CN105920604B - Combination medicine for treating leukaemia and its application in treatment leukaemia - Google Patents

Combination medicine for treating leukaemia and its application in treatment leukaemia Download PDF

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CN105920604B
CN105920604B CN201610403985.1A CN201610403985A CN105920604B CN 105920604 B CN105920604 B CN 105920604B CN 201610403985 A CN201610403985 A CN 201610403985A CN 105920604 B CN105920604 B CN 105920604B
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leukaemia
cell
hdac
daily
inhibitor
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CN105920604A (en
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龙俊
胡炯
李军民
郑仲征
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Di Shuobeiken Bio Tech Ltd Shanghai
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

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Abstract

The invention belongs to drug fields, disclose a kind of combination medicine for treating leukaemia and its application in treatment leukaemia.The present invention is by 3 inhibitor of histon deacetylase (HDAC) and Clinical Acute marrow series leukemia Common Chemotherapy Drug combination; the treatment complete remission rate of new hair leukaemia and Refractory and relapsed acute leukemia can be dramatically increased, and can more effectively reverse Refractory and relapsed acute leukemia cell to the sensibility of chemotherapeutics.

Description

Combination medicine for treating leukaemia and its application in treatment leukaemia
Technical field
The present invention relates to drug fields, and in particular to for treating the combination medicine of leukaemia and its in treatment leukaemia In application.
Background technique
Acute myeloid leukemia is a kind of common hematologic malignancy, with onset is hurried, clinical manifestation is dangerous, pre- , there is great threat in the features such as poor afterwards for life and health.
At present in clinical practice, combine a kind of anthracycline antibiotic frequently with cytarabine for acute myeloid leukemia Based on chemotherapy regimen.Cytarabine is pyrimidines antimetabolic drug, by inhibiting the synthesis of DNA in cell, DNA is caused to damage Wound, to make death of neoplastic cells.Anthracycline antibiotic is II type DNA topoisomerase enzyme inhibitor, and DNA can be made to generate double-strand Fracture, leads to DNA damage.In addition there are some chemotherapy regimens improved on this basis.But for now, although About 60% Patients with Acute Myeloid Leukemia can get clinically complete remission after receiving conventional chemotherapy, and wherein most patient is still It can recur after the treatment.For leukaemic once recurring, intracorporal tumour cell just shows the sensibility of original chemotherapy regimen Writing reduces, and after recurring hematopoietic stem cell transplantation again curative effect it is also very poor, result be exactly the leukaemia that recurs rapidly into Exhibition, leads to death.In addition, conventional chemotherapy regimen can not remove leukaemia cell of the patient's body with stemness (i.e. Leukemic stem cells).The chemotherapy of the course for the treatment of is and kills leukaemia cell of the patient's body to chemotherapy medicament sensitive for several times, and that The leukemic stem cells with very strong drug resistance are then retained by drug screening a bit.Therefore, white after multiple chemotherapy Blood patient often generates tolerance to conventional chemotherapy regimen, progresses to Refractory Leukemia.The chemotherapy of Refractory Leukemia Sensibility is very poor, and is easy recurrence, is the problem of leukaemia clinical treatment.
In consideration of it, for newly sending out leukaemia, can effectively remove patient's body it is necessary to explore new therapeutic scheme Leukemic stem cells；And for drug resistant Refractory and relapsed acute leukemia, leukemia cell drug-resistance can be effectively reversed, chemotherapy is increased Complete remission rate provides condition for successive treatment.
Summary of the invention
The present invention is the current Common Chemotherapy scheme of improvement to leukemia treating in view of the above defects of the prior art The deficiency of effect, provides a kind of new scheme for the treatment of leukaemia, and the program can dramatically increase and newly send out leukaemia and refractory multiple The treatment complete remission rate of leukaemia is sent out, and can more effectively reverse Refractory and relapsed acute leukemia cell to the sensitivity of chemotherapeutics Property.
For this purpose, one aspect of the present invention provide it is a kind of for treating the combination medicine of leukaemia, the drug include group an egg White 3 inhibitor of deacetylase and leukaemia conventional chemotherapy drug.
