Agent for suppressing side effect of anticancer drug, food composition for suppressing side effect, agent for improving / preventing anemia, and food composition for improving / preventing anemia

Abstract

The purpose of the present invention is to provide an agent for suppressing a side effect, the agent capable of suppressing a side effect of an anticancer drug from the viewpoint of blood components such as leukocytes and platelets.　Provided is an agent for suppressing a side effect of an anticancer drug, the agent containing, as an active ingredient, a component contained in edible bird's nests. According to each aspect of the present invention, it is possible to suppress a side effect of an anticancer drug from the viewpoint of blood components such as leukocytes and platelets, and to improve and / or prevent a symptom of anemia. It has never been anticipated that such an effect is exhibited by administration of edible bird's nests, and this can be considered a unique effect of the present invention.

Description

Anticancer agent side effect suppressor, food composition for side effect suppression, anemia improvement and prevention agent, and food composition for anemia improvement and prevention

[0001] The present invention relates to an anticancer agent side effect suppressor, a food composition for side effect suppression, an anemia improvement and prevention agent, and a food composition for anemia improvement and prevention, and particularly provides an anticancer agent side effect suppressor that suppresses side effects of anticancer agents, and the like.

[0002] It is generally known that administration of an anticancer agent to a living body causes a significant decrease in blood concentrations of components such as leukocytes. This makes it difficult to continuously administer the anticancer agent.

[0003] Figure 7 is a diagram showing an example of blood test results before and after administration of doxorubicin (DOX), which is a representative anticancer agent. As also shown in Figure 7, compared with before DOX administration (CTL), the values after DOX administration (DOX + CTL) worsened in most items. In particular, the values of white blood cells (WBC) and platelets (PLT) are markedly reduced to less than half.

[0004] Studies have been conducted so far reporting that mozuku-derived fucoidan has the effect of suppressing the side effects of drugs.

[0005] Japanese Unexamined Patent Publication No. 2004-075595

[0006] However, Patent Document 1 describes that the side effect suppression effect is verified by measuring the survival rate after mixing fucoidan with an anticancer agent against human gastric cancer cell lines and normal gastric cells.

[0007] In contrast, Patent Document 1 neither describes nor suggests the influence of the active ingredient on blood components, so it is unclear whether it has the effect of suppressing the side effects of drugs from the perspective of components such as leukocytes and platelets.

[0008] Therefore, an object of the present invention is to provide a side effect suppressor and the like that enable suppression of side effects of anticancer agents from the perspective of blood components such as leukocytes and platelets.

[0009] The first aspect of the present invention is an anticancer drug side effect inhibitor that suppresses the side effects of anticancer drugs, and which contains a component contained in bird's nest as an active ingredient.

[0010] A second aspect of the present invention is an anticancer drug side effect suppressant according to the first aspect, wherein the anticancer drug comprises at least one of doxorubicin hydrochloride, carboplatin, or vincristine.

[0011] A third aspect of the present invention is an anticancer drug side effect suppressor according to the first or second aspect, wherein the side effect includes any of the following: a decrease in the number of white blood cells, red blood cells, hemoglobin concentration, hematocrit value, platelet count, or hematopoietic stem cells in the bone marrow, or a decrease in body weight.

[0012] A fourth aspect of the present invention is an anticancer drug side effect suppressant according to any of the first to third aspects, wherein the active ingredient is a component contained in an aqueous solution obtained by hydrolyzing swiftlet nest without extraction treatment.

[0013] A fifth aspect of the present invention is an anticancer drug side effect suppressant according to the fourth aspect, wherein the hydrolysis is performed such that the proportion of products derived from swiftlet nests with a molecular weight of 6000 or less is in the range of 40-60%.

[0014] A sixth aspect of the present invention is an anticancer drug side effect suppressant according to the fourth aspect, wherein the hydrolysis is performed by preparing a solution such that the weight percentage of swiftlet nest is in the range of 5-15 ww%.

[0015] A seventh aspect of the present invention is a food composition for suppressing side effects of anticancer drugs, which contains a component contained in bird's nest as an active ingredient.

[0016] The eighth aspect of the present invention is an anemia-improving and / or preventing agent for improving and / or preventing the symptoms of anemia, wherein the agent contains a component contained in bird's nest as an active ingredient.

[0017] The ninth aspect of the present invention is a food composition for improving and / or preventing anemia, which improves and / or prevents the symptoms of anemia, and which contains a component contained in bird's nest as an active ingredient.

