CN109985240A - PARP inhibitor and oncolytic virus are in the application for preparing anti-tumor drug - Google Patents

PARP inhibitor and oncolytic virus are in the application for preparing anti-tumor drug Download PDF

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CN109985240A
CN109985240A CN201711478207.XA CN201711478207A CN109985240A CN 109985240 A CN109985240 A CN 109985240A CN 201711478207 A CN201711478207 A CN 201711478207A CN 109985240 A CN109985240 A CN 109985240A
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parp inhibitor
virus
parp
highly preferred
olaparib
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颜光美
朱文博
龚守芳
贺嵩敏
张海鹏
林园
梁剑开
蔡静
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Guangzhou Weirongte Pharmaceutical Technology Co Ltd
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Priority to PCT/CN2018/125014 priority patent/WO2019129233A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention belongs to biomedicine fields, are related to PARP (poly ADP-ribose polymerase, Poly ADP-ribose polymerase) inhibitor and oncolytic virus in the application for preparing anti-tumor drug.Present invention firstly discovers that PARP inhibitor can be used for preparing the antitumor synergist of oncolytic virus.It invents while being related to a kind of pharmaceutical composition comprising PARP inhibitor and oncolytic virus, it is set with comprising the drug of PARP inhibitor and oncolytic virus, and the purposes of PARP inhibitor and oncolytic virus in treatment tumour, tumour especially insensitive to the oncolytic virus.

Description

PARP inhibitor and oncolytic virus are in the application for preparing anti-tumor drug
Technical field
The invention belongs to biomedicine fields, are related to PARP inhibitor with combining for oncolytic virus and are preparing anti-tumor drug In application.
Background technique
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 that is natural or being genetically engineered, and in tumour cell Duplication has the function that targeting dissolution, killing tumor cell, but does not damage to normal cell.
M1 virus (Alphavirus M1) belongs to alphavirus (Alphavirus), in terms of preparing anti-tumor drug With preferable application effect.Such as Chinese invention patent application 201410425510.3 discloses M1 virus and can selectively cause Death of neoplastic cells has extraordinary application prospect without influencing normal cell survival, in anti-tumor aspect.However, different Tumour is different to the sensibility of M1 virus, and for certain tumours, when M1 virus independent medication, oncolysis is ideal not enough.Example As documented by Chinese invention patent application 201410425510.3, M1 as anti-tumor drug in use, for colorectal cancer, The effect of liver cancer, bladder cancer and breast cancer is obvious not as good as cancer of pancreas, nasopharyngeal carcinoma, prostate cancer and melanoma；And glioma, palace Neck cancer, lung cancer then more secondly；And gastric cancer is then least significant.The compound that screening increases oncolytic virus oncotherapy effect is expected to increase The antitumor spectra of solubilization tumor virus and anti-tumor intensity.
It has been reported that oncolytic virus can be enhanced to the lethality of tumour in existing a variety of anti-tumor drugs, however, In these numerous existing anti-tumor drugs, some drugs itself are more toxic, and may also generate toxicity to normal cell. Although antitumor effect promoting, side effect also enhances therewith, carrys out detrimental effect for the health care belt of patient.Therefore, Low toxicity is found diligent always in this field, does not have the synergist of virose oncolytic virus to normal cell preferably.
Summary of the invention
One of the objects of the present invention is to provide the applications in terms of a kind of anti-tumor synergist of oncolytic virus.
It is another object of the present invention to provide it is a kind of low toxicity, preferably do not have virose oncolytic virus to normal cell Synergist.
It is another object of the present invention to provide a kind of antitumor medicine compositions, and oncolytic virus can be made to play more Good anti-tumor effect.
It is another object of the present invention to provide a kind of anti-tumor compositions, are playing the same of anti-tumor drug effectiveness When, the toxicity of chemical drug compositions small as far as possible.
It is another object of the present invention to provide a kind of tumour insensitive for oncolytic virus, safely and effectively oncolytic Virus synergy drug.
Invention is achieved through the following technical solutions above-mentioned purpose:
For inventor by research, screening discovery, the oncolytic effect of oncolytic virus is unexpectedly can be enhanced in PARP inhibitor Fruit.
The PARP inhibitor is to inhibit the substance of the active substance of PARP or the PARP that degrades or reduction PARP horizontal Genetic tools.
