CN104887680A - New application of multi-poly ADP RNA polymerase inhibitor in treating HBV-related diseases - Google Patents
New application of multi-poly ADP RNA polymerase inhibitor in treating HBV-related diseases Download PDFInfo
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- CN104887680A CN104887680A CN201510233465.6A CN201510233465A CN104887680A CN 104887680 A CN104887680 A CN 104887680A CN 201510233465 A CN201510233465 A CN 201510233465A CN 104887680 A CN104887680 A CN 104887680A
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a drug combination of a multi-poly (ADP-ribose) polymerase (PARP) inhibitor, a method of treating or preventing HBV-related diseases by utilizing the drug combination, and the application of the drug combination. More specifically, the invention relates to a drug combination comprising 1-(ciprofloxacin formyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluoro benzoyl] piperazine, a method of treating or preventing HBV, liver cancer, liver cirrhosis and other HBV-related diseases by utilizing the drug combination, and the application of the drug combination.
Description
1. technical field
Present invention relates in general to poly (ADP ribose) polymerase (PARP) inhibitor as the therapeutic agent for the treatment of or prevent hepatitis virus diseases related.Specifically, the present invention relates to and be used for the treatment of or prevent hepatitis b virus infected diseases related phthalazone compounds, the compositions comprising it, Therapeutic Method and uses thereof.More specifically; the present invention relates to and be used for the treatment of or prevent hepatitis b virus infected diseases related 1-(cyclopropane carbonyl)-4-[5-[(3; 4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoyl] piperazine is (also known as Olaparib; Chinese Aura handkerchief Buddhist nun), comprise this inhibitor pharmaceutical composition, treat hepatitis B virus (Hapatitis BVirus, hereinafter referred to as HBV) with it and infect method that is diseases related, especially hepatocarcinoma and uses thereof.
2. background technology
Usually be converted into chronic infection after acute hepatitis b virus infection, long-term hepatitis B virus activity causes hepatocyte injury and necrosis, and stimulates local immunity to react, and causes hepatic lesions, comprises hepatic fibrosis, liver cirrhosis and hepatocarcinoma etc.
Also stably can not ensure at present the standard treatments of to a certain degree curative effect to hepatocarcinoma, the repellence of hepatocarcinoma to chemicals is high, though to reach temporary stabilization tumor, extending life target all very difficult.And the operation easier due to intra-arterial injection is the significant obstacle of clinical treatment, therefore Development of New Generation hepatocarcinoma
Chemotherapeutic clinical demand is urgent especially, and its key is the chemicals finding to kill and wound energetically hepatitis B virus masculine liver cancer cell.
Phthalazines ketone PARP enzyme inhibitor (comprising Aura handkerchief Buddhist nun) is a kind of heterocycle polyarylether derivant, such material has the effect of suppression poly (ADP-ribose) polymerase (PARP, poly (ADP-ribose) polymerase) family's enzymatic activity.Poly (ADP-ribose) polymerase family polymerase has about 18 kinds of albumen at present.Catalytic domain on these polymerase proteins all has homology dependency to a certain extent, but its functional areas are (Ame et al. far from each other then, BioEssays., 26 (8): 882-893, 2004), the different albumen of this family is caused to participate in various biological function, wherein PARP-1 and PARP-2 regulate core in extremely important (the Althaus & Richter of poly (ADP-ribose) chain structure, ADP-Ribosylation of Proteins:Enzymology and Biological Significance, Springer-Verlag, Berlin, 1987).The PARP of the state of activation associated with DNA utilizes NAD+ on target nucleoprotein, synthesize poly-ADP ribose chain.Phthalazines ketone PARP enzyme inhibitor Aura handkerchief Buddhist nun can be applied to treatment or Breast Cancer Prevention/ovarian cancer (US2014/01315973A1, publication date on October 23rd, 2014).
Report, PARP inhibitor can be used for treating the various diseases relevant with poly (ADP-ribose) polymerase (PARP), comprises neurodegenerative diseases (as senile dementia, Huntington Chorea, parkinson disease) before; Diabetes; Complication in ischemia or Ischemia-Reperfusion Injury, as myocardial infarction and acute renal failure; Blood circulation diseases, as septic shock; And diseases associated with inflammation is as (see such as CN102964354A, publication date: on March 13rd, 2013) such as chronic rheumatisms.Disclose the patent application of a series of phthalazines ketone PARP inhibitor at present, comprise WO2002036576, WO2004080976 and WO200602, all think that phthalazines ketone and derivant thereof may be used for the treatment of the diseases such as above metabolic, degeneration, struvite and tumor, but up to the present, also phthalazines ketone PARP inhibitor is not applied to the diseases related discovery treating and/or preventing aspect of hepatites virus infections.
3. summary of the invention
The present invention is at least partly based on the present inventor's Late Cambrian: PARP inhibitor phthalazines ketone, especially Aura handkerchief Buddhist nun (1-(cyclopropane carbonyl)-4-[5-[(3, 4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoyl] piperazine, also known as Olaparib) significantly can suppress growth and the propagation of HBV positive cell, such as its growth and propagation that significantly can suppress hepatitis B virus (HBV) full-length genome transgenic human hepatic cell line HL02-H1 and express HBx (hepatitis B virus coding X gene) cell, toxicity on pharmacological significance or lethal effect are not had to the hepatocyte of normal non-hepatitis b virus infection, in addition, the present inventor is surprised to find that, PARP inhibitor phthalazines ketone, especially Aura handkerchief Buddhist nun are sustainable stably significantly reduces serum HBV-DNA copy number and hepatitis B surface antigen (HBsAg) level.HBV masculine liver cancer cell has gene damage repair-deficiency, utilizes the single medicine of the Aura handkerchief Buddhist nun of low dosage effectively can suppress the propagation of HBV positive hepatocellular.Inventor also confirms in mouse model that Aura handkerchief Buddhist nun effectively suppresses and removes the hepatoma carcinoma cell of the HBV positive.
