KR101881142B1 - Composition for preventing, improving or treating disease caused by side effect of anticancer agent comprising Cistanchis Herba extract as effective component - Google Patents
Composition for preventing, improving or treating disease caused by side effect of anticancer agent comprising Cistanchis Herba extract as effective component Download PDFInfo
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- KR101881142B1 KR101881142B1 KR1020160024068A KR20160024068A KR101881142B1 KR 101881142 B1 KR101881142 B1 KR 101881142B1 KR 1020160024068 A KR1020160024068 A KR 1020160024068A KR 20160024068 A KR20160024068 A KR 20160024068A KR 101881142 B1 KR101881142 B1 KR 101881142B1
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- docetaxel
- extract
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- anticancer
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Abstract
The present invention relates to a composition for preventing, ameliorating or treating diseases caused by side effects of anticancer agents containing an extract for breeding as an active ingredient. The present invention relates to a composition for preventing, ameliorating or treating diseases caused by side effects of an anticancer agent, And the bone marrow suppression induced by the anticancer drug was remarkably restored in the animal model induced by the anti-cancer drug.
Therefore, the extract for breeding of the present invention can be usefully used as a composition for prevention, improvement and treatment of diseases caused by side effects of anticancer drugs, and it is possible to increase the effect of anticancer drugs by prescribing the anticancer drugs in combination with anticancer drugs.
Description
The present invention relates to a composition for preventing, ameliorating or treating a disease caused by an anticancer drug adverse effect containing an extract of Cistanchis Herba as an active ingredient.
Cancer is one of the top two causes of death in Korea, and 30% of deaths in the 50s and 60s in Korea are dying of cancer. Surgical surgery, radiation therapy, and chemotherapy are most commonly used for the treatment of these cancers. Among them, the development of anti-cancer drugs as chemotherapy has been tried variously, but to date, anti-cancer drugs have not been developed as genuine therapeutic drugs, and they are only helping with adjuvant therapy or short-term life extension.
An anticancer drug used in chemotherapy intervenes in the metabolic pathway of cancer cells to directly interfere with DNA to block the replication, transcription and translation of DNA, inhibit the synthesis of nucleic acid precursors, inhibit cell division, . However, the present anticancer drug has no specific selectivity for cancer, and exhibits therapeutic effect and toxic effect at the same time. Toxicity due to the administration of anticancer drug is caused by hemocyte depletion of white blood cells, platelets, red blood cells, Hair loss, dyspepsia and diarrhea, diarrhea, renal toxicity due to tubulo-necrosis, nervous system, nausea and vomiting due to adverse effects of hair loss, menstrual irregularities and male infertility due to hair loss symptoms, ovarian and testicular side effects, Various side effects such as peripheral neuritis and weakness caused by the disorder, vascular disorders such as vascular pain and rash, skin and nail discoloration occur. Therefore, it is urgent to develop a medicament that can increase the effectiveness of chemotherapy while minimizing side effects caused by the anticancer drug.
On the other hand, Cistanchis Herba is a fleshy stem for perennials and perennials. Symptoms include weakness and weakness of the back of the neck, weakness of the legs, noise from the ears, poor visual acuity, improved symptoms, and a lack of oocyte in men, urinary excretion and urine. It is also effective for infertility, lower abdomen and lower abdomen cold, and it is known to be effective for constipation due to major bleeding, excessive sweating, chronic disease, and geriatric constipation. The rootstock for breeding is lumpy. The stem is thick and does not shoot branches, it grows yellow but gradually turns reddish brown. It is a meat plant of about 15 ~ 30cm in height. The lower part is wrinkled and the upper part is dense with scaly leaves and looks like a snake skin. The scaly leaves are triangular and the ends are dull. The flower blooms in black purple in July ~ August, and the upper part of the main stem grows thick and many flowers run. In addition, it is used for medicines such as gymnastics, sternum, etc., and it is effective in blood pressure drop, stimulation of saliva secretion, and circulation. It shows kidney stamina and semen and blood, Salt, oil wells, infertility, osteomalacia, back and knee pain and sore, constipation of the elderly or weak, and various bleeding.
As a technique related to extract for breeding, Chinese Patent Laid-Open No. 001111996 discloses a medicinal herbal preparation for the treatment of non-regenerative anemia or leukopenia, which comprises a mixture of herbal medicines containing carrageenan as an active ingredient, Japanese Laid-Open Patent Application No. 2014-108959 Discloses a technique relating to a TNF-? Production regulator containing a sarcoma extract as an active ingredient, and Chinese Patent Laid-Open No. 104116024 discloses a functional food having an auxiliary suppressive colorectal cancer effect and its application However, a composition for preventing, ameliorating or treating a disease caused by the side effect of an anticancer drug containing the extract for breeding as an active ingredient of the present invention has not been disclosed.