Poly ADP-ribose polymerase (poly ADP-ribose polymerase, PARP), which has, keeps chromosome structure complete Whole property, the duplication for participating in DNA and transcription maintain the important function such as genome stabilization.Therefore PARP inhibitor is able to suppress tumour DNA Damage reparation enhances DNA of tumor cell to the sensibility of impairment factor.The research of PARP inhibitor receives in recent years More and more concerns.PARP inhibitor is expected to play a significant role in therapeutic field of tumor.
Inventor is by inhibiting PARP that can significantly increase the oncolytic effect of oncolytic virus.Inventor, which uses, inhibits PARP Active compound Olaparib cooperates with oncolytic virus especially M1 virus function in tumour cell, and experimental result is found, Olaparib can cooperate with oncolytic virus to enhance anti-tumor effect.
Present invention firstly discovers that PARP inhibitor can be used as anti-tumor synergist/reversal agent of drug resistance of oncolytic virus.
The present invention provides application of the PARP inhibitor in terms of preparing the anti-tumor synergist/reversal agent of drug resistance of oncolytic virus.
Reversal agent of drug resistance refers to, when being used to treat tumour as anti-tumor 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 PARP inhibitor (as reversal agent of drug resistance) is combined the mode of oncolytic virus, with reversing tumor to the resistance of the oncolytic virus.
The PARP inhibitor is selected from compound.Preferably, the PARP inhibitor includes but is not limited to followingization Close object or its derivative with PARP inhibiting effect or its pharmaceutically acceptable salt, solvate, tautomer, same Enantiomers: Olaparib (formula 1) or Veliparib (formula 2) etc. inhibit the active compound of PARP.The acquisition modes of compound Optional but be not limited to: oneself Chemical Decomposition or synthesis are bought from commercial channels.
In a preferred embodiment of the invention, the PARP inhibitor is Olaparib, structural formula such as 1 institute of formula Show:
In another preferred embodiment of the present invention, the PARP inhibitor is Veliparib, structural formula such as formula 2 It is shown:
Alternatively, the PARP inhibitor further includes for PARP gene expression inhibition tool, including but not limited to gene Interference, gene silencing and the tools means such as gene editing or knockout.
As an alternative embodiment, the PARP inhibitor is selected from DNA, RNA, PNA or DNA-RNA- heterozygote. They can be single-stranded or double-strand.
PARP 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 the table of PARP It reaches.
Alternatively, the PARP inhibitor further includes one of antibody, antibody functional segment, peptides and peptidomimetic class Or it is several.Wherein, the antibody may be monoclonal antibody, polyclonal antibody, multivalent antibody, multi-specificity antibody (such as: Bispecific antibody), and/or the antibody fragment being connected on PARP.The antibody can be chimeric antibody, humanized antibody, CDR Grafted antibody or human-like antibody.Antibody fragment can be, for example, Fab, Fab ', F (ab ') 2, Fv, Fd, scFv (scFv), tool The FV (sdFv) or VL, VH structural domain of disulfide bond.Antibody may be the form of a conjugation, for example, in conjunction with label, one A detectable label or a kind of cytotoxic agent.Antibody may be homotype IgG (such as: IgG1, IgG2, IgG3, IgG4), IgA, IgM, IgE or IgD.
The oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and simple One of property herpesviral is a variety of；Wherein, the Alphavirus is selected from M1 virus, getah virus.Implement as preferred Mode, the oncolytic virus are selected from M1 virus, getah virus or their combination.
Oncolytic virus described in the present invention (M1 virus, getah virus, adenovirus, vaccinia virus, measles virus, bubble mouth Scorching virus and herpes simplex virus) can existing oncolytic virus before feeling the pulse with the finger-tip in particular, but be also not excluded for some possible occur Natural variation or be mutated (natural mutation, it is mandatory mutation or selective mutation), gene modification, sequence increase Delete or partial replacement virus.Oncolytic virus described here includes the virus that above-mentioned change has been carried out.Preferably Above-mentioned change has no effect on described oncolytic virus and plays effect of the present invention.Described PARP inhibitor is that can play to strike It is low or influence PARP gene expression or reduce PARP amount or active substance (such as compound or amino acid sequence, nucleotide Sequence etc.) or tool etc..Those skilled in the art can modify its inhibiting compound or Genetic tools, replace, change Become etc., but as long as playing the role of above-mentioned inhibition PARP, then belongs to PARP inhibitor of the invention, belong to above-mentioned substance, chemical combination The homogeneity replacement of object or tool etc..
