CN112168829B - Application of antiviral drug in preparation of drug for treating myelodysplastic syndrome and prepared myelodysplastic syndrome drug - Google Patents
Application of antiviral drug in preparation of drug for treating myelodysplastic syndrome and prepared myelodysplastic syndrome drug Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- 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
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Abstract
The invention discloses an application of an antiviral drug in preparing a drug for treating myelodysplastic syndrome and the prepared myelodysplastic syndrome drug. The antiviral drug is famciclovir. The invention firstly defines the influence of famciclovir on hematopoietic development in zebra fish model organisms, and famciclovir can cause defects of the whole blood system by influencing hematopoietic stem-progenitor cells. Therefore, the invention provides the application of famciclovir antiviral drug in preparing drugs for treating myelodysplastic syndrome.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to application of an antiviral medicament in preparation of a medicament for treating myelodysplastic syndrome and the prepared myelodysplastic syndrome medicament.
Background
Famciclovir (FCV) is an oral prodrug of Penciclovir (PCV), a guanosine-like antiviral drug commonly used to treat viral infections. FCV is rapidly converted to PCV in vivo, and then PCV is gradually phosphorylated to a biologically active form, PCV triphosphate, mediated by viral thymidine kinase, and subsequently by host cell kinases. Active PCV triphosphate acts as a dGTP analogue, inhibiting viral DNA synthesis. In the clinic, FCV is reported for antiviral treatment after bone marrow transplantation, in particular to protect Hepatitis B Virus (HBV) infected patients. PCV is reported to have myelotoxicity (Haynes, P., Lambert, T.R., and Mitchell, I.D. (1996). comprehensive in-vivo genetic oxidation of antiviral nucleic acids analytes; pentaclovir, acyclovir, cancetilovir and the xanthine antibody, caffeine, in the mouse bone marrow tissue of Mutat Res 369,65-74.), but it is unclear whether and how FCV affects hematopoietic cells in vivo.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide an application of an antiviral medicament in preparing a medicament for treating myelodysplastic syndrome and the prepared myelodysplastic syndrome medicament.
The invention aims to determine the influence of an antiviral medicament on hematopoietic cells in vivo and proposes the possibility of the antiviral medicament as a medicament for treating myelodysplastic syndrome.
The object of the present invention is to determine the effect of famciclovir on hematopoietic cells in vivo by using zebrafish model animals and to propose it as a possibility for the treatment of myelodysplastic syndrome.
The purpose of the invention is realized by at least one of the following technical solutions.
The myelodysplastic syndrome is caused by abnormal expression of c-myb gene, namely c-mybhyperThe mutation causes.
The antiviral drug is famciclovir which is an oral form of penciclovir.
The general concept of the invention for verifying the possibility of preparing the medicine for treating myelodysplastic syndrome by using the antiviral medicine famciclovir is as follows:
(1) the influence of famciclovir on the hematopoietic development of wild zebra fish embryos is explored by adopting a drug soaking treatment mode;
(2) determining the effect of famciclovir on zebrafish Hematopoietic Stem Progenitor Cells (HSPCs);
(3) determining changes in proliferation and apoptosis of hematopoietic stem progenitor cells using Hoechst assay and AnnexinV/SYTOX assay, respectively;
(4) using c-mybhyperA zebrafish myelodysplastic syndrome (MDS) disease model, and determining whether famciclovir has an effect of relieving MDS.
The antiviral drug provided by the invention is used for preparing the drug for treating myelodysplastic syndrome, and the antiviral drug is famciclovir.
Further, famciclovir is administered at a concentration of 1mM to 5 mM.
Preferably, the famciclovir is administered at a concentration of 5 mM.
Further, the famciclovir is a formulation for oral, intravenous, subcutaneous, intramuscular, topical, intraperitoneal, intranasal, inhalation or intraocular administration.
The application of the antiviral drug in preparing the drug for treating myelodysplastic syndrome provided by the invention comprises the following steps: and mixing famciclovir and auxiliary materials to obtain the medicine for treating myelodysplastic syndrome.
Furthermore, the auxiliary materials are more than one of adhesive, filler, flavoring agent or wetting agent.
The invention provides a medicine for treating myelodysplastic syndrome, which is prepared by the application method.