In a preferred embodiment of the present invention, leukaemia conventional chemotherapy is cytarabine or adriamycin with drug.
In another preferred embodiment of the present invention, 3 inhibitor of histon deacetylase (HDAC) is RGFP966 or valproic acid Sodium (VPA).
In further preferred embodiment of the present invention, 3 inhibitor of histon deacetylase (HDAC) is oral preparation, white blood Sick conventional chemotherapeutic drugs are intravenous injection injection.The oral preparation is more preferably capsule or tablet.
Further aspect of the present invention provides combination medicine of the present invention in the drug of preparation treatment leukaemia Using wherein leukaemia is preferably acute myeloid leukemia.
In a preferred embodiment of the present invention, leukaemia be preferably recurrent, intractable or drug tolerance leukaemia.
In further preferred embodiment of the present invention, 3 inhibitor of histon deacetylase (HDAC) is oral preparation, white blood Sick conventional chemotherapeutic drugs are intravenous injection injection.The oral preparation is more preferably capsule or tablet.
In the more preferred embodiment of the present invention, in combination medicine of the present invention or application, egg is organized The dosage of white 3 inhibitor RGFP966 of deacetylase is to take orally daily 50-500mg；The dosage of sodium vedproate is oral daily 500-3000mg；The routine dose of leukaemia conventional chemotherapeutic drugs cytarabine intravenous injection is daily 20-250mg, continuous to use Medicine 5-14 days, or large dosage of daily 1-6g, continuous use 3 days；The dosage of Doxorubicin intravenous injections is daily 20-90mg, continuously Medication 3 days.
Seen from the above description, compared with prior art, the present invention has following advantage.
Although 1, existing experiment has confirmed that histon deacetylase (HDAC) inhibitor has antitumor effect, and And FDA has had been approved by several histon deacetylase (HDAC) inhibitors for oncotherapy.But DNA methylase inhibitor at present Enzyme inhibitor is mainly used for the treatment of lymthoma and Huppert's disease, for leukaemia, especially acute myeloid leukemia Clinical efficacy is not known.The present invention has probed into 3 inhibitor of histon deacetylase (HDAC) in acute myeloid leukemia for the first time Anti-tumor effect.
Although 2, cell experiment of the invention shows under conditions of histon deacetylase (HDAC) inhibitor is used alone, The proliferation of leukaemia cell and apoptosis are without substantially changeing；But cytarabine or adriamycin and histon deacetylase (HDAC) are pressed down Agents use, then can significant inducing leukemia apoptosis, the apoptosis induction effect is than single use any one Drug is intended to significantly.
3, the present invention uses MLL-AF9 leukemia mouse model, has probed into histon deacetylase (HDAC) inhibitor and chemotherapy The vivo efficacy of Drug combination.The experimental results showed that histon deacetylase (HDAC) inhibitor and chemotherapeutics is used in combination The life cycle that mouse can significantly be extended has more obvious depression effect to the amplification of leukaemia cell in Mice Body.
In conclusion histon deacetylase (HDAC) 3 is pressed down the present invention provides a kind of scheme of new treatment leukaemia Preparation and Clinical Acute marrow series leukemia Common Chemotherapy Drug combination, the program can dramatically increase new hair leukaemia and difficulty The treatment complete remission rate of recurrence leukaemia is controlled, and can more effectively reverse Refractory and relapsed acute leukemia cell to chemotherapeutics Sensibility.
Detailed description of the invention
Fig. 1: the apoptosis situation map under malignant myeloid cell lines K562 adriamycin-resistant cell Different treatments.
Fig. 2: the apoptosis situation map under leukemia cell line THP-1 cell Different treatments.
Fig. 3: malignant myeloid cell lines K562 adriamycin-resistant cell and using control virus or HDAC3 specifically strike low virus infection Afterwards, to the histogram of adriamycin IC50.
Fig. 4: after different modes processing, the apoptosis of leukemia percentage histogram of MLL-AF9 leukemia mouse.