In some embodiments, Alphavirus is that deposit number CCTCC V201423 (is preserved in China typical culture collection Center, preservation date on July 17th, 2014) M1 virus.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% as with M1 virus (Wen et al.Virus Genes.2007；35 (3): 597-603) homology virus, the two have very high identity, M1 virus is also classified as class getah virus by some documents.It is expected that the two has the same effect.Single onychonosus strain It can apply.In other embodiments, it is possible to use the Alphavirus of a variety of bacterial strains and/or type.
The present invention also provides a kind of for treating the pharmaceutical composition of tumour, and it includes PARP inhibitor and oncolytic diseases Poison.The present invention also provides the drug suits for treating tumour, it includes PARP inhibitor or derivatives thereof or their combination, And oncolytic virus.The place that drug suit is different from composition is that PARP inhibitor is different from the dosage form of oncolytic virus, and Be independent packaging (such as: pill or capsule or tablet or peace cut open in bottle, contain PARP inhibitor；Other pill or glue Capsule or tablet or peace are cutd open in bottle, and oncolytic virus is contained).In some embodiments, oncolytic virus, PARP inhibitor and oncolytic The combination of virus and PARP inhibitor, can also contain one or more adjuvants.The adjuvant refers in drug composition, can assist The ingredient of curative effect of medication.Drug suit also may include the PARP inhibitor of independent packaging and the oncolytic virus of independent packaging. The application of PARP inhibitor and oncolytic virus, can be and be administered simultaneously either with arbitrary tandem in drug suit Application, such as PARP inhibitor is applied before oncolytic virus, PARP inhibitor or two is perhaps applied after oncolytic virus Person is administered simultaneously.In various embodiments, patient can be mammal.In some embodiments, mammal can be people.
The PARP inhibitor includes but is not limited to the inhibition of Olaparib (formula 1) or Veliparib (formula 2) this kind The active compound of PARP.Or be directed to PARP gene expression inhibition tool, including but not limited to gene interference, gene silencing with And the tools means such as gene editing or knockout.As a preferred embodiment of the present invention, the PARP inhibitor is selected from At least one of Olaparib and Veliparib.
The oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and simple One of property herpesviral is a variety of；Wherein, the Alphavirus is selected from M1 virus and getah virus.Implement as preferred Mode, the oncolytic virus are selected from at least one of M1 virus and getah virus.
In composition or drug suit, the proportion of Olaparib or Veliparib and oncolytic virus is 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 are as follows: Olaparib or Veliparib use scope is 0.01mg/kg to 200mg/kg, simultaneously Oncolytic virus is MOI from 10 using titre3To 109(PFU/kg)；It is preferred that Olaparib or Veliparib use scope is 0.1mg/kg to 200mg/kg, while oncolytic virus is MOI from 10 using titre4To 109(PFU/kg)；More preferable Olaparib Or Veliparib use scope is 0.1mg/kg to 100mg/kg, while oncolytic virus is MOI from 10 using titre5To 109 (PFU/kg)。
The oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and simple One of property herpesviral is a variety of；Wherein, the Alphavirus is selected from M1 virus and getah virus.Implement as preferred Mode, the oncolytic virus are selected from at least one of M1 virus and getah virus.M1 virus belongs to the similar virus of lid tower, this two The homology of person is up to 97.8%.
In one embodiment, the tumour is solid tumor or blood tumor.In one embodiment, the solid tumor For liver cancer, colorectal cancer, bladder cancer, 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.
As optional embodiment, Olaparib or Veliparib provided by the present invention can be injection, piece Agent, capsule, patch, kit etc..As preferred embodiment, synergism medicine of the invention is injection；Preferably, it can adopt With intravenous injection.
As further preferred embodiment of the present invention:
Present invention finds the anti-tumor effect that PARP inhibitor, especially Olaparib can increase oncolytic virus, with Improve treatment validity of the oncolytic virus as anti-tumor drug when.Cytologic experiment proves that M1 virus and Olaparib are combined and answers With can significantly cause the morphology lesion of tumour cell, to significantly increase the inhibiting effect to tumour cell.
