle of the present invention or theory or the flexible model for being regarded as the present invention and protecting
Farmland.
Without being prescriptive, the material and experimental method that the present invention uses is conventional material and methods.
1 multiple target point of embodiment screens oncolytic virus M1 synergist NU7441
Material:
DMEM in high glucose culture medium (is purchased from Corning companies), and Human colorectal cancer cells HCT116 (is purchased from ATCC cell banks),
M1 viruses (deposit number CCTCC V201423), the compound (being shown in Table 1, be purchased from selleck companies) of 47 kinds of different target spots,
Phase contrast microscope is set, automatic enzyme-linked detection microplate reader.
The anticancer drug of the different target spots of table 1
Method:As shown in Figure 1A
A) culture of cell:Human colorectal carcinoma HCT116 is grown in containing 10%FBS, 100U/ml penicillin and 0.1mg/ml
In the DMEM complete mediums of streptomysin;All cell strains are placed in 5%CO2, 37 DEG C of constant-temperature enclosed formula incubator (relative humidity
95%) subculture in, inverted microscope observe growing state.Passage in about 2~3 days is primary, takes in exponential phase
Cell is for formally testing.
B) cell processing and morphological observation:Exponential phase cell, DMEM complete culture solutions is selected (to contain 10% tire ox blood
Clearly, 1% is dual anti-) cell suspension is made, cell is with 2.5 × 104The density in/hole is seeded in 24 well culture plates.For in table 1
Each compound is individually handled, viral (MOI=1) infection cells of M1, M1 viruses (MOI=1) with the compound of various concentration
The drug-treated cell of joint various concentration is control to be not added with M1 viruses and compound, micro- in inverted phase contrast after 48 hours
The variation of microscopic observation cytomorphology.
C) MTT is reacted with intracellular succinate dehydrogenase:When culture is to 48h, 20 μ l (5mg/ml) of MTT are added per hole,
Continue to be incubated 4 hours, the graininess bluish violet formazan crystallization that microscopy can be observed, be formed in living cells at this time.
D) Rong Xie formazans particle:Supernatant carefully is sucked, adds the 100 lysigenous crystallizations in the holes μ l/ of DMSO, in micro-oscillating
5min is shaken on device, then detects the optical density (OD values) in each hole with wavelength 570nm in enzyme detector.Every group of experiment repeats
3 times.Cell survival rate=drug-treated group OD values/control group OD value × 100%.
As a result:
It is applied alone according to experimental result, is combined drug respectively one survival rate curve of drafting, the area between curve and reference axis x-axis
Domain is area under the curve (area under curve, AUC), and according to area discrepancy DAUC=under formula calculated curve, (AUC is mono-
It is combined with-AUC)/AUC combinations (such as Figure 1B).Scatter plot is made according to area under the curve difference, can see by Fig. 1 C and table 1
The AUC differences of DNA-PK inhibitor NU7441 are up to 2.58, are ranked first.The oncolytic effect of NU7441 enhanced sensitivity viruses M1 is most apparent,
Possibility is also maximum.
2 DNA-PK inhibitor NU7441 of embodiment increases oncolysis of the oncolytic virus M1 in kinds of tumor cells, and
On normal cell without influence
Material:
DMEM in high glucose culture medium (is purchased from Corning), human bladder cancer cell strain T24 (being purchased from ATCC cell banks), people's colloid
Tumor cell strain U-87MG (is purchased from ATCC cell banks), and human pancreas cancer cell strain BxPC-3 (is purchased from Shanghai Chinese Academy of Sciences cell bank), people
Hepatoma cell strain Hep3B (is purchased from ATCC cell banks), and Human colorectal cancer cells HCT116 (is purchased from ATCC cell banks), people's normal hepatocytes
Cell strain L-02 (Zhongshan University gives), M1 virus (deposit number CCTCC V201423), DNA-PK inhibitor NU7441 (purchases
In selleck companies of the U.S.), inverted phase contrast microscope.
Method:
Inoculating cell, administration processing:Select exponential phase cell, DMEM complete culture solutions (containing 10% fetal calf serum,
1% is dual anti-) cell suspension is made, with every hole 2 × 105The density in/hole is seeded in 6 well culture plates.See that cell is complete after 12 hours
It is complete adherent, experiment divide control group, independent 1 μM of NU7441 group, M1 infected groups and NU7441/M1 combinations group or.Dosage used is:
M1 virus (MOI=1) infection cells;1μMNU7441.