Aura handkerchief Buddhist nun can remove the hepatitis b virus infected cell of activeness in a short time, and to not infecting HBV or stationary phase cells does not have a significant effect, this cell making special removing carry HBV virus becomes possibility.So both can suppress the active of hepatitis B virus to copy, and also can avoid causing large area hepatic injury.
Therefore, the invention provides PARP inhibitor phthalazines ketone, especially Aura handkerchief Buddhist nun treatment or prevention hepatitis virus, the particularly novelty teabag of HBV-induced hepatocellular hepatopathy.
The present inventor finds that the hepatoma carcinoma cell of the hepatitis B virus positive is responsive to Aura Pa Nite opposite sex ground level especially, makes Aura handkerchief Buddhist nun become the chemicals of new generation of hepatitis B virus associated hepatocellular carcinoma.
Therefore, first aspect, the present invention relates to the liver and gall diseases that PARP inhibitor phthalazines ketone, especially Aura handkerchief Buddhist nun may be used for treating and prevention hepatites virus infections causes, include but not limited to hepatitis virus carrier, the acute hepatitis that hepatites virus infections causes, chronic hepatitis, hepatocarcinoma, cholangiocellular carcinoma.
Again on the one hand, the present invention relates to PARP inhibitor phthalazines ketone, especially Aura handkerchief Buddhist nun to may be used for treatment and prevent hepatitis B virus (HBV) to infect the liver and gall diseases caused, include but not limited to hepatitis B virus (HBV) carrier, the acute hepatitis that HBV infection causes, chronic hepatitis, hepatocarcinoma, cholangiocellular carcinoma, hepatitis B virus (HBV) infect cause physically different, and (such as physical signs is abnormal, blood circulation symptom, gastrointestinal symptom etc.).
On the other hand; the invention provides for killing and wounding novel effective chemicals phthalazines ketone PARP inhibitor, particularly 1-(cyclopropane carbonyl)-4-[5-[(3 that carry hepatitis B virus (HBV) host cell; 4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoyl] piperazine, thus remove in hepatitis B virus patient body by the cell of HBV infection.Under same medicine concentration, phthalazines ketone PARP inhibitor does not have toxicity or lethal effect to the normal liver cell not infecting HBV.
Another target of the present invention is to provide the method for the Buddhist nun's treatment of application Aura handkerchief or preventing chronic patients with HBV infection, comprise the control of hepatitis b virus infected titre and virus load, described method comprises the Aura handkerchief Buddhist nun giving described patient effective amounts.
A yet further object of the present invention is to provide the Buddhist nun's treatment of application Aura handkerchief or prevention hepatitis virus, especially hepatitis B virus infection hepatic fibrosis, the method for liver cirrhosis patient and purposes, and described method comprises the Aura handkerchief Buddhist nun giving described patient effective amounts.
A present invention again target is to provide the Buddhist nun's treatment of application Aura handkerchief or prevents the method for hepatic fibrosis in late period, liver cirrhosis patient, and described method comprises the Aura handkerchief Buddhist nun giving described patient effective amounts.
Feature of the present invention is also the application of the Aura handkerchief Buddhist nun of low dosage in the oncotherapy of the hepatitis B virus positive, comprises the hepatocellular carcinoma/cholangiocellular carcinoma etc. of the hepatitis B virus positive.
One of feature of the present invention is the drug combination of Aura handkerchief Buddhist nun in the oncotherapy of the hepatitis B virus positive, comprises the use in conjunction of Aura handkerchief Buddhist nun and radiotherapy and platinum-containing anticancer drug.
One of target of the present invention provides one to comprise the compositions of poly (ADP ribose) polymerase (PARP) inhibitor, and it is used for the treatment of or prevents hepatitis virus relevant disease.
In the present invention program, described PARP inhibitor is phthalazone compounds.
In the present invention; described phthalazone compounds is Aura handkerchief Buddhist nun (1-(cyclopropane carbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoyl] piperazine) or its pharmaceutically acceptable salt or ester.
In pharmaceutical composition of the present invention, it comprises the PARP inhibitor of the low unit dose of 1-45mg.
In the present invention program, PARP inhibitor phthalazone compounds is for the preparation of the medicine being used for the treatment of or preventing hepatitis b virus infected property relevant disease.
In the present invention program, wherein said hepatitis b virus infected property relevant disease is acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, hepatocarcinoma, cholangiocellular carcinoma, hepatitis B virus infection cause, and physically different (such as physical signs is abnormal, blood circulation symptom, gastrointestinal symptom etc.).
In the present invention program, described PARP inhibitor phthalazines ketone medicine is used for the treatment of or prevents hepatites virus infections relevant disease, more preferably hepatitis b virus infected property disease, more preferably hepatitis b virus carrier, preferably hepatitis b virus infected again, most preferably hepatitis b virus infected dependency acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, hepatocarcinoma, cholangiocellular carcinoma.
In the present invention program, wherein said medicine can be given by oral or parental routes.
In the present invention program, wherein said medicine and other treat the Drug combination of hepatites virus infections relevant disease.
In the present invention program, wherein said other medicines are selected from cancer therapy drug, and preferred described cancer therapy drug is platinum class, camptothecine or HDAC (histon deacetylase (HDAC), histone deacetylase) inhibitor.
The present invention also provides a kind of method for the treatment of or prevention hepatites virus infections relevant disease, and it comprises the compositions comprising described PARP inhibitor phthalazines ketone giving effective dose.