Fig. 5: the survivorship curve figure of different disposal group MLL-AF9 second transplant mouse.
●: control group；■: chemotherapy group；▲: VPA processing group；◆: chemotherapy combined VPA processing group.
Fig. 6: different disposal group MLL-AF9 second transplant mouse different time points leukocyte counts curve graph.
●: control group；■: chemotherapy group；▲: VPA processing group；▼: chemotherapy combined VPA processing group.
Fig. 7: different disposal group MLL-AF9 second transplant mouse bone marrow cells MLL-AF9 positive cell number histogram.
Fig. 8: different disposal group MLL-AF9 second transplant mouse spleen variation diagram.
It is left: MLL-AF9 positive cell number histogram；
In: spleen weight histogram；
It is right: Spleen anatomy sample schematic diagram.
Fig. 9: different disposal group MLL-AF9 second transplant mouse peripheral blood MLL-AF9 positive cell number.
Specific embodiment
Below by embodiment, the present invention is described in further detail, it is intended to limit this for illustrating rather than Invention.It should be pointed out that those skilled in the art, it without departing from the principle of the present invention, can also be to this hair Bright some improvement and modification can also be carried out, these improvement and modification are similarly fallen under the scope of the present invention.
Embodiment 1: low histon deacetylase (HDAC) 3 is struck in targeting can enhance adriamycin to the apoptosis of K562 adriamycin-resistant cell Inductive effect.
The present embodiment is struck low using children purpura nephritis (shRNA, carrier pLVX-shRNA2 are purchased from Clontech company) (hereinafter referred to as KA is thin for K562 adriamycin-resistant cell (cell is purchased from hematology research institute, blood disease hospital, the Chinese Academy of Medical Sciences) Born of the same parents) in histon deacetylase (HDAC) 3 (HDAC3) expression, and with western blotting technique verifying strike poor efficiency.
With 2 × 105Cell is resuspended in the density of/ml, different processing modes is taken, then in 24 hours, 48 hours and 72 Hour collects cell, uses the ratio of mono- dye method flow cytometer detection positive cell (i.e. apoptotic cell) of Annexin V-APC.
Each processing group is KA groups of cells respectively, and KA cell HDAC3 strikes low group, and KA cell HDAC3 strikes low and uses 0.5 μ g/ Ml adriamycin processing group, KA cell HDAC3 strike low and use 1.0 μ g/ml adriamycin processing groups, and KA cell HDAC3 strikes low and makes With 2.0 μ g/ml adriamycin processing groups.
Annexin V-APC Staining Protocol is as follows: (1) collecting single cell suspension, be centrifuged and clean cell 2 with ice-cold PBS Time；(2) 1 × 10 is taken5Cell is resuspended in 100 μ 1 × binding of l buffer, and 2 μ l of Annexin V-APC is added；(3) room Temperature is protected from light incubation 15 minutes, and 300 μ l 1 × binding buffer, flow cytometer detection is then added.
Testing result is as shown in Figure of description 1.Wherein attached drawing 1 (A) is respectively from left to right control group, and HDAC3 strikes low Group, HDAC3 strike low and 0.5 μ g/ml adriamycin processing group of use, and HDAC3 strikes low and 1.0 μ g/ml adriamycin processing groups of use, HDAC3 strikes low and uses 2.0 μ g/ml adriamycin processing groups.It is from top to bottom respectively to handle for 24 hours, 48 hours and 72 hours Group.The variation of Apoptosis under each processing mode of histogram graph representation in attached drawing 1 (B).
From Figure of description 1 as can be seen that striking the HDAC3 in low KA cell, adriamycin under various concentration can be increased and drawn The KA Apoptosis risen.Therefore, HDAC3 strikes the low KA cell that increases to the sensibility of adriamycin.
Embodiment 2: targeted inhibition histon deacetylase (HDAC) 3 can enhance cytarabine to the apoptosis induction of THP-1 cell Effect.