As a result:
As shown in Fig. 2, for different tumour cell (Human colorectal cancer cells HCT116, human hepatoma cell strain Hep3B,
Human bladder cancer cell's strain T24, human glioma cells strain U-87MG, human pancreas cancer cell strain BxPC-3, M1 virus or NU7441 are mono-
Reason of staying alone has smaller survival rate inhibiting effect, however, when the M1 viruses of 1 μM of NU7441 and same MOI are combined (NU7441
+ M1) when, the tumour cell of survival declines to a great extent.Therefore illustrate that DNA-PK protein inhibitors can enhance M1 in cellular level
The oncolytic effect of virus.Under mirror on visible normal cell L-02, independent M1 is viral or is combined drug-treated cell by cell
Survival is all without apparent difference.DNA-PK inhibitor NU7441 increases oncolytics of the oncolytic virus M1 in kinds of tumor cells and makees
With, and on normal cell without influence.
More than 3 kinds of DNA-PK inhibitor of embodiment and M1 oncolytic virus Combined Treatments reduce the survival rate material of cell:
DMEM in high glucose culture medium (is purchased from Corning), M1 viruses (deposit number CCTCC V201423), Human colorectal carcinoma
Cell HCT116 (is purchased from ATCC), compound N U7441, NU7026 or KU0060648, (being purchased from U.S. Selleck), automatic enzyme
Microplate reader, Methyl thiazoly tetrazolium assay (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl are surveyed in joint inspection
Tetrazolium bromide, MTT)
Method:
A) inoculating cell, administration processing:Select exponential phase cell, DMEM complete culture solutions (containing 10% fetal calf serum,
1% is dual anti-) cell suspension is made, with every hole 4 × 103The density in/hole is seeded in 6 well culture plates.See that cell is complete after 12 hours
Complete adherent, experiment divides control group, independent NU7441/NU7026/KU0060648 groups, M1 infected groups and NU7441/M1, NU7026/
M1 combinations group or KU0060648/M1 combination groups.Dosage used is:Dosage used is:M1 virus (MOI=1) infection cells;
NU7026/KU0060648 sets different dose gradients.
B) MTT is reacted with intracellular succinate dehydrogenase:When culture is to 48h, 20 μ l (5mg/ml) of MTT are added per hole,
Continue incubation 4 hours, the graininess bluish violet formazan formed in living cells crystallization can be observed in microscopy at this time.
C) Rong Xie formazans particle:Supernatant carefully is sucked, adds the 100 lysigenous crystallizations in the holes μ l/ of DMSO, in micro-oscillating
5min is shaken on device, then detects the optical density (OD values) in each hole with wavelength 570nm in enzyme detector.Every group of experiment repeats
3 times.Cell survival rate=drug-treated group OD values/control group OD value × 100%.
As a result:
As shown in Figure 3.It is applied alone M1 groups (MOI=1) cell inhibitory rate relatively low, inhibitor cell survival rate is applied alone to compare control
Group, which reduces, is no more than 25%;And combination group (M1+ inhibitor) cell survival rate greatly reduces, more than 50%.This illustrates DNA-PK
Inhibitor NU7441, NU7026, KU0060648 can enhanced virus M1 antitumor actions.
Embodiment 4 strikes the oncolytic effect that low DNA-PKcs subunits promote virus M1
Material:
DMEM in high glucose culture medium (is purchased from Corning), M1 viruses (deposit number CCTCC V201423), Human colorectal carcinoma
Cell strain HCT116 (being purchased from ATCC), human pancreas cancer cell strain BxPC-3 (being purchased from Shanghai Chinese Academy of Sciences cell bank), SiRNA DNA-
Three bar segments of PKcs are respectively:
Si-1SEQ ID NO:1
(CCTGAATGCTCTAGAAGAA),
Si-2SEQ ID NO:2
(GTGTTGAAGTCCAGGTTTA),
Si-3SEQ ID NO:3
(GTACAGCTTTAACAGAAA)。
Method:
Exponential phase cell, DMEM complete culture solutions is selected to be modulated into cell suspension, cell is with 1 × 105Density connect
Kind is in 6 orifice plates.After 24 hours, when being added the Si RNA target gene segments 24 of liposome after, infection M1 viruses.Infection
After 48 hours, sample is handled.
A) protein sample is collected, Western blot is carried out and detects jamming effectiveness;
B) mtt assay calculates cells survival rate, is counted using One way ANOVA, and * * indicate p<0.01.As a result:
As shown in figure 4, after interfering DNA-PKcs subunits using siRNA fragment, Western blot detections find gene
DNA-PKcs expression quantity is remarkably decreased.It individually interferes DNA-PKcs or cell is not caused to largely reduce using M1 viruses, only
Interference DNA-PKcs use in conjunction M1 virus groups cause people's Colon and rectum cell HCT116 (Fig. 4 A) and pancreatic cancer cell
BxPC-3 (Fig. 4 B) survival rate is remarkably decreased.Illustrate the oncolytic effect for inhibiting DNA-PKcs subunit enhanced viruses M1.