In the present invention, hepatites virus infections includes but not limited to that hepatitis B virus (HBV) infects.
In the present invention, hepatites virus infections relevant disease refers to the various diseases that described hepatites virus infections causes, and includes but not limited to hepatitis virus carrier, acute and chronic infection, hepatic fibrosis, liver cirrhosis, hepatocarcinoma etc.
In the present invention, hepatites virus infections relevant disease is hepatitis b virus infected property disease, more preferably hepatitis b virus carrier, preferably hepatitis b virus infected again, most preferably hepatitis b virus infected dependency acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, hepatocarcinoma, cholangiocellular carcinoma.
In the present invention, it also comprises and gives other hepatites virus infections relevant disease medicine further, preferred platinum class, camptothecine or hdac inhibitor.
In the model such as HBV positive hepatocellular, liver cirrhosis, hepatic fibrosis, hepatocarcinoma of people-nude mouse, Aura handkerchief Buddhist nun has significant treatment and preventive effect.
Further, for the propagation of the transgenic hepatocytes of the HBV positive carry out the single medicine of Aura handkerchief Buddhist nun and with radiotherapy, platinum class, camptothecine, hdac inhibitor or their combinatorial association medication.Carry out in people-nude mouse model the single medicine of Aura handkerchief Buddhist nun and with the drug combination such as radiotherapy, platinum class, camptothecine, hdac inhibitor, in detection model, the hepatocellular propagation of the hepatitis B virus positive reaches remarkable suppression.
The propagation for HBV positive hepatocellular carry out the single medicine of Aura handkerchief Buddhist nun and with radiotherapy, platinum class, camptothecine, hdac inhibitor or their combinatorial association medication.The single medicine of Aura handkerchief Buddhist nun can reach survival rate lower than 1 ‰ in final concentration 1.5 μMs of concentration.
Carry out in the people-nude mouse model of HBV positive hepatocellular, hepatocarcinoma the single medicine of Aura handkerchief Buddhist nun and be significantly effective with radiotherapy, platinum class or their combinatorial association medication.
Those skilled in the art think and can comprise the various medicine disturbing DNA metabolism, copy and repair with the kind of Aura handkerchief Buddhist nun drug combination, comprise platinum class (but being not limited to cisplatin and carboplatin), camptothecin, amycin, anthracene ring antitumor medicinal etc.
In this application, the PARP inhibitor phthalazines ketone (such as Aura handkerchief Buddhist nun) of low unit dose refer to the low unit dose of 1-40mg (the single pharmaceutical quantities of the Aura handkerchief Buddhist nun in the present invention involved by Experiment of Zoology carry out mice-people's dose lonvestion according to criterion of pharmaceutics weight animals dose lonvestion coefficient after for dosage every day be 639mg, lower by nearly 20% than recommending to take dosage 800mg every day in Aura handkerchief Buddhist nun dispensatory; After converting, in two medicine animal model experiment, minimum effective using dosage of Aura handkerchief Buddhist nun is 156.5mg equally, lower by more than 80% than recommending to take dosage 800mg every day in Aura handkerchief Buddhist nun dispensatory.In the present invention, the follow-up zoopery of well afoot further implies that Aura handkerchief Buddhist nun has the application of more low dosage, therefore splendid reason application is had to be less than the more low-dose drugs specification of market already present 50mg specification capsule in the present invention), preferred 1-40mg, more preferably 5-35mg, more preferably 10-30, more preferred 15-20mg are in the present invention, the PARP inhibitor of the low unit dose of 1-40mg comprises any single dosage, such as 1mg and 40mg unit dose in described scope.
4. accompanying drawing explanation
Fig. 1. Aura handkerchief Buddhist nun induced hepatitis B virus full-length genome transgenic human hepatic cell line HL02-H1 cell and expression HBx (hepatitis B virus coding X gene) hepatocellular chromosome breakage, but the human liver cell strain HL-7702 cell of the non-hepatitis B positive is not had a significant effect.Upper figure shows HL02-H1 and human liver cell strain HL-7702 processes cell after 24 hours Aura handkerchief Buddhist nun, the metaphase chromosome of preparation.Arrow is depicted as obvious starlike chromosome and aberrant chromosomal.Figure below is the statistical result of above-mentioned experiment, and display Aura handkerchief Buddhist nun significantly improves the chromosomal generation quantity of HL02-H1 and HL-7702-HBx cell stellate.
Fig. 2. Aura handkerchief Buddhist nun is to the pharmacological evaluation of HL02-H1 cell model.HBV significantly improves the sensitivity of HL02-H1 cell to Aura handkerchief Buddhist nun.Aura handkerchief Buddhist nun is to the killing-efficiency high nearly about 500 times of the killing-efficiency of HBV positive cell (HL02-H1) compared with HL-7702 cell.When the two medicine coupling of Aura handkerchief Buddhist nun and conventional chemotherapeutic drugs cisplatin, carboplatin, present high Collaboration effect.
Fig. 3 .MTT method detects Aura handkerchief Buddhist nun to the impact of hepatitis B masculine liver cancer cell line HepG2.2.15, and Aura handkerchief Buddhist nun can significantly suppress HepG2.2.15 to grow.
Fig. 4. the single medicine of Aura handkerchief Buddhist nun and all significantly can suppress the growth of xenografted that formed by hepatitis B virus full-length genome transgenic human hepatic cell line HL02-H1 cell in people-nude mouse tumor model with platinum class drug combination.
Fig. 5. use Aura handkerchief Buddhist nun effectively reduces the serum-virus level in hepatitis B virus mouse model, and within 20 days, still can keep the low-level state of virus levels below positive marginal value after Aura handkerchief Buddhist nun drug withdrawal.
