CN115531391B - Medicine for treating leukemia and application - Google Patents
Medicine for treating leukemia and application Download PDFInfo
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- CN115531391B CN115531391B CN202211368912.5A CN202211368912A CN115531391B CN 115531391 B CN115531391 B CN 115531391B CN 202211368912 A CN202211368912 A CN 202211368912A CN 115531391 B CN115531391 B CN 115531391B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention relates to a medicament for treating leukemia and application thereof, wherein the active ingredients in the medicament composition at least comprise homoharringtonine and can also comprise a BCL-2 inhibitor, in particular to vitamin Narcola. The medicine has obvious curative effect on early precursor T acute lymphoblastic leukemia. The invention provides a better new medicine for treating early precursor T cell acute lymphoblastic leukemia clinically, and has good application prospect for clinical treatment of early precursor T acute lymphoblastic leukemia.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a medicine for treating early precursor T lymphocyte leukemia.
Background
Early precursor T-lymphocytic leukemia (Early T-cell precursor acute lymphoblastic leukemia, ETP-ALL) is a newly established special subtype of acute T-lymphocytic leukemia (T-ALL) in recent years, and has a characteristic immunophenotype. The currently internationally recognized immunophenotype of ETP-ALL is the lack of expression of CD1a, CD4, CD8, CD5, while at least one marker of myeloid lineage or stem cells, including CD11b, CD13, CD33, CD34, CD65 or HLA-DR1, is present. Studies have shown that ETP-ALL accounts for about 35% of adult T-ALL, and has poorer prognosis, and the complete remission rate and overall survival are far lower than those of non-ETP-ALL patients, and the recurrence rate is higher than those of non-ETP-ALL patients, so ETP-ALL is considered to be a high-risk subtype of adult T-ALL.
The current treatment of ETP-ALL is still mainly based on T-ALL traditional combined chemotherapy, and due to the special immunophenotype of ETP-ALL, researches show that compared with non-ETP-ALL, ETP-ALL is often accompanied with mutation of family genes such as cytokine receptor/RAS signal pathway, blood system development, histone modification and the like in genetics, so that ETP-ALL patients cannot obtain good clinical treatment effect under the current treatment means, and the ETP-ALL has low remission rate, high recurrence rate and short overall survival. There is a need to explore new therapeutic agents and treatment regimens for ETP-ALL. Studies show that the anti-apoptosis protein BCL2 is highly expressed by ETP-ALL patients, and the application of the vitamin E-ALL 2 inhibitor on ETP-ALL cells has better anti-tumor activity than that of the quasi-marketed BCL2 inhibitor, which suggests that BCL2 can be an optional therapeutic target of ETP-ALL, and the targeted inhibitor vitamin E is also an optional drug for ETP-ALL treatment.
Homoharringtonine (HHT), which is a cytotoxic alkaloid derived from cephalotaxus species, has a remarkable anti-hematological tumor effect and has been used for more than 30 years in combination with other drugs for AML treatment, with good results. The first nationwide multicenter, prospective, open and random contrast III-phase study is developed in the domestic blood field through the center lead, and the 'HAA' scheme taking HHT as a core medicament is also written into the Chinese AML treatment guide as a first-line scheme of the treatment of the domestic AML. HHT has been approved by the FDA in the United states for the treatment of chronic myelogenous leukemia. However, there is no current study on the therapeutic response of HHT in T-ALL, either alone or in combination.
There is no relevant report on the treatment of ETP-ALL by HHT in combination with Venezucchini.
Disclosure of Invention
The invention aims to solve the technical problems and provides a novel medicine for treating early precursor T lymphocyte leukemia, in particular to homoharringtonine and a vitamin naituo gram combined with a BCL-2 inhibitor thereof. Including ETP-ALL cell lines, primary cells, ETP-ALL animal models, and the like.