The medicine for treating myelodysplastic syndrome provided by the invention is decoction, pill, paste, powder, granule, tablet or capsule.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the invention utilizes the advantages of large egg laying amount, in vitro fertilization, transparent embryo and the like of the zebra fish, determines the influence of long-time treatment of high-dose famciclovir on embryo hematopoietic development, and firstly proposes the effect of famciclovir on MDS treatment; FCV is used in the treatment process of MDS, and can play a dual role; on one hand, the medicine can resist virus infection, and on the other hand, the medicine can reduce blood cells abnormally proliferated in MDS, so that the antiviral medicine famciclovir can be used for preparing the medicine for treating myelodysplastic syndrome;
(2) the FCV drug-treated zebrafish embryos of the invention have the following phenotype: firstly, after wild zebrafish embryos are subjected to famciclovir drug treatment, HSPCs are reduced at 3dpf, and hematopoietic lineages are reduced at 5 dpf; secondly, after famciclovir drug treatment is carried out on wild zebra fish embryos, the reduction of HSPCs is caused by inhibited proliferation and increased apoptosis; c-mybhyperAfter famciclovir drug treatment of zebrafish myelodysplastic syndrome (MDS) disease models, abnormally proliferating blood cells are reduced.
Drawings
FIG. 1 is a graph of the effect of directed hematopoiesis after treatment of embryos with famciclovir drug.
FIG. 2 is a graph showing the change in the number of CHT-zone HSPCs after treatment of embryos with famciclovir drug.
FIG. 3 is a graph showing the change in proliferation of HSPCs in the CHT region after treatment of embryos with famciclovir drug.
FIG. 4 is a graph showing the change in apoptosis of CHT-zone HSPCs after treatment of embryos with famciclovir drug.
FIG. 5 is a graph of the change in blood lineage after famciclovir treatment of embryos from a myelodysplastic syndrome zebrafish disease model.
FIG. 6 is a graph of the change in blood lineage after famciclovir treatment in adult fish in a myelodysplastic syndrome zebra fish disease model.
Detailed Description
The following description of the embodiments of the present invention is provided in connection with the accompanying drawings and examples, but the invention is not limited thereto. It is noted that the processes described below, if not specifically described in detail, are all realizable or understandable by those skilled in the art with reference to the prior art. The reagents or apparatus used are not indicated to the manufacturer, and are considered to be conventional products available by commercial purchase.
The terms "wild type" or "WT" as used herein both refer to wild type zebrafish.
The term "dpf" as used herein refers to the number of days after fertilization and "hpf" refers to the hour after fertilization.
Example 1
1. Materials and methods:
(1) zebra fish culture
Zebra fish breeding is described in The literature (Westerfield M. (2000.) The zebrafish book. A guide for The laboratory use of zebrafish (Danio relay). 4th ed. Univ. of Oregon Press, Eugene.).
(2) The following lines were used in the present invention: AB wild type zebrafish, Tg (mpl: GFP) transgenic zebrafish, Tg (cd41: GFP) transgenic zebrafish, Tg (c-myb: GFP) transgenic zebrafish (c-myb)hyperZebrafish myelodysplastic syndrome (MDS) disease model).
(3) Famciclovir drug treatment method
Famciclovir powder was dissolved in DMSO (dimethyl sulfoxide) so the control group added DMSO at the same ratio. Drug treatment embryos (AB wild type zebrafish, Tg (mpl: GFP) transgenic zebrafish, Tg (cd41: GFP) transgenic zebrafish or Tg (c-myb: GFP) transgenic zebrafish) were treated by soaking: the chorion of the embryo was removed with pronase prior to 25 hpf. At 25hpf, famciclovir (5mM) was added at the corresponding concentration and DMSO at the same ratio was used as control. Finally, embryos are collected at specific times and the phenotype of the blood system is examined.
(4) Methods for Overall in situ hybridization and antibody staining to explore the Effect of famciclovir on hematopoietic development of wild-type Zebra fish embryos
Whole in situ hybridization (wheel-mounted in situ hybridization) was performed according to the following standard experimental protocol (Thisse C, Thisse B. (2008). High-resolution in situ hybridization to white-mounted hybridization PROTOCOLS. VOL.3NO. 1).
Antibody staining (Antibody staining) fixed embryos were first incubated overnight (12-16 hours) with goat-derived GFP Antibody (Abcam; ab66580) and stained with anti-goat 488 (Thermo; A11055) fluorescein.