5 NU7441 of embodiment significantly inhibits Human colorectal carcinoma, cancer of pancreas growth of transplanted human with the viral combined applications of M1.
Material:
DMEM in high glucose culture medium (is purchased from Corning), M1 viruses (deposit number CCTCC V201423), Human colorectal carcinoma
Cell strain HCT116 (being purchased from ATCC), human pancreas cancer cell strain BxPC-3 (being purchased from ATCC), 4 week old female BAl BIcs/c nude mices.
Method:
This experiment is using the design random, list is blind.By 5 × 106HCT116 or 1 × 107BxPC-3 cells are injected into 4
Week old BALB/c nude mice dorsal subcutaneous.
Administering mode as shown in fig. 5 a and 5d, when tumor size reaches 50mm3When be grouped, including do not handle control group,
Be used alone NU7441 groups (intraperitoneal injection 10mg/kg/ days), be used alone M1 infected groups (tail vein injection M1 viruses 2 ×
106PFU/ times) and NU7441/M1 combinations group (same way gives NU7441 and the M1 virus of same dose), continuously inject 4
It is secondary.The volume of the every two days length and width and weight for measuring tumour, tumour is (long × wide according to formula2)/2.It is laggard to measure gross tumor volume
Row One way ANOVA statistics, * * indicate p<0.01.
As a result:
In two kinds of tumor cell transplantation tumor animal bodies, pathological anatomy measurement gross tumor volume shows and control group compares, single
The diminution that solely gross tumor volume can only be caused slight using NU7441 groups and independent M1 infected groups, and NU7441/M1 combinations group can draw
Gross tumor volume is played significantly to reduce (Fig. 5 B, 5E, 5G and 5H).In addition, different disposal group nude mice weight does not have notable difference (Fig. 5 C
And 5F).This shows that DNA-PK inhibitor NU7441 can enhance the oncolytic effect of M1 viruses and not have to nude mice weight in vivo
It influences.
Embodiment recorded in the present invention is only illustrative example, and embodiments of the present invention are not by above-mentioned limit
System, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications,
Equivalent substitute mode is should be, is included within the scope of the present invention.
Sequence table
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<120>The antitumor drug of synergy
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Claims (11)
1. application of the antitumor drug in terms of preparing the antitumor synergist of oncolytic virus or reversal agent of drug resistance;
The antitumor drug is selected from ATM inhibitor, ALK inhibitor, Akt inhibitor, Bcr-Abl inhibitor, Chk and inhibits
Agent, inhibitors of c-met, DNA synthesis inhibitor, DHFR inhibitor, EGFR inhibitor, FGFR inhibitor, FAK inhibit
Agent, GSK-3 inhibitor, hdac inhibitor, Hedgehog inhibitor, HSP90 inhibitor, I κ B/IKK inhibitor, JAK inhibitor,
Kinesin inhibitor, mek inhibitor, mTOR inhibitors, Microtubule Associated inhibitor, Mutant pan
Raf inhibitor, Wnt/beta-catenin inhibitor, PDGFR inhibitor, Proteasome inhibitor, PI3K inhibitor, PKC
Inhibitor, p38MAPK inhibitor, PLK inhibitor, Syk inhibitor, Topoisomerase inhibitor, TGF-beta/Smad suppressions
It is one or more in preparation, VEGFR inhibitor and DNA-PK inhibitor.
2. application of the oncolytic virus in terms of preparing antitumor drug synergist or reversal agent of drug resistance;
The antitumor drug is selected from ATM inhibitor, ALK inhibitor, Akt inhibitor, Bcr-Abl inhibitor, Chk and inhibits
Agent, inhibitors of c-met, DNA synthesis inhibitor, DHFR inhibitor, EGFR inhibitor, FGFR inhibitor, FAK inhibit
Agent, GSK-3 inhibitor, hdac inhibitor, Hedgehog inhibitor, HSP90 inhibitor, I κ B/IKK inhibitor, JAK inhibitor,
Kinesin inhibitor, mek inhibitor, mTOR inhibitors, Microtubule Associated inhibitor, Mutant pan
Raf inhibitor, Wnt/beta-catenin inhibitor, PDGFR inhibitor, Proteasome inhibitor, PI3K inhibitor, PKC
Inhibitor, p38MAPK inhibitor, PLK inhibitor, Syk inhibitor, Topoisomerase inhibitor, TGF-beta/Smad suppressions
It is one or more in preparation, VEGFR inhibitor and DNA-PK inhibitor.