[0018] According to various aspects of the present invention, it becomes possible to suppress the side effects of anticancer drugs, improve and / or prevent symptoms of anemia, and suppress the decrease in the number of hematopoietic stem cells in the bone marrow, in terms of blood components such as white blood cells and platelets. Such effects from the administration of swiftlet nest were never anticipated before and can be considered a unique effect of the present invention.

[0019] This reduces the burden on the body when using anticancer drugs, making it easier to continue using them than before. As a result, anticancer drugs can be used for longer periods than before, and it becomes possible to use anticancer drugs that could not be used in the past due to the excessive burden on the body.

[0020] Furthermore, according to a fourth aspect of the present invention, it becomes easier to produce anticancer drug side effect suppressants and the like that effectively contain the active ingredients found in bird's nest.

[0021] This figure illustrates the change in body weight of mice before and after DOX administration. This figure illustrates the change in blood components of mice before and after DOX administration. This figure illustrates an overview of the state of cellular tissue destruction in the bone marrow and thymus of mice before and after DOX administration. This figure shows an example of scoring the state of cellular tissue destruction in the bone marrow and thymus of mice before and after DOX administration. This figure illustrates the change in blood components of mice before and after carboplatin administration. This figure illustrates the change in blood components of mice before and after vincristine administration. This figure shows a typical example of changes in the concentration of blood components before and after administration of anticancer drugs. This figure illustrates the results of analysis of hematopoietic stem cells (HSCs) in the bone marrow of mice orally administered swiftlet nest extract.

[0022] Embodiments of the present invention will be described in detail below with reference to the drawings. However, the embodiments of the present invention are not limited to those described below.

[0023] The swallow's nest extract (bird's nest) used was prepared by M-Style Holdings Co., Ltd., one of the applicants for this application. The preparation procedure involved first drying Malaysian swiftlet nests (sample) to a moisture content of 10% or less, then mixing and immersing them in RO membrane-treated water so that the sample concentration was in the range of 5-15ww%. Subsequently, hydrolysis treatment was performed so that the proportion of molecules with a molecular weight of 6000 or less was in the range of 40-60%.

[0024] Subsequently, the finished hydrolyzed solution was sieved with a 100-mesh sieve to remove the residue. The residue was then centrifuged using a centrifuge (10,000 rpm / 20 min), and the supernatant was collected to obtain the extract sample (EBN).

[0025] The experiment used male mice (10 weeks old). They were reared and bred in an SPF environment at the Institute of Biological Sciences, Azabu University, and all mice were housed in plastic cages with free access to water and food. The room temperature was maintained at 24°C, and the light-dark cycle was 12 hours of light:12 hours of dark (lights turned on at 7:00 AM).

[0026] Mice reared as described above were administered doxorubicin hydrochloride (DOX, Sandoz KK) at a dose of 10 mg / kg via tail vein under 2% isoflurane anesthesia. The control group received physiological saline (Otsuka Saline Injection) via tail vein. Seven days after DOX administration, swiftlet nest vein (EBN) was administered daily (1.6 mg / kg po). (Each group n=8, CTL, EBN, DOX, DOX+EBN, 4 groups, 32 mice) Cardiac blood was collected 28 days after Dox administration, and complete blood count, blood biochemistry screening, and pathological examination were performed. Body weight was recorded twice a week during the experiment, and at the end of the experiment, the mice's urine was collected in a metabolic cage and immediately stored at -80°C. Subsequently, under 2% isoflurane anesthesia, cardiac blood was collected, and the mice were euthanized by cervical dislocation.

[0027] Complete blood counts were analyzed using Microsemi (Horiba), and blood biochemistry was performed by Wako (https: / / labchem-wako.fujifilm.com / jp / custom_service / products / 95021.html). Tumor organs were fixed with formalin and then embedded in paraffin. The femur was decalcified with K-CX AT for two days and then embedded in paraffin. The tissues were sectioned and stained with HE, and organ damage was scored on a four-point scale by a veterinarian with veterinary pathology specialist qualifications (0: normal, 1: mild, localized, 2: moderate, diffuse, 3: severe, diffuse). Similarly, mice that were intraperitoneally administered carboplatin (CBDCA, Cheplapharm) at 100 mg / kg and mice that were intravenously administered vincristine (VCR, Nippon Kayaku) at 0.5 mg / kg were also orally administered EBN.