We combine Olaparib and M1 virus function in Hep3B plants of human hepatocellular carcinoma, have now surprisingly been found that antiviral Compound Olaparib and M1 is viral combined in application, dramatically increasing tumour cell form lesion, and significant decrease tumour cell is raw Deposit rate.Such as in one embodiment of the invention, when M1 viral (MOI=0.001) individually processing liver cancer cells, tumour is thin Born of the same parents' survival rate is 79.9%, and when being combined with the M1 virus of 6.25 μM of Olaparib and same MOI, tumor cell survival It declines to a great extent to 43.3%.Compared with the antitumous effect that M1 virus is applied alone, when Olaparib and M1 are combined, oncolytic effect is significant It is promoted.
It is a discovery of the invention that Olaparib and oncolytic virus use in conjunction handle tumour cell, tumor cytotoxicity is acted on It is significantly better than the Olaparib that same concentrations are applied alone, such as when equally for example with 6.25 μM of Olaparib processing tumour cell When, tumor cell survival is still up to 85.6%, when being combined with 6.25 μM of Olaparib and M1 virus, tumor cell survival Rate declines to a great extent to 43.3%.As it can be seen that the oncolytic effect that Olaparib and M1 is substantially improved when being combined, is to have benefited from Olaparib Concertedness mechanism between M1 virus, not plays a role simply by the antitumor mechanism of Olaparib.
Olaparib is the product of nearly half a century research, research shows that PARPs can help DNA plerosis to damage.If Less than reparation, DNA double chain fracture can trigger cell death.The effect of the enzyme is inhibited to be less likely to kill healthy cell, because strong Health cell possesses a plurality of signal path for repairing DNA breakage.But some mutation can sometimes occur for cancer cell, destroy other types Reparation so that they especially inhibit sensitive to PARP.It therefore, can be in target cancer cell with the drug that this mechanisms play acts on While, healthy cell is bypassed, some toxic side effects of conventional chemotherapy bring are avoided.Oncolytic virus especially Alphavirus can be with Struma oncocyte is dissolved, its oncolytic effect can be improved with synergist, this respect is advantageous, but if synergist itself If bringing toxicity, and application prospect is will limit.And present invention discover that PARP inhibitor (such as Olaparib) and onychonosus After poison combination, oncolytic effect is not only increased, also, drug itself does not impact normal cell, safety is higher, simultaneously Benefit of both realizing goes out, this be it is rare, there is important and positive meaning to the health of tumor patient.
Detailed description of the invention
The viral combined processing of Fig. 1 Olaparib and M1 significantly reduces human hepatocellular carcinoma strain Hep3B survival rate；
Specific embodiment
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.
The viral combined processing of 1 Olaparib of embodiment and M1 significantly reduces human hepatocellular carcinoma strain Hep3B survival rate material:
Human hepatocellular carcinoma Hep3B (is purchased from ATCC), M1 virus (deposit number CCTCC V201423), DMEM in high glucose culture Base (deposit number CCTCC V201423), automatic enzyme-linked detection microplate reader.
Method:
A) inoculating cell, drug treatment: selection logarithmic growth phase cell, DMEM complete culture solution (containing 10% fetal calf serum, 1% is dual anti-) cell suspension is made, with every hole 4 × 103The density in/hole is seeded in 96 well culture plates.See that cell is complete after 12 hours Complete adherent, experiment divides control group, independent Olaparib group, M1 infected group and Olaparib/M1 combination group.Dosage used are as follows: institute With dosage are as follows: M1 virus (MOI=0.001) infection cell；Olaparib is 6.25 μM.
B) MTT is reacted with intracellular succinate dehydrogenase: when culture is to 48h, 20 μ l (5mg/ml) of MTT is added in every hole, Continue to be incubated for 4 hours, the graininess bluish violet formazan crystallization that microscopy can be observed, be formed in living cells at this time.
C) Rong Xie formazan particle: carefully sucking supernatant, adds the 100 lysigenous crystallization in the hole μ l/ of DMSO, in micro-oscillating 5min is shaken on device, then detects the optical density (OD value) in each hole with wavelength 570nm in enzyme detector.Cell survival rate= Drug-treated group OD value/control group OD value × 100%.