3. application according to claim 1 or 2, which is characterized in that the ATM inhibitor is selected from KU-60019 or CP-
466722;The ALK inhibitor is selected from Crizotinib;The Akt inhibitor is selected from MK-2206;The Bcr-Abl
Inhibitor is selected from Ponatinib;The Chk inhibitor is selected from AZD7762;The inhibitors of c-met is selected from SU11274;
The DNA synthesis inhibitor is selected from Gemcitabine or Oxaliplatin;The DHFR inhibitor is selected from
Pemetrexed;The EGFR inhibitor is selected from Lapatinib Ditosylate or Gefitinib;The FGFR inhibits
Agent is selected from PD173074;The Fak inhibitor is selected from PF-562271;The GSK-3 inhibitor is selected from CHIR-
99021HCl;The hdac inhibitor is selected from Vorinostat;The Hedgehog inhibitor is selected from Vismodegib;Institute
The HSP90 inhibitor stated is selected from Ganetespib or AUY922;The I κ B/IKK inhibitor is selected from TPCA-1;The JAK
Inhibitor is selected from Tofacitinib or Cyt387;The Kinesin inhibitor is selected from SB 743921;The MEK inhibits
Agent is selected from GSK1120212;The mTOR inhibitors are selected from Rapamycin;The Microtubule Associated suppressions
Preparation is selected from Paclitaxel or Docetaxel;The Mutant pan Raf inhibitor is selected from Vemurafenib;It is described
Wnt/beta-catenin inhibitor be selected from FH535;The PDGFR inhibitor is selected from Imatinib;Described
Proteasome inhibitor is selected from Bortezomib;The PI3K inhibitor is selected from CAL-101 or GDC-0941;Described
Pkc inhibitor is selected from Sotrastaurin;The p38MAPK inhibitor is selected from BIRB 796;The PLK inhibitor is selected from
BI6727;The Syk inhibitor is selected from R935788;The Topoisomerase inhibitor is selected from Doxorubicin;Institute
The TGF-beta/Smad inhibitor stated is selected from LY2157299;The VEGFR inhibitor be selected from Axitinib or
Vandetanib;
Preferably, the DNA-PK inhibitor is the activity for inhibiting DNA-PK activity or inhibiting wherein any one subunit
Or express or block the assembling of subunit or the substance of degradation of dna-PK;Or preferably, the DNA-PK inhibitor is
The gene expression inhibition tool of the arbitrary subunits of DNA-PK;Preferably, the DNA-PK inhibitor be selected from following compound or its
Derivative with DNA-PK inhibiting effect or its pharmaceutically acceptable salt, solvate, tautomer, isomerism
Body:NU7441,NU7026,KU-0060648,LTURM34,CC-115,PIK-90,Wortmannin,LY3023414,M3814,
SF2523,Compound 401;
Or preferably, the DNA-PK inhibitor is gene interference, gene editing, gene silencing or gene knockout material;
It is highly preferred that the DNA-PK inhibitor is gene interfering material;It is more preferred still that the DNA-PK inhibitor is selected from
SEQ ID NO:1,SEQ ID NO:2 or SEQ ID NO:3.
4. application according to claim 1 or 2, which is characterized in that the oncolytic virus be selected from Alphavirus, adenovirus,
It is one or more in vaccinia virus, measles virus, vesicular stomatitis virus and herpes simplex disease;Preferably, it is selected from Alphavirus;
It is highly preferred that selected from M1 viruses and/or getah virus.
5. a kind of pharmaceutical composition for treating tumour, including:
(a) antitumor drug;
The antitumor drug is selected from ATM inhibitor, ALK inhibitor, Akt inhibitor, Bcr-Abl inhibitor, Chk and inhibits
Agent, inhibitors of c-met, DNA synthesis inhibitor, DHFR inhibitor, EGFR inhibitor, FGFR inhibitor, FAK inhibit
Agent, GSK-3 inhibitor, hdac inhibitor, Hedgehog inhibitor, HSP90 inhibitor, I κ B/IKK inhibitor, JAK inhibitor,
Kinesin inhibitor, mek inhibitor, mTOR inhibitors, Microtubule Associated inhibitor, Mutant pan
Raf inhibitor, Wnt/beta-catenin inhibitor, PDGFR inhibitor, Proteasome inhibitor, PI3K inhibitor, PKC
Inhibitor, p38MAPK inhibitor, PLK inhibitor, Syk inhibitor, Topoisomerase inhibitor, TGF-beta/Smad suppressions
It is one or more in preparation, VEGFR inhibitor and DNA-PK inhibitor;
Preferably, the ATM inhibitor is selected from KU-60019 or CP-466722;The ALK inhibitor is selected from
Crizotinib;The Akt inhibitor is selected from MK-2206;The Bcr-Abl inhibitor is selected from Ponatinib;Described
Chk inhibitor is selected from AZD7762;The inhibitors of c-met is selected from SU11274;The DNA synthesis inhibitor choosing