As shown in fig. 1, the expression of each of the hematopoietic lineage cell markers, including β e1-globin (red blood cell marker), mfap4 (macrophage marker), lyz (neutrophil marker) and rag1 (lymphocyte marker), was significantly reduced in the drug-treated group relative to the control group. As can be seen in FIG. 1, the embryo treated with famciclovir was deficient in directed hematopoiesis. In addition, Tg (mpl: GFP) labeled platelets were also significantly reduced in the treated group. Control of FIG. 1 represents a control group; FCV of figure 1 represents famciclovir; hpf of FIG. 1 represents the number of hours after fertilization; dpf in FIG. 1 represents days post fertilization; CHT in figure 1 represents tail hematopoietic tissue. Section a of fig. 1 is the time axis for drug treatment; embryos were given FCV drug treatment at 25hpf and the committed hematopoietic phenotype was examined at 4 or 5 dpf. The overall in situ hybridization results expressed at lyz at 5dpf for part B in fig. 1 were divided into control (left) and FCV famciclovir-treated (right). The lower left corner of each graph represents the proportion of the phenotype represented by this graph. Statistical results for lyz positive cell numbers in control and treatment groups at 5dpf in section C of figure 1 (Student's t test;. P < 0.0001). Overall in situ hybridization results for mfap4 expression at 5dpf in section D of fig. 1 were divided into control (left) and FCV famciclovir-treated (right). The lower left corner of each graph represents the proportion of the phenotype represented by this graph. Figure 1, part E, is a statistic of mfap4 positive cell numbers in control and treatment groups at 5dpf (Mann-Whitney U test;. P < 0.0001). FIG. 1F, at 5dpf, shows the results of total in situ hybridization expressed at rag1, which were divided into control (upper panel) and FCV famciclovir-treated (lower panel). The lower left corner of each graph represents the proportion of the phenotype represented by this graph. The overall in situ hybridization results for β e1-globin expression at 5dpf for panel G of FIG. 1 were divided into control (upper panel) and FCV famciclovir-treated panel (lower panel). The lower left corner of each graph represents the proportion of the phenotype represented by this graph. FIG. 1, section H at 4dpf, immunofluorescent staining of eGFP in the tail hematopoietic tissue (CHT) of Tg (mpl: eGFP) embryos. The left side is the control group and the right side is the treatment group. Figure 1, panel I, at 4dpf, is a statistic of the number of GFP positive cells in control and treated groups (Mann-Whitney U test;. P < 0.0001).
(5) Overall in situ hybridization and Sudan Black B staining to determine the Effect of famciclovir on Zebra Fish Hematopoietic Stem and Progenitor Cells (HSPCs)
Dyeing with Sudan black B: fixed embryos were stained in Sudan Black B (Sigma-Aldrich, St Louis, MO, USA; 199664) for 1 hour, and then washed, as described in the previous report (Wang, K.and Z.Huang, et al (2012), "Large-Scale aware Genetic Screening Analysis of Development of hematology in Zebraphis." Journal of Genetics and Genomics 39(9): 473-.
The results are shown in FIG. 2, where after 48 hours of FCV drug treatment HSPCs (c-myb-labeled cells) were affected, while other blood cells, such as neutrophils (SB positive cells), were unaffected, indicating that the deficiency in targeting adult blood cells of various lineages in hematopoiesis may be due to a deficiency in HSPCs. As can be seen in figure 2, the number of HSPCs in CHT decreased abnormally following famciclovir drug treatment. Control of FIG. 2 represents the control group; FCV represents famciclovir treatment group; hpf denotes the number of hours after fertilization. FIG. 2, part A, shows the results of global in situ hybridization of c-myb at 60hpf, with control on the left and treatment (FCV) on the right. Part B of FIG. 2 is a statistical result of the number of c-myb positive cells in the control and treatment groups at 60hpf (Student's t test; ns, no statistical difference). FIG. 2, section C, shows the results of global in situ hybridization of C-myb at 72hpf, with control on the left and treatment on the right. Part D of figure 2 is the statistical result of the number of c-myb positive cells in the control and treatment groups at 72hpf (Student's t test;. P < 0.0001). Part E of FIG. 2 is the result of bulk in situ hybridization of scl at 72 hpf. The control group was on the left side and the treatment group was on the right side. Statistical results of the number of scl positive cells in the control and treatment groups (Student's t test;. P <0.0001) at 3dpf in panel F of figure 2. FIG. 2, panel G, is the SB staining of control and treated group embryos at 72 hpf. The control group was on the left side and the treatment group was on the right side. Statistical results for SB positive cell numbers in control and treatment groups at 3dpf in section H of FIG. 2 (Student's t test; ns, no statistical difference).
(6) Proliferation and apoptosis detection of post-famciclovir-treated embryonic-stage HSPCs
The Hoechst experiment was performed with reference to the description. Transgenic line Tg (cd41: GFP) embryos from control and FCV treated groups were first disaggregated to give single cell suspensions, which were then stained with Hoechst 33342(Sigma-Aldrich) and analyzed by flow cytometry (Beckman MoFlo Astrios EQ, USA).