As a result:
As shown in Figure 1, individually processing presses down tumour cell Hep3B with lesser survival rate to M1 virus (MOI=0.001) Production is used, and tumor cell survival reaches 79.9%, and 6.25 μM of Olaparib processing group tumor cell survival is still up to 85.6%, however, when same 6.25 μM of Olaparib and M1 viral (MOI=0.001) combination (Olaparib+M1), Tumor cell survival declines to a great extent to 43.3%.

Claims (9)

  1. Application of the 1.PARP inhibitor in terms of preparing the antitumor synergist of oncolytic virus or reversal agent of drug resistance；
    Preferably, the oncolytic virus be selected from Alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and One of herpes simplex virus is a variety of；
    Preferably, the Alphavirus is selected from least one of M1 virus and getah virus.
  2. 2. application as described in claim 1, which is characterized in that the PARP inhibitor be inhibit the active substance of PARP, Degradation PARP substance or reduce PARP level Genetic tools or their any combination；
    Preferably, the PARP inhibitor is selected from compound；
    It is highly preferred that the PARP inhibitor be selected from following compound or its derivative with PARP inhibiting effect or its Pharmaceutically acceptable salt, solvate, tautomer, isomer: Olaparib, Veliparib；
    It is highly preferred that the structural formula of the Olaparib is as shown in Equation 1:
    It is highly preferred that the structural formula of the Veliparib is as shown in Equation 2；
    Or preferably, the PARP inhibitor is selected from one of antibody, antibody functional segment, peptides and peptidomimetic class Or it is several；
    Or preferably, the PARP inhibitor is selected from gene interference, gene silencing, gene editing or gene knockout material；
    Or preferably, the PARP inhibitor is selected from: one of DNA, RNA, PNA and DNA-RNA- heterozygote is several Kind；
    It is highly preferred that the PARP inhibitor is selected from: one or more of siRNA, dsRNA, miRNA, shRNA and ribozyme；
    It is highly preferred that the PARP inhibitor is cancer target PARP inhibitor.
  3. 3. a kind of pharmaceutical composition for treating tumour, includes:
    (a) PARP inhibitor；
    The PARP inhibitor is the substance for inhibiting the active substance of PARP or the PARP that degrades or the base for reducing PARP level Because of tool or their any combination；
    Preferably, the PARP inhibitor is selected from compound；
    It is highly preferred that the PARP inhibitor be selected from following compound or its derivative with PARP inhibiting effect or its Pharmaceutically acceptable salt, solvate, tautomer, isomer: Olaparib, Veliparib；
    It is highly preferred that the structural formula of the Olaparib is as shown in Equation 1:
    It is highly preferred that the structural formula of the Veliparib is as shown in Equation 2；
    Or preferably, the PARP inhibitor is selected from one of antibody, antibody functional segment, peptides and peptidomimetic class Or it is several；
    Or preferably, the PARP inhibitor is selected from gene interference, gene silencing, gene editing or gene knockout material；
    Or preferably, the PARP inhibitor is selected from: one of DNA, RNA, PNA and DNA-RNA- heterozygote is several Kind；
    It is highly preferred that the PARP inhibitor is selected from: one or more of siRNA, dsRNA, miRNA, shRNA and ribozyme；
    It is highly preferred that the PARP inhibitor is cancer target PARP inhibitor；
    (b) oncolytic virus；The oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, bubble stomatitis disease One of poison and herpes simplex virus are a variety of；
    Preferably, the Alphavirus is selected from least one of M1 virus and getah virus.