From Gemcitabine or Oxaliplatin;
The DHFR inhibitor is selected from Pemetrexed;The EGFR inhibitor be selected from Lapatinib Ditosylate or
Gefitinib;The FGFR inhibitor is selected from PD173074;The Fak inhibitor is selected from PF-562271;Described
GSK-3 inhibitor is selected from CHIR-99021HCl;The hdac inhibitor is selected from Vorinostat;The Hedgehog suppressions
Preparation is selected from Vismodegib;The HSP90 inhibitor is selected from Ganetespib or AUY922;The I κ B/IKK inhibit
Agent is selected from TPCA-1;The JAK inhibitor is selected from Tofacitinib or Cyt387;The Kinesin inhibitor is selected from SB
743921;The mek inhibitor is selected from GSK1120212;The mTOR inhibitors are selected from Rapamycin;Described
Microtubule Associated inhibitor is selected from Paclitaxel or Docetaxel;The Mutant pan Raf suppressions
Preparation is selected from Vemurafenib;The Wnt/beta-catenin inhibitor is selected from FH535;The PDGFR inhibitor choosing
From Imatinib;The Proteasome inhibitor is selected from Bortezomib;The PI3K inhibitor be selected from CAL-101 or
GDC-0941;The pkc inhibitor is selected from Sotrastaurin;The p38MAPK inhibitor is selected from BIRB 796;It is described
PLK inhibitor be selected from BI6727;The Syk inhibitor is selected from R935788;The Topoisomerase inhibitor choosing
From Doxorubicin;The TGF-beta/Smad inhibitor is selected from LY2157299;The VEGFR inhibitor is selected from
Axitinib or Vandetanib;Preferably, the DNA-PK inhibitor is to inhibit DNA-PK activity or inhibit wherein to appoint
The activity of one subunit of meaning or expression or the substance of the assembling of blocking subunit or degradation of dna-PK;Or preferably, described
DNA-PK inhibitor is the gene expression inhibition tool of the arbitrary subunits of DNA-PK;Preferably, the DNA-PK inhibitor is selected from
Following compound or its derivative with DNA-PK inhibiting effect or its pharmaceutically acceptable salt, solvate, mutually variation
Structure body, isomer:NU7441,NU7026,KU-0060648,LTURM34,CC-115,PIK-90,Wortmannin,
LY302341,M3814,SF2523,Compound 401;
Or preferably, the DNA-PK inhibitor is gene interference, gene editing, gene silencing or gene knockout material;
It is highly preferred that the DNA-PK inhibitor is gene interfering material;It is more preferred still that the DNA-PK inhibitor is selected from
SEQ ID NO:1,SEQ ID NO:2 or SEQ ID NO:3;
(b) oncolytic virus;
Preferably, the oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and simple
It is one or more in property herpesviral;It is highly preferred that being selected from Alphavirus;It is more preferred still that selected from M1 viruses and/or lid tower disease
Poison.
6. a kind of drug suit, including:
(a) antitumor drug;
The antitumor drug is selected from ATM inhibitor, ALK inhibitor, Akt inhibitor, Bcr-Abl inhibitor, Chk and inhibits
Agent, inhibitors of c-met, DNA synthesis inhibitor, DHFR inhibitor, EGFR inhibitor, FGFR inhibitor, FAK inhibit
Agent, GSK-3 inhibitor, hdac inhibitor, Hedgehog inhibitor, HSP90 inhibitor, I κ B/IKK inhibitor, JAK inhibitor,
Kinesin inhibitor, mek inhibitor, mTOR inhibitors, Microtubule Associated inhibitor, Mutant pan
Raf inhibitor, Wnt/beta-catenin inhibitor, PDGFR inhibitor, Proteasome inhibitor, PI3K inhibitor, PKC
Inhibitor, p38MAPK inhibitor, PLK inhibitor, Syk inhibitor, Topoisomerase inhibitor, TGF-beta/Smad suppressions
It is one or more in preparation, VEGFR inhibitor and DNA-PK inhibitor;
Preferably, the ATM inhibitor is selected from KU-60019 or CP-466722;The ALK inhibitor is selected from
Crizotinib;The Akt inhibitor is selected from MK-2206;The Bcr-Abl inhibitor is selected from Ponatinib;Described
Chk inhibitor is selected from AZD7762;The inhibitors of c-met is selected from SU11274;The DNA synthesis inhibitor choosing
From Gemcitabine or Oxaliplatin;The DHFR inhibitor is selected from Pemetrexed;The EGFR inhibitor choosing
From Lapatinib Ditosylate or Gefitinib;The FGFR inhibitor is selected from PD173074;The FAK inhibits
Agent is selected from PF-562271;The GSK-3 inhibitor is selected from CHIR-99021HCl;The hdac inhibitor is selected from
Vorinostat;The Hedgehog inhibitor is selected from Vismodegib;The HSP90 inhibitor is selected from Ganetespib