As shown in FIG. 3, the DNA content of the cells was examined by Hoechst 33342 staining, and it was found that the FCV-treated group GFP was present in comparison with the control group (13.6. + -. 2.3%)lowThe proportion of G2/M phase (27.6. + -. 2.3%) in the cells (labeled HSPCs) increased abnormally, which indicated that the cell cycle of HSPCs in embryos arrested at G2/M phase after FCV treatment. Control of FIG. 3 represents the control group; FCV represents famciclovir treatment group; hpf denotes the number of hours after fertilization. As can be seen in FIG. 3, proliferation of HSPCs in the CHT zone was hindered after FCV treatment. Part A of FIG. 3 is a graph obtained by passing Hoechst 33342Staining assay cd41 eGFPlowThe DNA content of the cell; number of cells on the Y-axis and DNA content on the X-axis. The proportion of the various phases of the cell cycle is shown. Part B of FIG. 3 is a statistical analysis of the cell proportion at each stage (Student's t test; n-3;. P)<0.05)。
Pacific Blue Annexin V/SYTOX AADadvanced double staining experiment used Violet Annexin V/Dead Cell Apoptosis Kit (Invitrogen, USA). The 3dpf transgenic line Tg (cd41: GFP) embryos of the control group and the FCV treated group are decomposed to obtain single cell suspensions, and then GFP positive cells and partial GFP negative cells are separated by a flow cytometer. The selected cells were stained with Pacific Blue Annexin V/SYTOX AADadvanced according to the instructions and finally subjected to flow analysis.
As shown in FIG. 4, Pacific Blue Annexin V/SYTOX AADadvanced staining results show GFP in the FCV-treated grouplow(labeled HSPCs) cells have an increased proportion of annexin V +/SYTOX + double positive cells. These results indicate that the reduction of HSPCs is caused by FCV-induced apoptosis. Control of FIG. 4 represents the control group; FCV represents famciclovir treatment group; hpf denotes the number of hours after fertilization. As can be seen in fig. 4, apoptosis of HSPCs in the FCV treated group was increased. Part A of FIG. 4 is cd41 eGFP at 3dpflowAnnexin V/SYTOX double staining of cells. The values in the pictures contain the percentage of cells in the four quadrants: q1, Q2, Q3, and Q4. The Q4 quadrant (Annexin V-/SYTOX-), the Q3 quadrant (Annexin V +/SYTOX-), the Q2 quadrant (Annexin V +/SYTOX +) and the Q1 quadrant (Annexin V-/SYTOX +) represent the percentage of normal, early, late and necrotic cells, respectively. Part B of fig. 4 is at 3dpf, cd41: eGFPlowStatistical results of the percentage of early and late apoptotic cells of the cells (Student's t test; n-3;. P)<0.05)。
(7) Using c-mybhyper(c-myb overexpression) zebra fish myelodysplastic syndrome (MDS) disease model, and determining the effect of famciclovir on MDS treatment by adopting whole in situ hybridization, Sudan black B staining and flow analysis experiment
FCV treatment was given at 12hpf and then withdrawal at 2.5dpf at embryonic stage, with 3dpf c-myb, 5dpf SB, rag1 and β e1 and 7dpf SB, respectively, being tested.