Fig. 6. use Aura handkerchief Buddhist nun effectively reduces the serum-virus antigen levels in hepatitis B virus mouse model, and after Aura handkerchief Buddhist nun drug withdrawal 20 days still keep the low-level state of virus levels below positive marginal value.
5. detailed description of the invention
Following non-limiting example is used for illustrating selected embodiment of the present invention.Should be understood that, the ratio change of shown component and alternative elements will be apparent to those skilled in the art, and are therefore fall in the scope of embodiment of the present invention.
HL-7702 cell line (human liver cell in the following example, have another name called L-02, American Type Culture Collection committee of Chinese Academy of Sciences cell bank, numbering: GNHu6), HepG2 (human liver cancer cell, or name HEPG2, ATCC preserving number is HB-8065), HepG2.2.15 (HBV full-length genome transfection recipients cell HepG2 gained stable cell lines), nude mice (BALB/c-Nude, SPF level, female, derive from Sichuan University's Experimental Animal Center) for testing use in the present invention, not as other purposes.The Aura handkerchief Buddhist nun (KU0059436 used in embodiment, Selleck), cisplatin (cisplatin, 131102, Supertrack Bio-pharmaceutical), carboplatin (carboplatin, H20020180, Qilu Pharmaceutical Co., Ltd.), hepatitis B virus surface antigen diagnostic kit (S10910113, Shanghai Kehua Bio-engineering Co., Ltd), hepatitis B virus (HBV) nucleic acid amplification (PCR) fluorescence quantitative detection kit (S20030059, Hai Kehua biological engineering limited company).Various antibody and various chemical reagent are commercial products, for testing use in the present invention, not as other purposes.
Embodiment 1 Aura handkerchief Buddhist nun improves chromosome breakage probability in HL02-H1 cell.
1. hepatitis B virus (HBV) full-length genome transgenic human hepatic cell line HL02-H1
HL-7702 cell is cultured to density and reaches 90% in 5cm × 5cm culture bottle.After trypsinization, paving dish 3 coils totally to 6cm culture dish again, incubated overnight.Often coil cell and proceed to 10 μ gpcDNA3.1-HBV-wholeGenome plasmids, transfection process is as follows: 10 μ g plasmids and TurboFect transfection reagent (Thermo, #R0531) are added Opti-MEM serum-free medium, mixing, leaves standstill 20min.Mixed liquor is added in the cell of incubated overnight, add G418 after 48 hours and carry out screening (final concentration 800 μ g/ml).Continue screening one month, by the cell dissociation of surviving, be diluted to 4/ml with complete medium, the cell culture diluted added in 96 orifice plates, every hole 200 μ l, ensure that in 96 orifice plates, every hole is monoclonal.Cultivate 2-3 week, treat that monoclonal cell covers with, get 100 μ l supernatant culture medium, by integrated enzyme reaction kit measurement hepatitis B surface antigen level, choose the porocyte that OD pH-value determination pH is the highest.Digestion, puts into cell bottle and increases, and obtains HL02-H1 and surely turns cell line.Described HL02-H1 cell line is preserved in China typical culture collection center (China Center for Type Culture Collection on April 3rd, 2015, be called for short CCTCC, Luo Jia Shan, wuchang, wuhan, postcode: 430072), preserving number is: CCTCCC201554.
2.HL-7702-HBx cell strain and compared with control cells strain thereof are set up by slow virus infection
HL-7702 cell is cultured to density and reaches 90% in 5cm × 5cm culture bottle.After trypsinization, and paving dish spreads 12 dishes altogether to 3.5cm culture dish again.Density about 25%.37 DEG C, 5%CO2 incubator incubated overnight.Contrast (pLV) slow virus of the secondary daily HBx of carrying gene and empty carrier carries out infecting (HBx and empty control plasmid (PLV) slow virus are packed according to illustrating in Ji triumphant gene slow virus packaging transfection reagent box), set up HL-7702-pLV, HL-7702-HBx cell line.Empty control plasmid (PLV) slow virus is packed according to illustrating in Ji triumphant gene slow virus packaging transfection reagent box, virus liquid is infected HL-7702 cell line.
3. Aura handkerchief Buddhist nun is to the specific cytotoxicity effect of HBV positive cell HL02-H1 and HL-7702-HBx
Get HL-7702, HL02-H1, HL-7702-pLV and HL-7702-HBx cell, be seeded to 2 6cm culture dishs respectively, treat cell attachment, get a dish in each cell line and add 1 μM of Aura handkerchief Buddhist nun, another dish is used for dosing contrast and adds isopyknic DMSO, and process is spent the night.Add the Colchicine of final concentration 200ng/ml next day.Process 1.5 hours, according to the film-making of following steps fixed cell: trypsinization, PBS cleans 1 time.Remove waste liquid, remain 200 μ l and mix cell.Add the 75mMKCl of 6ml37 DEG C of preheating, jog sample in adition process is in order to avoid cell caking.37 DEG C of incubation 16-25min.200 μ l methanol and glacial acetic acid mixed stationary liquid (methanol: glacial acetic acid=3:1) is added, mixing, 1000rpm, centrifugal 10min in sample after incubation.Remove supernatant, with residue 50 μ l residual solution mixing cell, continue to add methanol and glacial acetic acid fixative 5ml, gently mix, 4 DEG C of standing 20min.1000rpm, centrifugal 10min, remain a little fixative, re-suspended cell.Repeat step 3-5 fixed cell 3 times.Leave and take 500 μ l fixatives after centrifugal for the last time, 4 DEG C leave standstill and preserve (sample can preserve one week).Microscope slide ethanol is invaded bubble and rinse process 2-3 time, add a little distilled water and be placed in-20 DEG C of freezing 10min.The Cell sap fixed is dropped to from > 20cm on the Borneolum Syntheticum of anticipating, dries slide.The slide Giemsa staining liquid dyeing dyeing 10min dried.Wash out excess stain liquid, dry slide, drip resin mounting.Mounting is taken pictures with just putting microscope 100 times of lower observations and counts.