The homoharringtonine has a structural formula shown below, and is an alkaloid extracted and separated from harringtonine or its congeneric plants. Pharmacological studies show that homoharringtonine has remarkable anti-tumor activity, has anti-tumor activity in solid tumors and blood system tumors, and is first-line medicine in AML treatment.
The valnemulin has the structural formula shown below, is a selective BCL-2 targeted inhibitor, and is clinically an oral preparation. Including valnemulin manufactured by ibovi corporation, as well as other BCL-2 inhibitors manufactured by other pharmaceutical companies. Pharmacological studies show that valnemulin has remarkable anti-tumor activity and has remarkable anti-tumor activity in AML.
The invention discloses a brand new combination scheme for treating ETP-ALL by combining homoharringtonine with BCL-2 inhibitor vitamin Netropine for the first time, which comprises the effects of synergistically inhibiting proliferation, promoting apoptosis and prolonging survival time of mice. In particular, the invention discloses an application of homoharringtonine combined with BCL-2 inhibitor valnemulin in preparing a medicament for treating ETP-ALL cell lines.
Further, the invention discloses application of homoharringtonine combined with BCL-2 inhibitor valnemritol in preparation of medicines for treating primary ETP-ALL cells.
Furthermore, the invention discloses application of homoharringtonine and vitamin E Tokyo combined with BCL-2 inhibitor in preparation of medicines for treating ETP-ALL CDX model.
In the invention, homoharringtonine and BCL-2 inhibitor single drugs can be prepared into various pharmaceutically acceptable dosage forms with pharmaceutically acceptable auxiliary materials, such as injection, tablet, capsule and other dosage forms well known to those skilled in the pharmaceutical field, and the two drugs can be combined to prepare a composite preparation.
The beneficial effects of the invention are as follows: the medicine and the combination thereof can synergistically treat the early precursor T acute lymphoblastic leukemia, and have obvious curative effect on the early precursor T acute lymphoblastic leukemia. The invention provides a better new medicine for treating early precursor T cell acute lymphoblastic leukemia clinically, and has good application prospect for clinical treatment of early precursor T acute lymphoblastic leukemia.
Drawings
FIG. 1 is a graph showing the results of inhibition of cell proliferation of ETP-ALL cell lines by homoharringtonine and its combination, wherein A is a bar graph of inhibition of ETP-ALL cell lines Loucy by different concentrations of vitamin Natuk (VEN), HHT single drug and its combination. B is a collaborative index table of different concentration of vitamin Natropine (VEN) combined HHT to ETP-ALL cell strain Loucy calculated by CompuSyn collaborative calculation software.
FIG. 2 is a graph showing the results of the effects of homoharringtonine and its combination on apoptosis in ETP-ALL cell lines, wherein A is a flow chart of the effects of vitamin Natropine (VEN) 50nmol/L, HHT20ng/ml single and combination on apoptosis in ETP-ALL cell lines. B is a bar graph of 50nmol/L of vitamin Nadotox (VEN), 20ng/ml of HHT single medicine and combination, 75nmol/L of vitamin Nadotox (VEN), 30ng/ml of HHT single medicine and combination on the Loucy apoptosis effect of ETP-ALL cell line cells.
FIG. 3 is a graph showing the results of inhibition of ETP-ALL primary cell proliferation by homoharringtonine and its combination with vitamin A, wherein A is a bar graph of the inhibition of ETP-ALL primary patient by different concentrations of vitamin A Toke (VEN), HHT single drug and its combination. B is a collaborative index table of the ETP-ALL primary patient cells by calculating the vitamin Netuk (VEN) combined HHT with different concentrations through CompuSyn collaborative calculation software.
FIG. 4 is a graph showing the results of apoptosis of ETP-ALL primary cells by homoharringtonine and its combination with Veneticla, wherein A is a flow chart of apoptosis of ETP-ALL primary patients by Veneticla (VEN) 0.4. Mu. Mol/L, HHT 16ng/ml single drug and its combination. B is a histogram of the effect of vitamin Nadotox (VEN) 0.4. Mu. Mol/L, HHT 16ng/ml single and combination on ETP-ALL primary apoptosis.