The present invention provides a composition for preventing, ameliorating or treating diseases caused by side effects of anticancer drugs comprising an extract for breeding as an active ingredient. More specifically, the present invention relates to a composition for preventing, In the animal model in which the survival of the hematopoietic stem cells was significantly restored and the bone marrow suppression was induced by intraperitoneal injection of docetaxel, bone marrow suppression by docetaxel was remarkably restored by treatment with bone marrow cells of mice in which hematopoietic stem cells were reduced by administration of docetaxel , Thereby completing the present invention.
In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by side effects of anticancer drugs containing an extract for breeding as an active ingredient.
The present invention also provides a health functional food for preventing or ameliorating diseases caused by side effects of anticancer drugs containing an extract for breeding as an active ingredient.
The present invention also provides an anticancer adjuvant containing an extract for breeding as an active ingredient.
The present invention relates to a pharmaceutical composition for preventing or treating diseases caused by the side effects of anticancer drugs containing an extract for breeding as an active ingredient, which not only remarkably reduces the reduction of hematopoietic stem cell colonies induced by anticancer agents, Can be remarkably restored. Therefore, the extract for breeding of the present invention can be used as a pharmaceutical composition, a health functional food, or an anti-cancer adjuvant for the prevention and treatment of diseases caused by side effects of anticancer drugs.
FIG. 1 shows the effect of a colony forming unit (CFU) assay on the growth and differentiation of bone marrow cells isolated from the femur of mice by treatment with docetaxel. * And *** are statistically different from those of the control coliform forming unit (CFU) without treatment with docetaxel. * Indicates that the p value is less than 0.05, *** indicates the p value Is less than 0.001.
Fig. 2 shows the results of confirming the number of bone marrow cells from the femur after (A) and (b) 7 days after intraperitoneal injection of 50, 100 and 150 mg / kg of docetaxel into C5BL6 mice. ** and *** indicate statistically significant differences in cell survival rates of docetaxel treated animals compared to control animals treated with docetaxel, ** indicates that the p value is less than 0.01, *** indicates p Value is less than 0.001.
FIG. 3 shows the results of confirming the effect of reducing the bone marrow cells of mice by treatment with docetaxel, and suppressing the decrease of bone marrow cells by simultaneously treating the docetaxel with the 25, 50 and 100 μg / ml of the hot water extract of breeding of the present invention. # Indicates that the CFU of the docetaxel-treated group was significantly different from the control group not treated with docetaxel, indicating that the p value was less than 0.0001, **, *** indicates that docetaxel treated group and docetaxel And CFU of the group treated with the seed extract were significantly different. ** indicates that the p value is less than 0.01 and *** indicates that the p value is less than 0.001.
FIG. 4 shows the results of confirming the degree of reduction of bone marrow cells by administration of docetaxel and the degree of inhibition of bone marrow cells reduction by simultaneously treating docosahexaenoic acid extract of the present invention with docetaxel, and (A) (B) is a photograph of mouse bone marrow cells treated with 15 nM docetaxel, and (C) is a photograph of mouse bone marrow cells treated with 15 nM docetaxel and 100 μg / ml of hot water extract for breeding at the same time.
FIG. 5 shows the effect of reducing the bone marrow cells of mice by treatment with docetaxel and the simultaneous treatment of the 15 nM docetaxel with 125 μg / ml and 250 μg / ml of the hot water extract for breeding according to the present invention to inhibit the decrease of bone marrow cells The result is confirmed. Control is a control without any treatment, Docetaxel + Sarcoma-125 and Docetaxel + Sarcoma-250 mean concurrent administration of docetaxel and 125 and 250 μg / ml of hot water extract for breeding. # Indicates that the value of CFU of treated docetaxel was significantly different from that of control not treated with docetaxel, indicating that the p value is less than 0.05, ** indicates that docetaxel treated group, docetaxel, and seedling extract This means that the CFU of the combined treatment group is statistically significantly different, meaning that the p value is less than 0.01.
Fig. 6 shows the results of the treatment of docetaxel with 125 占 퐂 / ml (for breeding-125) and 250 占 퐂 / ml of hot water extract for breeding -250) were treated with H & E staining to confirm that marrow cell abnormalities did not occur.