[0028] Furthermore, the numerical values ​​shown in Figure 7 to describe the side effects of typical anticancer drugs were also obtained under the experimental conditions described above.

[0029] Figure 1 illustrates the change in body weight of mice before and after administration of DOX, a representative anticancer drug.

[0030] As shown in Figure 1, mice administered with DOX (DOX + CTL and DOX + EBN) showed a significantly greater decrease in body weight compared to mice not administered with DOX (CTL and EBN). However, even among mice administered with DOX, those orally administered with swiftlet nest extract starting 7 days after DOX administration (DOX + EBN) showed significantly less weight loss compared to mice administered with DOX and physiological saline (DOX + CTL).

[0031] The effect of suppressing weight loss in mice administered anticancer drugs by oral administration of bird's nest extract was first discovered by the inventors of this invention.

[0032] Figure 2 illustrates the changes in blood components in mice before and after DOX administration. Figure 2 shows the values ​​for common parameters, including white blood cell count (WBC), red blood cell count (RBC), hemoglobin concentration (Hgb), hematocrit (Hct), mean corpuscular volume (MCH), mean corpuscular pigment concentration (MCHC), erythrocyte distribution width (RDW), platelet count (PLT), mean platelet volume (MPV), procalcitonin (PCT), and platelet distribution width (PDW).

[0033] Mice administered orally with swiftlet nest extract starting 7 days after DOX administration (DOX + EBN) showed improvements in many parameters compared to mice administered with DOX and physiological saline (DOX + CTL). In particular, improvements in white blood cell count (WBC), red blood cell count (RBC), and platelet count (PLT) are highly significant in reducing the burden on the body. The platelet count (PLT) showed a particularly remarkable improvement. These results from oral administration of swiftlet nest extract to mice suggest that it contributes to weight maintenance.

[0034] Furthermore, the observed improvement in red blood cell count (RBC) and platelet count (PLT) indicates that swiftlet nest can be used as an anemia-improving and / or preventing agent, or as an active ingredient in an anemia-improving and / or preventing food compositions.

[0035] Figure 3 illustrates an overview of the tissue destruction of cells in the bone marrow and thymus of mice before and after DOX administration. Figure 3 shows the results of examinations of each tissue in the bone marrow and thymus. The letters (a-c) in Figure 3 indicate significant differences in the analysis results.

[0036] As shown in Figure 3, regarding bone marrow and thymus tissue, mice that received oral administration of swiftlet nest extract starting 7 days after DOX administration (DOX + EBN) showed a significant difference in tissue condition compared to mice that received DOX and physiological saline (DOX + CTL).

[0037] Figure 4 shows an example of scoring the degree of cell tissue destruction in the bone marrow and thymus of mice before and after DOX administration. Figure 4 shows that tissue improvement was observed after oral administration of swiftlet nest extract.

[0038] Referring to Figure 4, the white areas represent fat cells. The red areas represent anucleated red blood cells. The blue areas represent hematopoietic stem cells. It can be clearly seen that hematopoietic stem cells have increased in the tissues of two organs of mice that were orally administered swiftlet nest extract. The effect that was shown as a numerical difference in Figure 2 can now be visually confirmed.

[0039] Figure 5 illustrates the changes in blood components in mice before and after administration of carboplatin (CBDCA: 100 mg / kg ip), an example of an anticancer drug different from doxorubicin. Figure 6 illustrates the changes in blood components in mice before and after administration of vincristine (VCR: 0.5 mg / kg iv), another example of an anticancer drug different from doxorubicin. Both carboplatin and vincristine are commonly used anticancer drugs, similar to doxorubicin. Mice were administered these anticancer drugs, and then orally administered EBN starting 7 days later.

[0040] Referring to Figures 5 and 6, it is shown that oral administration of swiftlet nest extract improves values ​​such as white blood cell count (WBC), red blood cell count (RBC), hemoglobin concentration (Hgb), hematocrit (Hct), and platelet count (PLT) regardless of whether carboplatin or vincristine is administered as an anticancer drug. In particular, a significant improvement in platelet count (PLT) can be seen in both cases.