As shown in FIG. 5, in the embryonic period, the over-production of c-myb and SB-positive neutrophils was reduced in the FCV-drug-treated group compared to the control group, and FCV was likely to be effective in alleviating c-mybhyperMDS-like phenotypes in zebrafish disease models. Control of FIG. 5 represents the control group; FCV represents famciclovir treatment group; dpf represents the number of days post fertilization; hpf denotes the number of hours after fertilization; SB denotes Sudan black staining. As can be seen in FIG. 5, administration of famciclovir effectively ameliorates myelogenous hyperchylia of the myelodysplastic syndrome zebrafish embryos. FIG. 5, part A, is a representation of c-myb after treatment with FCV drughyperOverexpression in (a) is restored. The overall in situ hybridization results for c-myb are shown, with control on the left, treatment (FCV) on the right, wild type on the top and c-myb on the bottomhyper. Part B of FIG. 5 is at 3dpf, at wild type and c-myb, respectivelyhyperStatistical results of the number of c-myb positive cells in the control group and the treatment group (Student's t test;. P;)<0.01，****P<0.0001). FIG. 5C is a graph showing SB staining of embryos at 5dpf, with control group on the left, treatment group on the right, wild type on the upper layer, and C-myb on the lower layerhyper. Part D of FIG. 5 is at 5dpf, at wild type and c-myb, respectivelyhyperStatistical results of SB positive cell numbers in control and treatment groups (Student's t test;. P;)<0.0001). FIG. 5, part E, is the overall in situ hybridization results for rag1 expression at 5dpf, with control on the left, treatment on the right, wild-type in the upper layer, and c-myb in the lower layerhyper. Global in situ hybridization results for rag1 and β e1 expression in control (left) and FCV treated (right) groups at 5 dpf. FIG. 5, panel F, is the global in situ hybridization results for β e1-globin expression at 5dpf, control on the left, treatment on the right, wild type on the upper layer, c-myb on the lower layerhyper. FIG. 5 depicts part G of SB staining of embryos at 7dpf, control on the left, treatment on the right, wild type in the upper layer and c-myb in the lower layerhyper. The area of renal medullary indicated by the dashed circle. Part H of FIG. 5 is renal medullaStatistical results for SB-positive cells of the area (Student's t test; mean. + -. standard deviation;
*P<0.05，****P<0.0001). As can be seen in section G, H of FIG. 5, at 7dpf the FCV was reduced by c-mybhyperIncreased myeloid cells in the middle renal medullary region, but not in the wild-type.
The adult zebra fish is administrated by intraperitoneal injection, the dose is 0.16mg/fish twice a day, the injection is continuously stopped for two days, and the injection is repeated for four times. Renal medulla was collected on day 9 to prepare a cell suspension, and cell components were analyzed by flow cytometry.
As shown in FIG. 6, c-myb in the FCV drug-treated group compared to the control group during adulthoodhyperThe hyperproliferative myeloid lineage cells of zebrafish were reduced, suggesting that FCV may be effective in alleviating adult c-mybhyperMDS-like phenotypes in zebrafish disease models. Taken together, FCV can relieve embryonic and adult c-mybhyperMyelinated phenotype in zebrafish disease models. Control of FIG. 6 represents the control group; FCV represents famciclovir treatment group; precursor represents Precursor cells; lymphocytes represent Lymphocytes; myelonomycocytes represent myeloid cells. As can be seen in fig. 6, FCV was effective in alleviating the symptoms of myelosis in adult myelodysplastic syndrome zebrafish. FIG. 6, part A, is a flow assay of wild type and c-mybhyperCellular components of zebrafish kidney medulla; FSC is proportional to cell size, SSC denotes cell granularity; relative means for each cell population were obtained from 4 zebrafish samples. Part B of FIG. 6 is wild-type and c-mybhyperStatistics of the proportion of renal medullary blood cells of zebrafish (Student's t test, n 4; ns, no statistical difference,. P<0.05)。
The above examples are only preferred embodiments of the present invention, which are intended to be illustrative and not limiting, and those skilled in the art should understand that they can make various changes, substitutions and alterations without departing from the spirit and scope of the invention.
Claims (7)
1. An application of an antiviral drug in preparing a drug for treating myelodysplastic syndrome is characterized in that the antiviral drug is famciclovir.
2. The use of an antiviral agent in the preparation of a medicament for the treatment of myelodysplastic syndrome according to claim 1, wherein famciclovir is administered at a concentration of 1mM to 5 mM.
3. Use of an antiviral agent in the preparation of a medicament for the treatment of myelodysplastic syndrome according to claim 2, wherein famciclovir is administered at a concentration of 5 mM.
4. Use of an antiviral agent in the manufacture of a medicament for the treatment of myelodysplastic syndrome according to claim 1, wherein said famciclovir is in a formulation for oral, intravenous, subcutaneous, intramuscular, topical, intraperitoneal, intranasal, inhalation or intraocular administration.
5. Use of an antiviral agent according to claim 1 in the manufacture of a medicament for the treatment of myelodysplastic syndrome, comprising: and mixing famciclovir and auxiliary materials to obtain the medicine for treating myelodysplastic syndrome.
6. The use of an antiviral agent in the manufacture of a medicament for the treatment of myelodysplastic syndrome according to claim 5, wherein the excipient is one or more of a binder, a filler, a flavoring agent, or a wetting agent.
7. The use of an antiviral agent in the preparation of a medicament for the treatment of myelodysplastic syndrome according to claim 1, wherein the medicament for the treatment of myelodysplastic syndrome is in the form of a decoction, a pill, a paste, a powder, a granule, a tablet or a capsule.
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