The present embodiment is with 2 × 105THP-1 cell (cell is purchased from Chinese Academy of Sciences's cell bank) is resuspended in the density of/ml, takes difference Processing mode use the bis- dye method flow cytometer detections sun of Annexin V-FITC/PI then in 24 hours and 48 hours collection cells The ratio of property cell (i.e. apoptotic cell).
Each processing group is control group respectively, and cytarabine (hereinafter referred to as Ara-c) processing group, (HDAC3 is special by RGFP966 Property inhibitor) processing group, Ara-c and RGFP966 Combined Treatment group.Wherein Ara-c concentration is 5 μM, and RGFP concentration is 2 μM.
Annexin V-FITC/PI Staining Protocol is as follows: (1) collecting single cell suspension, be centrifuged and cleaned carefully with ice-cold PBS Born of the same parents 2 times；(2) 1 × 10 is taken5Cell is resuspended in 100 μ 1 × binding of l buffer, and it is each that Annexin V-FITC and PI is added 2μl；(3) room temperature is protected from light incubation 15 minutes, and 300 μ l 1 × binding buffer, flow cytometer detection is then added.
Testing result is as shown in Figure of description 2.Wherein attached drawing 2 (A) is respectively control group, Ara-c processing from left to right Group, RGFP966 processing group, Ara-c and RGFP966 Combined Treatment group.It is from top to bottom respectively 24 hours and 48 hours processing groups. The variation of Apoptosis under each processing mode of histogram graph representation in attached drawing 2 (B).
From Figure of description 2 as can be seen that exclusive use Ara-c or RGFP966 has no THP-1 cell and significantly withers When dying inductive effect, but Ara-c and RGFP966 is used in combination, obvious apoptosis occurs for THP-1 cell.
Embodiment 3: low histon deacetylase (HDAC) 3 is struck in targeting can increase KA cell to the sensibility of adriamycin.
In the present embodiment, after KA cell and use control virus or HDAC3 specifically strike low virus infection, tried using CCK-8 Agent box (kit is purchased from eastern Renhua subject skill (Shanghai) Co., Ltd.) detects IC50 value of the adriamycin to each cell, and (half inhibits Rate).
Be the principle of CCK-8 detection cell survival and proliferation below: containing WST -8 in CCK-8 reagent, it can be in cell High water soluble yellow formazan product (Formazan) is reduced under the action of mitochondrial dehydrogenase.The number of generation formazan product It measures directly proportional to the quantity of living cells.Then the absorbance value (A) at 450nm wavelength is detected with enzyme-linked immunosorbent assay instrument, i.e., It can reflect the quantity of living cells.
Logarithmic growth phase cell adjusts concentration, with every hole 2 × 104For a cell inoculation in 96 orifice plates, volume is 90 μ l. And zeroing hole is set and (culture medium of 100 μ l is only added；Since the adriamycin used has autofluorescence, when experiment is related to Ah When mycin, zeroing hole be+10 μ l respective concentration of 90 μ l culture medium adriamycin), control wells (cell, drug dissolving medium, culture Liquid totally 90 μ l) and various concentration dosing group (3 multiple holes are arranged in every kind of concentration, and the drug concentration of KA and KA vector group is respectively 10, the drug concentration of 20,30,40,50,60,70,80 μ g/ml, KA shHDAC3 groups is 0.5,1,2,3,4,5,6,8,10 μ g/ Ml), every pore system is 100 μ l.The sterile PBS of 100 μ l is added in the blank well that makes a circle in experimental port week, prevents thin in incubation Cytosol evaporation, interference experiment result.37 DEG C are continued to cultivate.10 μ l CCK-8 reagents are added in every hole after 48 hours, continue to cultivate 4h, Completely after colour developing, absorbance (A) value in every hole is detected at 450nm with microplate reader.Every 3 holes take mean value, are as a result pressed down with cell Rate processed indicates: inhibiting rate (%)=100- (A sample-A blank)/(A control-A blank) × 100%.And it is calculated using software IC50 value.
Testing result is as shown in Figure of description 3.From Figure of description 3 as can be seen that targeting strike low HDAC3 after, KA is thin Born of the same parents increase the sensibility of adriamycin.