Experimental result: Fig. 1 show HL-7702, HL02-H1, HL-7702-pLV and HL-7702-HBx cell DMSO and Aura handkerchief Buddhist nun process after chromosomal abnormality situation and statistical result.The number of HL02-H1, HL-7702-HBx cell stellate chromosome and aberrant chromosomal is far above matched group HL-7702, HL-7702-pLV, together this exception is formed because the end of fracture reconnects by the cell tendency when meeting with DNA break simply, have high cytotoxicity, a large amount of accumulation can cause cell death.Gap after adding Aura handkerchief Buddhist nun between the number of HL02-H1, HL-7702-HBx cell stellate chromosome and aberrant chromosomal and matched group more significantly (statistical test * * *: p < 0.001).Visible Aura handkerchief Buddhist nun can significantly improve the chromosomal generation quantity of HL02-H1 and HBx cell stellate, therefore can expect that Aura handkerchief Buddhist nun has the effect that specificity effectively kills HBV positive proliferative cell.
Embodiment 2 Aura handkerchief Buddhist nun significantly suppresses hepatitis B virus full-length genome transgenic human hepatic cell line HL02-H1 cell proliferation
In order to confirm the inhibitory action that Aura handkerchief Buddhist nun breeds HBV positive cell further, colony formation is utilized to test Aura handkerchief Buddhist nun to the inhibitory action of HBx positive malignant hepatocyte HL02-H1.
The HL02-H1 cell of cell HL-7702 as a control group and the HBV positive is inoculated in 10cm diameter Petri dishes, after cell attachment, adds the DMSO of medicine or same volume in contrast.37 DEG C, 5%CO
2cultivate 10 days, use methanol fixed cell afterwards, according to the dyeing of Giemsa stain test kit description, and calculate clone's number.Required paving dish sum needs to determine according to medicine gradient concentration.The single medicine final concentration of Aura handkerchief Buddhist nun is 0,0.25,0.5,1,1.5 μM, and the cisplatin dose of drug combination is final concentration 0.1,0.05,0.025,0.001,0.005 μM with it, and carboplatin dose is 0.25,0.5,0.75,1 μM.Aura handkerchief Buddhist nun is 0.25 μM, is 0 μM in matched group.Wherein Aura handkerchief Buddhist nun is for continuing medication, and cisplatin and carboplatin are administration process in 24 hours.Count results is shown in Fig. 2.
Experimental result: can to find out in this experiment no matter single medicine or two medicine conbined usage by above data, Aura handkerchief Buddhist nun has obvious inhibitory action to HL02-H1 cell under low dosage.In this experiment, Aura handkerchief Buddhist nun reaches more than 99% when 1.5 μMs of concentration to HL02-H1 cell kill ratio, and when in current bibliographical information, the experimental drug dosage of the same type of hepatitis B virus negative cells system reaches 2 μMs, cell survival rate is still up to more than 20% (J Biol Chem, 2011,286:12157-12165,2010); In two medicine experiment, Aura handkerchief Buddhist nun concentration is 0.25 μM, and dose ratio list medicine using dosage reduces further; Cisplatin consumption is lower than least concentration (1-10 μM in current most of bibliographical information cellulotoxic experiment of the same type dosage used, Matrix Stiffness Modulates Proliferation, Chemotherapeutic Response and Dormancy in Hepatocellular Carcinoma Cells
schrader, Timothy T Gordon-Walker Hepatology.2011April; 53 (4); Aurora-A promotes chemoresistance in hepatocelluar carcinoma by targeting NF-kappaB/microRNA-21/PTEN signaling pathway; Kai Zhang, Jing Chen, Oncotarget.2014Dec; 5 (24): 12916 – 12935) 1-10% concentration under, i.e. the concentration of 0.1 μM, namely can reach the suppression ratio of more than 99.9% to HL02-H1 cell.Carboplatin dose, in most document, only has and at least reaches more than 5 μMs and could produce obvious inhibition (suppression ratio 60-90%).And carboplatin dose reaches 0.5 μM and can reach suppression ratio 90% in this experiment, when dosage reaches 1 μM further, suppression ratio can reach more than 99%, being very rare in the cellulotoxic experiment that this situation is correlated with at current all carboplatins, illustrating that carboplatin has high Collaboration lethal effect (be high Collaboration effect according to both CI formulae discovery) when sharing with Aura handkerchief Buddhist nun to hepatitis B virus cell strain HL02-H1.And the normal liver cell of HBV feminine gender as a control group in single medicine and two medicine experiment under equal Drug level survival rate be in impregnable scope in pharmaceutics meaning.According to our result, the HL02-H1 cell inhibitory rate of more than 99.8% be obtained, need the single medicinal concentration of Aura handkerchief Buddhist nun: ICX, A=1200nM, the medicinal concentration of cisplatin list: ICX, B=600nM; And Aura handkerchief Buddhist nun Drug level is DA=250nM under drug combination, cisplatin Drug level is DB=100nM.Synergy index (combinedindex in pharmacological experiment is calculated according to above data, CI): CI0=DA/ICX, A+DB/ICX, B=250/1200+100/600=0.375,0.2≤CI0 < 0.4, can determine to be strong synergism between two kinds of medicines thus.