FIG. 5 is a graph showing the results of inhibition of ETP-ALL animal models by homoharringtonine and its combination with valicarb, wherein A is a flow chart of the mice experiments with Valicarb (VEN), HHT single drug and combination CDX models. B is a histogram of tumor burden in ETP-ALL CDX model mice before and after Winetolk (VEN), HHT single drug and combination therapy. C is a survival chart of ETP-ALL CDX model mice in comparison with survival time of treatment with single drug and combined drug of Winetoloch (VEN).
Detailed Description
To further illustrate the present invention, the use of homoharringtonine and its combination valnemulin according to the present invention for the treatment of early precursor T-lymphoblastic leukemia is described in detail below with reference to the examples.
EXAMPLE 1 inhibition of cell proliferation of ETP-ALL cell lines by homoharringtonine in combination with Venezucchine of the invention
(1) Cell culture and test grouping
The cell culture medium is RPMI-1640 medium containing 10% fetal bovine serum, the cultured LOUCY cells are counted after trypan blue staining, and 0.2X10 cells are inoculated in each well of a 96-well cell culture plate 6 200. Mu.L of LOUCY cells, 37℃and 5% CO 2 Pre-incubation was performed for 24h with drug added for testing. The test was divided into 3 groups in total: homoharringtonine group; a set of valnemulin; combination groups. The drug concentrations added to each test group were: the homoharringtonine group HHT concentrations were 10ng/mL,20ng/mL,30ng/mL,40ng/mL, and the Venezuela concentrations, respectively: drug concentration in combination of 0.025. Mu. Mol/L, 0.05. Mu. Mol/L, 0.075. Mu. Mol/L, 0.100. Mu. Mol/L: homoharringtonine: the Venezuela is respectively 10ng/mL, 0.025 mu mol/L,20ng/mL, 0.05 mu mol/L,30ng/mL, 0.075 mu mol/L and 40ng/mL, and 0.10 mu mol/L. Each of the above groups was tested at 37℃with 5% CO 2 After 24h of incubation, 60. Mu.l of each was added to the black bottom plate, and then 60. Mu.L of the LCellTiter-Glo reagent was added to 60. Mu.L of the cell-containing medium. Mixing, placing the plate under room temperature, incubating for 10 minutes in dark, and measuring the luminescence value by using a FilterMax F5 type multifunctional micropore plate reader. The test was repeated 3 times and the relative cell viability = experimental group mean luminescence/control group mean luminescence, proliferation inhibition (%) = (1-experimental group average luminescence value/control group average luminescence value) ×100%.
(2) Test results
The results of the relative cell viability after 24 hours of dosing for each test group are shown in figure 1, which shows significantly stronger inhibition of Loucy cells by the combination of vitamin necpra and HHT than the single drug group treated with vitamin necpra (figure 1A). Further, by analysis of CompuSyn cooperative computing software, the combined concentrations of the Winescra and the HHT have a cooperative effect on Loucy, and the cooperative index is less than 1, which shows that the combined concentrations have a remarkable cooperative effect (figure 1B).
EXAMPLE 2 effects of homoharringtonine in combination with Venezuccharan on apoptosis of ETP-ALL cell lines according to the invention
(1) Cell culture and grouping
The cell culture medium is RPMI-1640 medium containing 10% fetal bovine serum, the cultured LOUCY cells are counted after trypan blue staining, and each well is inoculated with 1×10 in 24-well cell culture plate 6 LOUCY cells/mL, 37 ℃, 5% CO 2 Pre-incubation was performed for 24h with drug added for testing. The test was divided into 3 groups in total: homoharringtonine group; a set of valnemulin; combination groups. The drug concentrations added to each test group were: homoharringtonine group: HHT concentrations were 20ng/mL, respectively, for the Winegram group: venezuki concentration: drug concentration of combination drug at 0.05. Mu. Mol/L: homoharringtonine: winescla is 20ng/mL and 0.05 mu mol/L respectively. Each of the above groups was tested at 37℃with 5% CO 2 Cells were collected after culturing for 24 hours under the condition, washed with annexin v1 x buffer 1ml and resuspended.