Or AUY922;The I κ B/IKK inhibitor is selected from TPCA-1;The JAK inhibitor be selected from Tofacitinib or
Cyt387;The Kinesin inhibitor is selected from SB743921;The mek inhibitor is selected from GSK1120212;Described
MTOR inhibitors are selected from Rapamycin;The Microtubule Associated inhibitor be selected from Paclitaxel or
Docetaxel;The Mutant pan Raf inhibitor is selected from Vemurafenib;The Wnt/beta-catenin suppressions
Preparation is selected from FH535;The PDGFR inhibitor is selected from Imatinib;The Proteasome inhibitor is selected from
Bortezomib;The PI3K inhibitor is selected from CAL-101 or GDC-0941;The pkc inhibitor is selected from
Sotrastaurin;The p38MAPK inhibitor is selected from BIRB 796;The PLK inhibitor is selected from BI6727;Described
Syk inhibitor is selected from R935788;The Topoisomerase inhibitor is selected from Doxorubicin;The TGF-beta/
Smad inhibitor is selected from LY2157299;The VEGFR inhibitor is selected from Axitinib or Vandetanib;
Preferably, the DNA-PK inhibitor inhibit DNA-PK activity or inhibit the wherein activity of any one subunit or
Expression or the substance of the assembling of blocking subunit or degradation of dna-PK;Or preferably, the DNA-PK inhibitor is DNA-
The gene expression inhibition tool of the arbitrary subunits of PK;Preferably, the DNA-PK inhibitor is selected from following compound or its and has
The derivative of DNA-PK inhibiting effect or its pharmaceutically acceptable salt, solvate, tautomer, isomer:
NU7441,NU7026,KU-0060648,LTURM34,CC-115,PIK-90,Wortmannin,LY302341,M3814,
SF2523,Compound 401;
Or preferably, the DNA-PK inhibitor is gene interference, gene editing, gene silencing or gene knockout material;
It is highly preferred that the DNA-PK inhibitor is gene interfering material;It is more preferred still that the DNA-PK inhibitor is selected from
SEQ ID NO:1,SEQ ID NO:2 or SEQ ID NO:3;
(b) oncolytic virus;
Preferably, the oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and list
It is one or more in pure property herpesviral;It is highly preferred that being selected from Alphavirus;It is more preferred still that selected from M1 viruses and/or lid tower
Virus;
Preferably, antitumor drug of the drug suit comprising independent packaging and the oncolytic virus of independent packaging.
7. being set with according to any composition/drug of claim 5 or 6, which is characterized in that also include pharmaceutically acceptable
Carrier.
8. being set with according to any composition/drug of claim 5 or 6, which is characterized in that the composition/drug
Dosage form in suit is selected from freeze-dried powder, injection, tablet, capsule or patch.
9. composition as described in claim 5 or 6 is any/drug suit, which is characterized in that the antitumor drug with it is molten
The proportioning of tumor virus is:0.01~200mg:103~109PFU;It is preferred that 0.1~200mg:104~109PFU;Further preferably
0.1~100mg:105~109PFU;
Preferably, dosage is:Antitumor drug use scope is 0.01mg/kg to 200mg/kg, while oncolytic virus makes
It is MOI from 10 with titre3To 109(PFU/kg);More preferable antitumor drug use scope is 0.1mg/kg to 200mg/kg, together
When oncolytic virus the use of titre is MOI from 104To 109(PFU/kg);It is 0.1mg/kg even more preferably from antitumor drug use scope
To 100mg/kg, while oncolytic virus is MOI from 10 using titre5To 109(PFU/kg);
Preferably, the antitumor drug be selected from following compound or its with the derivative of antitumor action or its pharmaceutically
Acceptable salt, solvate, tautomer, isomer:KU-60019,CP-466722,Crizotinib,MK-
2206,Ponatinib,AZD7762,SU11274,Gemcitabine,Oxaliplatin,Pemetrexed,Lapatinib
Ditosylate,Gefitinib,PD173074,PF-562271,CHIR-99021HCl,Vorinostat,Vismodegib,
Ganetespib,AUY922,TPCA-1,Tofacitinib,Cyt387,SB 743921,GSK1120212,Rapamycin,
Paclitaxel,Docetaxel,Vemurafenib,FH535,Imatinib,Bortezomib,CAL-101,GDC-0941,
Sotrastaurin,BIRB 796,BI6727,R935788,Doxorubicin,LY2157299,Axitinib,
Vandetanib,NU7441,NU7026,KU-0060648,LTURM34,CC-115,PIK-90,Wortmannin,
LY302341,M3814,SF2523,Compound 401;It is highly preferred that the antitumor drug is selected from:NU7441,NU7026,
KU-0060648, LTURM34, CC-115, PIK-90, Wortmannin, LY302341, M3814, SF2523 and Compound
One or more of 401;Even more preferably from one or more of NU7441, NU7026 and KU-0060648.