  4. 4. a kind of drug suit, includes:
    (a) PARP inhibitor；
    The PARP inhibitor is the substance or reduction PARP for inhibiting the substance of PARP protein active or PARP albumen of degrading The Genetic tools of protein level or their any combination；
    Preferably, the PARP inhibitor is selected from compound；
    It is highly preferred that the PARP inhibitor be selected from following compound or its derivative with PARP inhibiting effect or its Pharmaceutically acceptable salt, solvate, tautomer, isomer: Olaparib, Veliparib；
    It is highly preferred that the structural formula of the Olaparib is as shown in Equation 1:
    It is highly preferred that the structural formula of the Veliparib is as shown in Equation 2；
    Or preferably, the PARP inhibitor is selected from one of antibody, antibody functional segment, peptides and peptidomimetic class Or it is several；
    Or preferably, the PARP inhibitor is selected from gene interference, gene silencing, gene editing or gene knockout material；
    Or preferably, the PARP inhibitor is selected from: one of DNA, RNA, PNA and DNA-RNA- heterozygote is several Kind；
    It is highly preferred that the PARP inhibitor is selected from: one or more of siRNA, dsRNA, miRNA, shRNA and ribozyme；
    It is highly preferred that the PARP inhibitor is cancer target PARP inhibitor；
    (b) oncolytic virus；The oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, bubble stomatitis disease One of poison and herpes simplex virus are a variety of；
    Preferably, the Alphavirus is selected from least one of M1 virus and getah virus；
    Preferably, the PARP inhibitor comprising independent packaging and the oncolytic virus of independent packaging.
  5. Application of the combination of 5.PARP inhibitor and oncolytic virus in preparation tumor；
    The oncolytic virus is selected from Alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and pure blister One of exanthema virus is a variety of；
    Preferably, the Alphavirus is selected from least one of M1 virus and getah virus；
    The PARP inhibitor is the substance for inhibiting the active substance of PARP or the PARP that degrades or the base for reducing PARP level Because of tool or their any combination；
    Preferably, the PARP inhibitor is selected from compound；
    It is highly preferred that the PARP inhibitor be selected from following compound or its derivative with PARP inhibiting effect or its Pharmaceutically acceptable salt, solvate, tautomer, isomer: Olaparib, Veliparib；
    It is highly preferred that the structural formula of the Olaparib is as shown in Equation 1:
    It is highly preferred that the structural formula of the Veliparib is as shown in Equation 2；
    Or preferably, the PARP inhibitor is selected from one of antibody, antibody functional segment, peptides and peptidomimetic class Or it is several；
    Or preferably, the PARP inhibitor is selected from gene interference, gene silencing, gene editing or gene knockout material；
    Or preferably, the PARP inhibitor is selected from: one of DNA, RNA, PNA and DNA-RNA- heterozygote is several Kind；
    It is highly preferred that the PARP inhibitor is selected from: one or more of siRNA, dsRNA, miRNA, shRNA and ribozyme；
    It is highly preferred that the PARP inhibitor is cancer target PARP inhibitor.
  6. 6. application/composition a method as claimed in any one of claims 1 to 5/drug suit, it is characterised in that the PARP inhibitor For Olaparib and/or Veliparib.
  7. 7. application/composition a method as claimed in any one of claims 1 to 5/drug suit, it is characterised in that the tumour is entity Tumor or blood tumor；Preferably, the solid tumor be liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical carcinoma, prostate cancer, Glioma, melanoma, cancer of pancreas, nasopharyngeal carcinoma, lung cancer or gastric cancer；
    Or preferably, the tumour is the tumour insensitive to oncolytic virus；
    It is highly preferred that the tumour be the liver cancer insensitive to oncolytic virus, colorectal cancer, bladder cancer, breast cancer, cervical carcinoma, Prostate cancer, glioma, melanoma, cancer of pancreas, nasopharyngeal carcinoma, lung cancer or gastric cancer.
  8. 8. composition as described in claim 3 or 4 is any/drug suit, it is characterised in that the Olaparib or The proportion of Veliparib and oncolytic virus are as follows: 0.01~200mg:103~109PFU；It is preferred that 0.1~200mg:104~ 109PFU；Further preferred 0.1~100mg:105~109PFU；
    It is further preferred that dosage are as follows: Olaparib or Veliparib use scope is 0.01mg/kg to 200mg/kg, Oncolytic virus is MOI from 10 using titre simultaneously3To 109(PFU/kg)；It is preferred that Olaparib or Veliparib use scope is 0.1mg/kg to 200mg/kg, while oncolytic virus is MOI from 10 using titre4To 109(PFU/kg)；More preferable Olaparib Or Veliparib use scope is 0.1mg/kg to 100mg/kg, while oncolytic virus is MOI from 10 using titre5To 109 (PFU/kg)。
  9. 9. pharmaceutical composition according to claim 3, wherein described pharmaceutical composition also includes pharmaceutically acceptable load Body；The carrier is preferably chosen from freeze-dried powder, injection, tablet, capsule, kit or patch.
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