Embodiment 4: histon deacetylase (HDAC) inhibitor sodium vedproate can enhance cytarabine to the white blood of MLL-AF9 mouse The apoptosis induction effect of sick cell.
In the present embodiment, MLL-AF9 fusion leukemia mouse model is initially set up.
The specific method is as follows: (it is limited that mouse is purchased from Shanghai Si Laike experimental animal to the C56BL/6 mouse of execution 6-8 week old Company), separate two sides femur and shin bone.Femur and shin bone are placed in culture dish, drawn with syringe containing 2% fetal calf serum DMEM culture medium blows out marrow, and blows and beats repeatedly for several times, obtains single bone marrow cell suspension, is then filtered with 70 micron screens Cell suspension.Bone marrow cell suspension is centrifuged, precipitating is collected.Obtained bone marrow cell magnetic bead sorting buffer is resuspended, Cell concentration is counted, suitable anti-mouse CD117 magnetic bead is then added, is incubated for 20 minutes on ice, concussion in every 5 minutes mixes.So 30 milliliters of magnetic bead sorting buffer solution for cleaning are added afterwards, centrifugation obtains cell precipitation.It is resuspended with 0.5-1 milliliters of magnetic bead sorting buffers Cell, carries out magnetic bead sorting, and enrichment obtains the bone marrow cell of the CD117 positive.(culture completely is resuspended with complete medium after centrifugation Based component: 20% fetal calf serum, 5%WEHI-3B cells and supernatant, 1 × Pen .- Strep, 1 × glutamine, The 100ng/ml mouse stem cells factor, 10ng/ml mouse interleukin-13, the small mIL6 of 10ng/ml are supplied with IMDM).Use table Retroviral cell up to MLL-AF9 is infected, and 24 as a child superinfections are primary.Cell is injected through mouse tail vein and is passed through In the C57BL/6 Mice Body of lethal dose (800cGy) irradiation.The leucocyte of peripheral blood expressing green fluorescent protein is detected weekly Ratio, for judging the incidence of mouse leukemia, as first generation MLL-AF9 leukemia mouse.
When receptor C57BL/6 mouse peripheral blood green fluorescent protein positive cell ratio reaches 80% or so, show It is leukaemia morbidity latter stage.Mouse is put to death, separates the leukaemia cell in two sides femur and shin bone, and use complete medium With 1 × 106/ ml density is resuspended cell and, then in 48 hours collection cells, uses Annexin using different processing modes The ratio of the bis- dye method flow cytometer detection positive cells (i.e. apoptotic cell) of V-PE/7-AAD.Each group is respectively control group, Ara-c processing Group, sodium vedproate (VPA, a kind of hdac inhibitor) processing group, Ara-c and VPA Combined Treatment group.Ara-c concentration is 5nm, VPA Concentration is 0.2mM.
Testing result is as shown in Figure of description 4.From Figure of description 4 as can be seen that Ara-c or VPA is used alone When having no apparent apoptosis induction effect to MLL-AF9 mouse leukemia cell, but Ara-c and VPA be used in combination, cell hair Raw obvious apoptosis.
Embodiment 5: histon deacetylase (HDAC) inhibitor sodium vedproate combined chemotherapy has significant response to treatment to leukaemia.
In the present embodiment, the leukaemia cell of first generation MLL-AF9 leukemia mouse is separated, through tail vein injection by non- In the C57BL/6 Mice Body of lethal dose (400cGy) irradiation, it is configured to second generation MLL-AF9 leukemia mouse model.Transplanting 1 By mice group after week, take different processing modes respectively: control group (is used ● indicate, mouse quantity is 15), chemotherapy group (mouse gives cytarabine and adriamycin processing, is indicated with ■, and mouse quantity is 15), (mouse gives VPA to VPA processing group Processing, with ▲ indicate, mouse quantity is 15), (mouse gives cytarabine to chemotherapy combined VPA group, and adriamycin and VPA are common Processing is used ◆ or ▼ is indicated, mouse quantity is 15).Dosage and time are as follows: cytarabine 100mg/kg × 5 day, Ah mould Plain 3mg/kg × 3 day, 300mg/kg × 5 day VPA.