10. application of the combination of antitumor drug and oncolytic virus in preparing tumor;
The antitumor drug is selected from ATM inhibitor, ALK inhibitor, Akt inhibitor, Bcr-Abl inhibitor, Chk and inhibits
Agent, inhibitors of c-met, DNA synthesis inhibitor, DHFR inhibitor, EGFR inhibitor, FGFR inhibitor, FAK inhibit
Agent, GSK-3 inhibitor, hdac inhibitor, Hedgehog inhibitor, HSP90 inhibitor, I κ B/IKK inhibitor, JAK inhibitor,
Kinesin inhibitor, mek inhibitor, mTOR inhibitors, Microtubule Associated inhibitor, Mutant pan
Raf inhibitor, Wnt/beta-catenin inhibitor, PDGFR inhibitor, Proteasome inhibitor, PI3K inhibitor, PKC
Inhibitor, p38MAPK inhibitor, PLK inhibitor, Syk inhibitor, Topoisomerase inhibitor, TGF-beta/Smad suppressions
It is one or more in preparation, VEGFR inhibitor and DNA-PK inhibitor;
Preferably, the ATM inhibitor is selected from KU-60019 or CP-466722;The ALK inhibitor is selected from
Crizotinib;The Akt inhibitor is selected from MK-2206;The Bcr-Abl inhibitor is selected from Ponatinib;Described
Chk inhibitor is selected from AZD7762;The inhibitors of c-met is selected from SU11274;The DNA synthesis inhibitor choosing
From Gemcitabine or Oxaliplatin;The DHFR inhibitor is selected from Pemetrexed;The EGFR inhibitor choosing
From Lapatinib Ditosylate or Gefitinib;The FGFR inhibitor is selected from PD173074;The FAK inhibits
Agent is selected from PF-562271;The GSK-3 inhibitor is selected from CHIR-99021HCl;The hdac inhibitor is selected from
Vorinostat;The Hedgehog inhibitor is selected from Vismodegib;The HSP90 inhibitor is selected from Ganetespib
Or AUY922;The I κ B/IKK inhibitor is selected from TPCA-1;The JAK inhibitor be selected from Tofacitinib or
Cyt387;The Kinesin inhibitor is selected from SB 743921;The mek inhibitor is selected from GSK1120212;Described
MTOR inhibitors are selected from Rapamycin;The Microtubule Associated inhibitor be selected from Paclitaxel or
Docetaxel;The Mutant pan Raf inhibitor is selected from Vemurafenib;The Wnt/beta-catenin suppressions
Preparation is selected from FH535;The PDGFR inhibitor is selected from Imatinib;The Proteasome inhibitor is selected from
Bortezomib;The PI3K inhibitor is selected from CAL-101 or GDC-0941;The pkc inhibitor is selected from
Sotrastaurin;The p38MAPK inhibitor is selected from BIRB 796;The PLK inhibitor is selected from BI6727;Described
Syk inhibitor is selected from R935788;The Topoisomerase inhibitor is selected from Doxorubicin;The TGF-beta/
Smad inhibitor is selected from LY2157299;The VEGFR inhibitor is selected from Axitinib or Vandetanib;
Preferably, the DNA-PK inhibitor inhibit DNA-PK activity or inhibit the wherein activity of any one subunit or
Expression or the substance of the assembling of blocking subunit or degradation of dna-PK;Or preferably, the DNA-PK inhibitor is DNA-
The gene expression inhibition tool of the arbitrary subunits of PK;Preferably, the DNA-PK inhibitor is selected from following compound or its and has
The derivative of DNA-PK inhibiting effect or its pharmaceutically acceptable salt, solvate, tautomer, isomer:
NU7441,NU7026,KU-0060648,LTURM34,CC-115,PIK-90,Wortmannin,LY302341,M3814,
SF2523,Compound 401;
Or preferably, the DNA-PK inhibitor is gene interference, gene editing, gene silencing or gene knockout material;
It is highly preferred that the DNA-PK inhibitor is gene interfering material;It is more preferred still that the DNA-PK inhibitor is selected from
SEQ ID NO:1,SEQ ID NO:2 or SEQ ID NO:3;
Preferably, the oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and list
It is one or more in pure property herpesviral;It is highly preferred that being selected from Alphavirus;It is more preferred still that selected from M1 viruses and/or lid tower
Virus.
11. application/composition/drug suit as described in claim 1-10 is any, it is characterised in that the tumour is real
Body tumor or blood tumor;
Preferably, the solid tumor be colorectal cancer, cancer of pancreas, liver cancer, carcinoma of urinary bladder, breast cancer, cervical carcinoma, prostate cancer,
Glioma, melanoma, nasopharyngeal carcinoma, lung cancer or gastric cancer;
It is highly preferred that the tumour is the tumour insensitive to oncolytic virus.