[0041] Next, the analysis of hematopoietic stem cells (HSC) in the bone marrow of mice is described. First, the analysis method is described. Mice were divided into a control group and a bird's nest group, and 80 mg / head was orally administered to the bird's nest group once daily for 21 consecutive days. The control group was administered the same volume of distilled water. After 21 days, the mice were anesthetized with 2% isoflurane, subjected to cardiac blood collection, then euthanized by cervical dislocation. After that, the attached muscles were carefully removed, and both femurs were extracted. The ends of the bones were excised with scissors, and the bone marrow cavity was flushed with Easy Sep Buffer (containing 1% FBS and 2 mM EDTA) using a syringe equipped with a 25G needle to obtain a cell suspension. The suspension was filtered through a 70 μm cell strainer, then centrifuged at 4°C, 500×g for 5 minutes, and the supernatant was removed. Finally, the cells were resuspended in FACS Buffer, and 1×10^6 cells per sample were used for staining. Subsequently, the following antibodies were added, and the reaction was allowed to proceed at 4°C in the dark for 40 minutes: Lineage cocktail (APC), anti-c-Kit (BV421), and anti-Sca-1 (PE). After the reaction, the cells were washed with FACS Buffer (500×g, 5 minutes), resuspended in 500 μL of buffer, and subjected to measurement.

[0042] The measurement was performed using BD FACSCelesta (registered trademark), and 1,000,000 events were acquired for each sample. First, a rough gating of the cell population was performed based on FSC-A / SSC-A, then a Lineage-negative (APC-negative) population was selected. Within this population, two-dimensional plotting of c-Kit (BV421) and Sca-1 (PE) was performed, and the region positive for both c-Kit and Sca-1 was defined as hematopoietic stem cells (HSC). The number of HSCs was calculated from the proportion of HSCs relative to the total number of obtained bone marrow mononuclear cells (proportion × total number of recovered cells per individual).

[0043] FIG. 8 is a diagram exemplifying the analysis results of hematopoietic stem cells (HSC) in bone marrow of mice orally administered with bird's nest.

[0044] Referring to FIG. 8, first, bone marrow cells are recovered, and from a population excluding Lineage-positive cells, c-Kit and Sca-1 are used as indicators to obtain Lin - c-Kit + Sca-1 +The cells were identified as HSCs. Figure 8(A) shows representative flow cytometry analysis gating results for the control group (CTLs) and the EBN-treated group.

[0045] As shown in Figure 8(B), the number of HSCs in the bone marrow showed an increasing trend in the EBN-administered group compared to the control group. Although the difference was not statistically significant (p = 0.1784), it was suggested that EBN administration may contribute to the maintenance or increase of HSCs in the bone marrow.

[0046] Thus, it was confirmed that oral administration of EBN also has a certain effect on the number of hematopoietic stem cells. In addition to the previously known effects of reducing the side effects of anticancer drugs and improving hematopoiesis, it has become clear that it also has effects related to maintaining and increasing the hematopoietic stem cell population in the bone marrow environment.

Claims

1. An anticancer drug side effect inhibitor that suppresses the side effects of anticancer drugs, wherein the anticancer drug side effect inhibitor contains a component found in bird's nest as an active ingredient.

2. The anticancer drug side effect suppressor according to claim 1, wherein the anticancer drug comprises at least one of doxorubicin hydrochloride, carboplatin, or vincristine.

3. The anticancer drug side effect suppressor according to claim 1 or 2, wherein the side effect includes any of the following: a decrease in the number of white blood cells, red blood cells, hemoglobin concentration, hematocrit value, platelet count, or hematopoietic stem cells in the bone marrow, or a decrease in body weight.

4. The anticancer drug side effect suppressant according to claim 1, wherein the active ingredient is a component contained in an aqueous solution obtained by hydrolyzing swiftlet nest without extraction treatment.

5. The anticancer drug side effect suppressant according to claim 4, wherein the hydrolysis is performed such that the proportion of products derived from swiftlet nests with a molecular weight of 6000 or less is in the range of 40-60%.

6. The anticancer drug side effect suppressant according to claim 4, wherein the hydrolysis is carried out by preparing a solution and performing the procedure such that the weight percentage of swiftlet nest is in the range of 5-15 ww%.

7. A food composition for suppressing side effects of anticancer drugs, comprising a component contained in bird's nest as an active ingredient.

8. An anemia-improving and / or preventing agent for improving the symptoms of anemia, comprising a component contained in bird's nest as an active ingredient.

9. A food composition for improving and / or preventing anemia, which improves and / or prevents the symptoms of anemia, and which contains a component contained in bird's nest as an active ingredient.

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