(2) Apoptosis detection
The cell suspension 100. Mu.l after 24 hours of the above experimental groups was taken by PE-Annexin V/DAPI method, and the cell suspension was stained with PE-Annexin V antibody at room temperature for 15 minutes in a dark place, washed 1 time with Annexin V1 Xbuffer 1ml, centrifuged to discard the supernatant, and stained with 300. Mu.l of a pre-prepared mixed reagent (Annexin V1 Xbuffer+DAPI 2000:1). Finally, the detection is carried out by a flow cytometer. The above experiments were repeated 3 times. The apoptosis rate of LOUCY cells was calculated for 24 hours in each experimental group.
(3) Test results
The experimental results of inducing apoptosis of LOUCY cells in each experimental group are shown in fig. 2, compared with the single drug group treated by the vitamin and the HHT, the apoptosis promoting effect of the vitamin and the HHT combined with each other on the Loucy cells is obviously stronger than that of the single drug group (fig. 2A), and the difference has obvious statistical significance, as shown in the bar graph of fig. 2B.
EXAMPLE 3 inhibition of ETP-ALL primary cell proliferation by homoharringtonine in combination with Venezucchine of the present invention
(1) Primary isolation, culture and test grouping
Taking 5ml of bone marrow liquid of an ETP-ALL patient which is not treated, and separating ETP-ALL cells by using a density gradient centrifugation method, wherein the specific steps are as follows: taking a sterile 15ml centrifuge tube, adding 5ml of lymphocyte separation liquid, sucking 5ml of bone marrow liquid of an ETP-ALL patient by using a syringe, slowly adding the centrifuge tube along the wall of the centrifuge tube, centrifuging for 20 minutes at 2000 rpm, and sucking white membrane layer cells at the junction of the lymphocyte separation liquid and serum to obtain an ETP-ALL cell layer. The cell culture medium is RPMI-1640 culture containing 10% fetal bovine serum, the isolated primary cells are counted after trypan blue staining, and 0.2X10 cells are inoculated in 96-well cell culture plate 6 200. Mu.L of isolated primary cells, 37℃and 5% CO 2 Pre-incubation was performed for 24h with drug added for testing. The test was divided into 3 groups in total: homoharringtonine group; a set of valnemulin; combination groups. The drug concentrations added to each test group were: the HHT concentration of the homoharringtonine group was 8ng/mL,16ng/mL,24ng/mL,32ng/mL, and the Venezuela concentration, respectively: drug concentration of combination drug at 0.2. Mu. Mol/L, 0.4. Mu. Mol/L, 0.6. Mu. Mol/L, 0.8. Mu. Mol/L: homoharringtonine: the Venezuela is 8ng/mL, 0.2. Mu. Mol/L,16ng/mL, 0.4. Mu. Mol/L,24ng/mL, 0.6. Mu. Mol/L,32ng/mL, 0.8. Mu. Mol/L, respectively. Each of the above groups was tested at 37℃with 5% CO 2 After 24h of incubation, 60. Mu.l of the black bottom plate was added, followed by 60. Mu.l of CellTiter-Glo reagent to 60. Mu.l of cell-containing medium. Mixing, placing the plate under room temperature, incubating for 10 minutes in dark, and measuring the luminescence value by using a FilterMax F5 type multifunctional micropore plate reader. The test was repeated 3 times, cell relative viability = experimental group mean luminescence value/control group mean luminescence value, proliferation inhibition rate(%) = (1-average luminescence value of experimental group/average luminescence value of control group) ×100%.