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| CN202210101101.2A CN114522237A (en) | 2018-07-25 | 2018-07-25 | Application of antitumor drug in preparation of oncolytic virus antitumor synergist or drug resistance reversal agent |
| CN202210102453.XA CN114668847A (en) | 2018-07-25 | 2018-07-25 | Application of combination of anti-tumor drug and oncolytic virus in preparation of drug for treating tumor |
| CN202210102471.8A CN114668848A (en) | 2018-07-25 | 2018-07-25 | Application of oncolytic virus in preparation of antitumor drug synergist or drug resistance reversal agent |
| CN201810824134.3A CN108686221B (en) | 2018-07-25 | 2018-07-25 | Synergistic antitumor drug |
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| CN201810824134.3A CN108686221B (en) | 2018-07-25 | 2018-07-25 | Synergistic antitumor drug |
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| CN202210102453.XA Division CN114668847A (en) | 2018-07-25 | 2018-07-25 | Application of combination of anti-tumor drug and oncolytic virus in preparation of drug for treating tumor |
| CN202210101101.2A Division CN114522237A (en) | 2018-07-25 | 2018-07-25 | Application of antitumor drug in preparation of oncolytic virus antitumor synergist or drug resistance reversal agent |
| CN202210102471.8A Division CN114668848A (en) | 2018-07-25 | 2018-07-25 | Application of oncolytic virus in preparation of antitumor drug synergist or drug resistance reversal agent |
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| CN202210102471.8A Pending CN114668848A (en) | 2018-07-25 | 2018-07-25 | Application of oncolytic virus in preparation of antitumor drug synergist or drug resistance reversal agent |
| CN202210102453.XA Pending CN114668847A (en) | 2018-07-25 | 2018-07-25 | Application of combination of anti-tumor drug and oncolytic virus in preparation of drug for treating tumor |
| CN202210101101.2A Pending CN114522237A (en) | 2018-07-25 | 2018-07-25 | Application of antitumor drug in preparation of oncolytic virus antitumor synergist or drug resistance reversal agent |
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| CN202210102453.XA Pending CN114668847A (en) | 2018-07-25 | 2018-07-25 | Application of combination of anti-tumor drug and oncolytic virus in preparation of drug for treating tumor |
| CN202210101101.2A Pending CN114522237A (en) | 2018-07-25 | 2018-07-25 | Application of antitumor drug in preparation of oncolytic virus antitumor synergist or drug resistance reversal agent |
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Cited By (7)
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| CN110314222A (en) * | 2019-08-07 | 2019-10-11 | 上海交通大学医学院附属瑞金医院 | Application of the composition of bortezomib and pabishta or Vorinostat in the drug of preparation treatment drug-resistant type MLL leukaemia |
| CN111603562A (en) * | 2020-05-29 | 2020-09-01 | 中山大学 | Application of 5-lipoxygenase inhibitor and oncolytic virus in preparation of antitumor drugs |
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| CN114917222A (en) * | 2022-04-29 | 2022-08-19 | 佛山病原微生物研究院 | Application of Ganetespib in preparation of medicine for resisting adenovirus infection |
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| CN110314222B (en) * | 2019-08-07 | 2023-05-26 | 上海交通大学医学院附属瑞金医院 | Application of bortezomib and panobinostat or vorinostat composition in preparation of drug-resistant MLL leukemia treatment drugs |
| CN111603562A (en) * | 2020-05-29 | 2020-09-01 | 中山大学 | Application of 5-lipoxygenase inhibitor and oncolytic virus in preparation of antitumor drugs |
| CN111632146A (en) * | 2020-05-29 | 2020-09-08 | 中山大学 | Application of OAT inhibitor and oncolytic virus in preparation of antitumor drugs |
| CN111632146B (en) * | 2020-05-29 | 2021-09-28 | 中山大学 | Application of OAT inhibitor and oncolytic virus in preparation of antitumor drugs |
| WO2023284597A1 (en) * | 2021-07-13 | 2023-01-19 | 杭州阿诺生物医药科技有限公司 | Combined therapy for treating cancer |
| CN114366747A (en) * | 2021-12-27 | 2022-04-19 | 大连医科大学 | Use of DNA-dependent kinase inhibitors |
| CN114917222A (en) * | 2022-04-29 | 2022-08-19 | 佛山病原微生物研究院 | Application of Ganetespib in preparation of medicine for resisting adenovirus infection |
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| CN108686221B (en) | 2022-02-22 |
| CN114522237A (en) | 2022-05-24 |
| CN114668848A (en) | 2022-06-28 |
| CN114668847A (en) | 2022-06-28 |
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