Embodiment 3. Aura handkerchief Buddhist nun is to the lethal effect experimental technique of hepatitis B virus positive hepatoma carcinoma cell (HepG2.2.15): collect logarithmic (log) phase hepatocellular carcinoma H22 and HepG2.2.15 cell, cell counting count board is utilized to count, adjustment concentration of cell suspension, two kinds of cells are added respectively two plate 96 orifice plates, every hole adds 100ul, adjustment cell adjusts density 1000/hole, and the aseptic PBS of edge hole fills.5%CO2, hatches for 37 DEG C, is paved with at the bottom of hole to cell monolayer, adds the Aura handkerchief Buddhist nun of gradient concentration, makes every hole Chinese medicine final concentration be 0,2,2.5,3.5,4.5 μM.3 multiple holes are established in every hole.Zeroing hole (culture medium, MTT, dimethyl sulfoxide) is set simultaneously.At 5%CO2, after hatching 16-48 hour under 37 DEG C of conditions, in every hole, add 20ulMTT solution (5mg/ml, i.e. 0.5%MTT), continue to cultivate 4h.Stop cultivating, carefully suck culture fluid in hole.Every hole adds 150ul dimethyl sulfoxide, puts low-speed oscillation 10min on shaking table, crystal is fully dissolved.The light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument OD value 490nm place.Enzyme mark reading, OD value is scaled survivaling cell number by the standard growth curve equation according to HepG2 and HepG2.2.15 cell, and the Aura handkerchief Buddhist nun being plotted in variable concentrations acts on lower cell survival rate chart.
Experimental result: experimental result display reaches more than 2.5 μMs when Aura handkerchief Buddhist nun acts on final concentration, and HepG2.2.15 cell line survival rate and HepG2 have notable difference (* * * P < 0.001), as shown in Figure 3.The hepatoma carcinoma cell that this result proof Aura handkerchief Buddhist nun is directed to the HBV positive has very effective inhibition.
Embodiment 4 is used alone Aura handkerchief Buddhist nun or significantly can suppresses with platinum-based chemotherapy Drug combination the growth of xenografted that formed by HL02-H1 cell in nude mice.
The athymic female nude mice 20 in random choose 4-8 age in week, is divided into 4 groups, inoculation HL02-H1 cell in two oxter and double inguinal groove place, the about 4x10 of each injection point
6individual cell.Treat that HL02-H1 induces into tumor volume and is about 3-4mm
3time start injectable drug.Drug dose is with reference to suitably reducing after clinical dosage (carrying out determining after people-mice is converted according to pharmacology's conversion coefficient), and drug dose is as follows: the single survival dose of Aura handkerchief Buddhist nun is 131.5mg/kg/ days.Aura handkerchief Buddhist nun 32mg/kg/ days in testing with the genotoxic chemotherapy drugs drug combination of the tool DNA damage effects such as platinum class), cisplatin (0.21mg/kg/4 days).Matched group DMSO volume is organized identical with Aura handkerchief Buddhist nun.Single medicine experiment is injected 9 days continuously, within 3,6,7,8,9 days, measures the length at tumor body surface place at injectable drug; Two medicine experiment is injected 14 days continuously, measures tumor length at 0,7,9,12,14 day.According to ellipsoid computing formula: oval volume=length × wide × height × 3.14/6 calculates gross tumor volume size.And the suppression ratio of each medication group is calculated according to tumor control rate=(matched group gross tumor volume-medication group gross tumor volume)/matched group gross tumor volume × 100%, draw a diagram.Fig. 4 is the change of gross tumor volume under different pharmaceutical process.
Experimental result: in single medicine group, the tumor of HL02-H1 induction is always suppressed, even has the phenomenon that disappears.And in two medicine experiment, the average daily consumption of cisplatin be about dosage in other Experiment of Zoology models about 1/5 (Intraperitoneal Cisplatin injection mice dosage is generally 2mg/kg/2 days, every other day administration, see Li Shan equality, the impact that Maixuekang combination with cisplatin grows lotus MHCC97H people Liver Cancer Bearing Nude Mice subcutaneous transplantation tumor, " Chinese Chinese medicine academic periodical " the 28th volume 009 phase in 2010; Or dosage is: 4mg/kg/4 days, see The Role of Proline Rich Tyrosine Kinase 2 (Pyk2) on Cisplatin Resistance in Hepatocellular Carcinoma, Wei Geng, Kevin T.P.Ng, Chris K.W.PLoS One.2011; 6 (11)), Aura handkerchief Buddhist nun is (according to ToC in the low dosage situation of about 45%, Deng in people's mouse experiment model, the effective dose of Aura handkerchief Buddhist nun is 200mg/kg/d, and Aura handkerchief Buddhist nun clinical application amount is 800mg/kg, see To & Kim, The PARP inhibitors, veliparib and olaparib, are effective
chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice, Cancer Prevention Research 7:698-707,2014; Kaufman & Shapira-Frommer, Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2mutation.Journal of Clinical Oncology 33 (3): 244-250,2015), the tumor that still can effectively suppress HL02-H1 to induce, experimentally data carry out variance analysis, determine Aura handkerchief Buddhist nun 1.64mg/ pcs/day, under the dosage of cisplatin 0.015mg/ pcs/day, two kinds of medicines have synergism.
Embodiment 5. uses Aura handkerchief Buddhist nun effectively can reduce serum-virus level in hepatitis B virus mouse model, and after discontinuing medication, virus levels also can be suppressed to go up.