(2) Test results
The results of the relative cell viability after 24 hours of dosing for each test group are shown in FIG. 3, which shows significantly greater inhibition of primary cells by the Wilnaclar in combination with HHT than by the Wilnaclar, HHT treatment alone (FIG. 3A). Further, by analysis of CompuSyn cooperative computing software, the combined concentrations of the Wineskora and HHT have a cooperative effect on primary cells, and the cooperative index is less than 1, which shows that the combined concentrations have a remarkable cooperative effect (FIG. 3B).
EXAMPLE 4 apoptosis of ETP-ALL Primary cells by homoharringtonine in combination with Venezucchini according to the invention
(1) Primary isolation, culture and test groups were as in example 3.
(2) Apoptosis detection
The cell suspension 100. Mu.l after 24 hours of the above experimental groups was taken by PE-Annexin V/DAPI method, and the cell suspension was stained with PE-Annexin V antibody at room temperature for 15 minutes in a dark place, washed 1 time with Annexin V1 Xbuffer 1ml, centrifuged to discard the supernatant, and stained with 300. Mu.l of a pre-prepared mixed reagent (Annexin V1 Xbuffer+DAPI 2000:1). Finally, the detection is carried out by a flow cytometer. The above experiments were repeated 3 times. The apoptosis rate of primary ETP-ALL was calculated for 24 hours in each experimental group.
(3) Test results
The experimental results of the induction of apoptosis of primary ETP-ALL cells in each experimental group are shown in FIG. 4. Compared with the single drug group treated by the vitamin and HHT, the apoptosis promotion effect of the vitamin and HHT combined with the vitamin and HHT on the primary ETP-ALL cells is obviously stronger than that of the single drug group (figure 4A), and the difference has obvious statistical significance, as shown in a bar graph of figure 4B.
EXAMPLE 5 inhibition of ETP-ALL animal models by homoharringtonine in combination with Venezucchini according to the invention
(1) Establishing mouse ETP-ALL model
Selecting 24 female immunodeficiency mice NSG mice of 6-8 weeks of week age, irradiating with 200cGy, and processing according to 2×10 6 Mouse ETP-ALL model was constructed by intravenous injection of LOUCY cells from rat tail. MovingMouse venous blood is collected through the eye socket after 3 weeks of implantation, human CD45 antibody is marked after erythrocyte lysis, and a flow cytometer is used for detecting the implantation condition of tumor cells. Then, blood is drawn and detected every 2 weeks, 24 mice are randomly divided into 4 groups until the proportion of the human CD45 cells in the peripheral blood reaches about 1%, and the groups are respectively as follows: a treatment group of vitamin naiclar + homoharringtonine, a treatment group of vitamin naiclar; homoharringtonine-treated group, control group. Wherein, the valnemulin is infused in the cyclodextrin according to the dosage of 25mg/kg after being emulsified, the homoharringtonine is infused in the abdomen according to the dosage of 1mg/kg after being diluted by PBS, and the control group is infused in the stomach by cyclodextrin and injected in the PBS for 10 days continuously. Peripheral blood of each group of mice is collected before and after medication, tumor load in the peripheral blood is detected, and survival conditions of each group of mice are followed.
(2) Test results
The Zhou Xiezhong tumor burden and survival results of mice in each group before and after treatment are shown in fig. 5, compared with the single drug group treated by the vitamin and the HHT, the tumor burden of mice can be reduced by combining the vitamin and the HHT (fig. 5B), and the survival time of the mice can be prolonged remarkably (fig. 5C).
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary or exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.
Claims (2)
1. The application of a pharmaceutical composition consisting of homoharringtonine and BCL-2 inhibitor vitamin-Toxotrope in preparing medicines for treating early precursor T cell lymphoblastic leukemia.
2. The use according to claim 1, wherein the homoharringtonine drug in the pharmaceutical composition is an injection, a capsule or a tablet.
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| Venetoclax and decitabine in refractory TP53-mutated early T-cell precursor acute lymphoblastic leukemia;Jinyu Kong等;Annals of hematology;第101卷;第697-699页 * |
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