Figure of description 5 shows the Survival of detection each group mouse.As shown in figure 5, compared with the control group, VPA Processing can be with the life cycle of mild prolonged mouse, but without obvious statistical difference.Chemotherapy can significantly extend the existence of mouse Phase, and chemotherapy and VPA joint further significantly can extend life cycle.
Figure of description 6 shows the quantity of monitoring peripheral blood leukocytes weekly after transplanting, wherein every group comprising 5 small Mouse.As shown in fig. 6, chemotherapy can reduce the quantity of peripheral white blood cells, and chemotherapy and VPA joint can further decrease peripheral blood The quantity of leucocyte.
21 days after transplanting, part leukemia mouse, the bone marrow cell in the left and right femur and humerus of separating mouse, meter are put to death The quantity of MLL-AF9 Positive Leukemic Cells in number bone marrow cell, wherein every group includes 3 mouse.As shown in fig. 7, chemotherapy and Leukaemia cell's quantity of the MLL-AF9 positive is substantially less than other each groups in VPA joint group mouse bone marrow cells.
21 days after transplanting, part leukemia mouse is put to death, the weight of spleen is taken pictures and weighed to the spleen of separating mouse, counts The quantity of MLL-AF9 Positive Leukemic Cells in number spleen, wherein every group includes 3 mouse.As shown in figure 8, chemotherapy and VPA connection The leukaemia cell's quantity for being combined the MLL-AF9 positive in mouse spleen is substantially less than other each groups, and the important and body of spleen Product is also closer to normal.
21 days after transplanting, the quantity of MLL-AF9 Positive Leukemic Cells in peripheral blood is counted, wherein every group includes 5 small Mouse.As shown in figure 9, leukaemia cell's quantity of chemotherapy and the VPA joint group mouse peripheral blood MLL-AF9 positive is substantially less than other Each group.

Claims (9)

1. a kind of for treating the combination medicine of leukaemia, the drug includes 3 inhibitor of histon deacetylase (HDAC) RGFP966 and leukaemia conventional chemotherapy drug cytarabine or adriamycin.
2. combination medicine according to claim 1, wherein 3 inhibitor RGFP966 of histon deacetylase (HDAC) is oral Preparation, leukaemia conventional chemotherapeutic drugs are intravenous injection injection.
3. combination medicine according to claim 2, the oral preparation is capsule or tablet.
4. application of the described in any item combination medicines of the claims in the drug of preparation treatment leukaemia, wherein white Blood disease is acute myeloid leukemia.
5. application according to claim 4, wherein leukaemia be recurrent, intractable or drug tolerance leukaemia.
6. application according to claim 4, wherein 3 inhibitor RGFP966 of histon deacetylase (HDAC) is oral preparation, white Blood disease conventional chemotherapeutic drugs are intravenous injection injection.
7. application according to claim 6, the oral preparation is capsule or tablet.
8. combination medicine according to any one of claim 1-3, wherein 3 inhibitor of histon deacetylase (HDAC) The dosage of RGFP966 is to take orally daily 50-500mg；The routine dose of leukaemia conventional chemotherapeutic drugs cytarabine intravenous injection For daily 20-250mg, continuous use 5-14 days, or large dosage daily 1-6g, continuous use 3 days；The use of Doxorubicin intravenous injections Measuring is daily 20-90mg, continuous use 3 days.
9. the application according to any one of claim 4-7, wherein 3 inhibitor RGFP966 of histon deacetylase (HDAC) Dosage is to take orally daily 50-500mg；The routine dose of leukaemia conventional chemotherapeutic drugs cytarabine intravenous injection is daily 20- 250mg, continuous use 5-14 days, or large dosage of daily 1-6g, continuous use 3 days；The dosage of Doxorubicin intravenous injections is daily 20-90mg, continuous use 3 days.
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