Experimental technique: mice is divided into 4 groups at random, often organizes 5.(inject 4 points, oxter groin injects 4x10 respectively with the HepG2.2.15 cell of HBV full-length genome for every injected in mice
6individual cell).Extract tail vein 100 μ l every 4 days subsequently, utilize HBV copy number in quantitative fluorescent PCR determination blood, when HBV-DNA copy number to 10
5start medication.Press human body recommended dose, every mice dosage is as follows: Aura handkerchief Buddhist nun, 168mg/kg/ days; Entecavir (entecavir), 0.07mg/kg/ days; Lamivudine (lamivudine), 1.6mg/kg/ days.The DMSO of matched group injection and Aura handkerchief Buddhist nun same volume.Administration in continuous 10 days, every day extracts about 200 μ l tail veins, by with HBV copy number in quantitative fluorescent PCR determination blood, drug withdrawal in the 11st day.Count using administration starting date as 0 day.Respectively take out tail vein 200 μ l at the 15th, 20,25,28,30 day and utilize HBV copy number in quantitative fluorescent PCR determination blood, determine the change situation of HBV copy number in mouse blood.
Experimental result: it is all kinds of HBV related liver diseases medicine effect of assessment the most reliable method that the copy number of serum HBV-DNA detects.According to " lamivudine clinical practice instruction in 2000 "; the object of China's chronic HBV infection patient is exactly mainly reduce serum HBV DNA; make glutamate pyruvate transaminase (ALT) normalization, improve liver histological pathological changes, reduce the incidence rate of liver cirrhosis and hepatocarcinoma.As shown in Figure 5, (the HBV-DNA copy number to 10 when the content of HBV-DNA of mouse model reaches the critical positive of clinical regulation
5time) starting medication, the level of serum HBV-DNA all can control within clinical negative range by Aura handkerchief Buddhist nun and now conventional clinically ucleosides liver disease drug Entecavir (entecavir) and Lamivudine (lamivudine) in 10 days.But after drug withdrawal in 20 days, the level of HBV-DNA in serum of Entecavir and Lamivudine medication group mice has progressively gone back up to Positive Level; Aura handkerchief Buddhist nun organize mice level of HBV-DNA in serum be then within stable negative range always.In DMSO matched group, content of HBV-DNA is in more than positive marginal value always.This shows that Aura handkerchief Buddhist nun overcomes at present for the greatest weakness of hepatitis b virus infected diseases related all ucleosides antiviral clinical medicines in all kinds of hepatopathys of the treatment HBV positive: although can reduce virus replication, but can not infection cell be removed, steady decrease organism infection level.
Embodiment 6. uses Aura handkerchief Buddhist nun effectively can reduce serum-virus antigen levels in hepatitis B virus mouse model, and after discontinuing medication, virus antigen also can be suppressed to go up.
Experimental technique: mice is divided into 4 groups often to organize 5 at random.(inject 4 points, oxter groin injects 4x10 to every injected in mice HepG2.2.15 cell respectively
6individual cell).Extract tail vein 100 μ l every 4 days afterwards, utilize HBV copy number in quantitative fluorescent PCR determination blood, when HBV-DNA copy number to 10
5start medication.1-5 after mice administration, the blood sample 200 μ l of 15,20 days, room temperature leave standstill 2-3 as a child after the centrifugal 20min of 3000rpm, get serum, carry out detection HBV antigen HBsAg level according to hepatitis B virus surface antigen diagnostic kit description.Draw a diagram according to gained OD value.Experimental result: Fig. 6 shows, carry out ELISA by mouse tail vein blood sampling separation of serum and monitor HBsAg in serum level continuously, find after medication, Aura handkerchief Buddhist nun and now conventional clinically ucleosides liver disease drug Entecavir (entecavir) and Lamivudine (lamivudine) all can make HBsAg drop to clinical HBsAg feminine gender critical level in 5 days.After drug withdrawal in 20 days, the HBsAg level of Entecavir and Lamivudine medication group mice is progressively gone up, but the HBsAg level that Aura handkerchief Buddhist nun organizes mice is then within stable negative range always.This also shows different from the short-term drug effect of Entecavir and Lamivudine, and Aura handkerchief Buddhist nun can remove infection cell, steady decrease organism infection level.
Claims (15)
1. comprise a compositions for poly (ADP ribose) polymerase (PARP) inhibitor, it is used for the treatment of or prevents hepatitis virus relevant disease.
2. the compositions of claim 1, wherein said PARP inhibitor is phthalazone compounds.
3. the compositions of claims 1 or 2; wherein said phthalazone compounds is (1-(cyclopropane carbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoyl] piperazine).
4. the compositions of any one of claim 1-3, it comprises the PARP inhibitor unit dosage forms of the low unit dose of 1-40mg.
5. the compositions of aforementioned any one claim, it is used for the treatment of or prevents hepatitis b virus infected and diseases related, such as hepatitis b virus infected property relevant disease.
6. the compositions of claim 5, the physical signs exception that wherein said hepatitis b virus infected property relevant disease is acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, hepatocarcinoma, cholangiocellular carcinoma and hepatitis B virus infection cause, blood circulation symptom, gastrointestinal symptom.
7. the compositions of any one of claim 1-6 is preparing the purposes in medicine, described medicine is used for the treatment of or prevents hepatites virus infections relevant disease, particularly hepatitis b virus infected property disease, more preferably hepatitis b virus infected property disease, more preferably hepatitis b virus carrier, preferably hepatitis b virus infected again, most preferably hepatitis b virus infected dependency acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, hepatocarcinoma, cholangiocellular carcinoma, wherein said pharmaceutical pack is containing the PARP inhibitor of 1-45mg.
8. the purposes of claim 7, wherein said medicine can be given by oral or parental routes.
9. the purposes of claim 7 or 8, wherein said medicine and other treat the Drug combination of hepatites virus infections relevant disease.
10. the purposes of claim 9, wherein said other medicines are selected from cancer therapy drug, and preferred described cancer therapy drug is platinum class.
The purposes of 11. claim 7 or 8, wherein said pharmaceutical composition and chemotherapy combined radiotherapy are applied.
The purposes of 12. claim 10, wherein said platinum class is selected from cisplatin and carboplatin.
13. a method for treatment or prevention hepatites virus infections relevant disease, it comprises the compositions of any one of claim 1-6 giving effective dose.
The method of 14. claim 11, wherein hepatites virus infections relevant disease is hepatitis b virus infected property disease, more preferably hepatitis b virus carrier, preferably hepatitis b virus infected again, most preferably hepatitis b virus infected dependency acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, hepatocarcinoma, cholangiocellular carcinoma.
15. the method for claim 11 or 12, it also comprises and gives other hepatites virus infections relevant disease medicine further, preferred platinum class.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019029656A1 (en) * | 2017-08-10 | 2019-02-14 | 中国科学院上海药物研究所 | Pyridazinone compound, method for preparation thereof, pharmaceutical composition thereof, and use thereof |
| CN109364079A (en) * | 2018-10-08 | 2019-02-22 | 四川大学华西第二医院 | Purposes of the Ta Lapani in preparation treatment or prevention hepatitis virus related disease drug |
| WO2020155141A1 (en) * | 2019-02-02 | 2020-08-06 | 中国科学院上海有机化学研究所 | Pharmaceutical composition for treatment of neurodegenerative diseases or diseases caused by abnormality of rna binding protein and applications thereof |
| CN112125881A (en) * | 2019-06-25 | 2020-12-25 | 中国科学院上海药物研究所 | 4-pyridine substituted phthalazinone compound, preparation method, pharmaceutical composition and application thereof |
| CN114306341A (en) * | 2022-03-02 | 2022-04-12 | 南京大学 | Use of phthalazine derivatives for the treatment of liver fibrosis diseases |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110241198A (en) * | 2019-05-30 | 2019-09-17 | 成都吉诺迈尔生物科技有限公司 | A kind of genome recombination fingerprint and its identification method characterizing hHRD HR defective |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1098926A (en) * | 1993-08-14 | 1995-02-22 | 焦柏忠 | Capsule for treating hepatism and preparation technology thereof |
| WO2015015318A2 (en) * | 2013-07-31 | 2015-02-05 | Zenith Epigenetics Corp. | Novel quinazolinones as bromodomain inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2742342A1 (en) * | 2011-02-12 | 2012-08-12 | Baylor Research Institute | Msh3 expression status determines the responsiveness of cancer cells to the chemotherapeutic treatment with parp inhibitors and platinum drugs |
| CN104513252B (en) * | 2013-09-26 | 2017-11-10 | 广东东阳光药业有限公司 | Substituted urea derivative and its application in medicine |
-
2015
- 2015-05-08 CN CN201510233465.6A patent/CN104887680A/en active Pending
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1098926A (en) * | 1993-08-14 | 1995-02-22 | 焦柏忠 | Capsule for treating hepatism and preparation technology thereof |
| WO2015015318A2 (en) * | 2013-07-31 | 2015-02-05 | Zenith Epigenetics Corp. | Novel quinazolinones as bromodomain inhibitors |
Non-Patent Citations (4)
| Title |
|---|
| GUILLOT ET AL.: "PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models", 《 BMC CANCER》 * |
| ZHANG,ET AL.: "Synergistic Inhibition of Hepatocellular Carcinoma Growth by Cotargeting Chromatin Modifying Enzymes and Poly (ADP-ribose) Polymerises", 《HEPATOLOGY》 * |
| 迟永春等: "《中医治疗癌症验案秘方》", 30 June 2001 * |
| 黄洁夫: "《胆道肿瘤学前沿》", 30 September 2012 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019029656A1 (en) * | 2017-08-10 | 2019-02-14 | 中国科学院上海药物研究所 | Pyridazinone compound, method for preparation thereof, pharmaceutical composition thereof, and use thereof |
| CN109134429B (en) * | 2017-08-10 | 2021-06-01 | 中国科学院上海药物研究所 | Phthalazinone compound, preparation method, pharmaceutical composition and application thereof |
| US11040952B2 (en) | 2017-08-10 | 2021-06-22 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Phthalazinone compound, method for preparation thereof, pharmaceutical composition thereof, and use thereof |
| CN109364079A (en) * | 2018-10-08 | 2019-02-22 | 四川大学华西第二医院 | Purposes of the Ta Lapani in preparation treatment or prevention hepatitis virus related disease drug |
| CN109364079B (en) * | 2018-10-08 | 2021-01-05 | 四川大学华西第二医院 | Application of talapanib in preparation of medicine for treating or preventing hepatitis virus related diseases |
| WO2020155141A1 (en) * | 2019-02-02 | 2020-08-06 | 中国科学院上海有机化学研究所 | Pharmaceutical composition for treatment of neurodegenerative diseases or diseases caused by abnormality of rna binding protein and applications thereof |
| CN112125881A (en) * | 2019-06-25 | 2020-12-25 | 中国科学院上海药物研究所 | 4-pyridine substituted phthalazinone compound, preparation method, pharmaceutical composition and application thereof |
| WO2020259539A1 (en) * | 2019-06-25 | 2020-12-30 | 中国科学院上海药物研究所 | 4-pyridine substituted phthalazinone compound and preparation method, pharmaceutical composition, and use thereof |
| CN114306341A (en) * | 2022-03-02 | 2022-04-12 | 南京大学 | Use of phthalazine derivatives for the treatment of liver fibrosis diseases |
| CN114306341B (en) * | 2022-03-02 | 2022-05-24 | 南京大学 | Use of phthalazine derivatives for the treatment of liver fibrosis diseases |
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