Fig. 7 shows histopathological analysis of thymus, showing tissue shrinkage by administration of docetaxel and disappearance of functional lymphatic organs (yellow arrow), 125 [mu] g / ml of docetaxel and 125 [ ) And 250 μg / ml of hot water extract for breeding (-250 for breeding) were simultaneously treated to recover tissue shrinkage and loss of functioning lymphatic organs.
Fig. 8 shows the results of confirming the bone marrow-suppressing ability in the anti-cancer drug-induced bone marrow suppression animal model of the hot water extract for breeding. Docetaxel + Sarcoma-125 and Docetaxel + Sarcoma-250 mean concurrent administration of docetaxel and sarcoma at 125 and 250 μg / ml. * Indicates the statistically significant difference in the IL-3 between the docetaxel-treated group and the docetaxel-treated group and the 125 [mu] g / ml of the sarcoma extract-treated group, which means that the p value is less than 0.05.
The present invention relates to a pharmaceutical composition for preventing or treating diseases caused by side effects of anticancer drugs containing an extract for breeding as an active ingredient.
The breeding extract may be produced by a method including, but not limited to, the following steps:
1) extracting with an extraction solvent for seeding;
2) filtering the extract of step 1); And
3) Concentrating the filtrate obtained in step 2) under reduced pressure and drying to prepare an extract.
In the step 1), the extraction solvent is preferably water, a C 1 -C 4 lower alcohol, or a mixture thereof, but is not limited thereto.
In the above production method, the extraction for breeding may be performed by any conventional method known in the art such as filtration, hot water extraction, immersion extraction, reflux cooling extraction, and ultrasonic extraction. The extraction solvent is preferably extracted by adding 1 to 20 times the volume of the dried planting volume, more preferably 3 to 10 times. The extraction temperature is preferably 20 to 50 DEG C, but is not limited thereto. The extraction time is preferably 10 to 100 hours, more preferably 24 to 96 hours, most preferably 72 hours. In the above method, it is preferable to use a vacuum decompression concentrator or a vacuum rotary evaporator for the decompression concentration in step 3), but it is not limited thereto. The drying is preferably performed under reduced pressure, vacuum drying, boiling, spray drying or freeze drying, but not always limited thereto.
It is preferable that the cancer is any one selected from lung cancer, breast cancer, liver cancer, stomach cancer, colon cancer, colon cancer, skin cancer, bladder cancer, prostate cancer, ovarian cancer, cervical cancer, thyroid cancer, kidney cancer, fibrosarcoma, melanoma and blood cancer However, the present invention is not limited thereto, and any cancer that can be diagnosed is not limited.
The anticancer agent includes all anticancer drugs including, but not limited to, antitumor antibiotics, topoisomerase inhibitors, or taxane drugs, which can be used clinically, pharmacologically, or biomedically .
The antineoplastic antibiotic may be selected from the group consisting of actinomycin D, bleomycin sulfate, daunomycin, daunorubicin, doxorubicin, epirubicin, But are not limited to, one or more selected from the group consisting of idarubicin, mitomycin, mitomycin-C and mitramycin.
The topoisomerase inhibitor may be selected from the group consisting of irinotecan, camptothecin, novobiocin, epirubicin, dactinomycin, amsacrine, and at least one selected from the group consisting of teniposide and etoposide, but is not limited thereto.
It is preferable that the taxane-based drug is paclitaxel or docetaxel or both, and in a preferred embodiment of the present invention, docetaxel is most preferable.
The disease caused by the side effect is preferably at least one selected from the group consisting of hematopoietic toxin, anemia and neutropenia, but is not limited thereto.
The composition of the present invention may contain 0.1 to 99.9% by weight of the extract for breeding of the present invention as an active ingredient based on the total weight of the composition, and may include a pharmaceutically acceptable carrier, excipient or diluent.
The compositions of the present invention may be of various oral or parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of suppositories include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
The composition of the present invention may be administered orally or parenterally, and it is preferable to select the intraperitoneal, rectal, rectal, intravenous, intramuscular, subcutaneous, intrauterine or intracerebral injection methods for parenteral administration, It is used for external skin.
The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
The dosage of the composition of the present invention varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease, and the daily dose is based on the amount of the extract , Preferably 30 to 500 mg / kg, more preferably 50 to 300 mg / kg, and may be administered 1 to 6 times a day. The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
The present invention also relates to a health functional food for preventing or ameliorating diseases caused by side effects of anticancer drugs containing an extract for breeding as an active ingredient. The extraction solvent of the seedling extract is preferably water, a C 1 -C 4 lower alcohol or a mixture thereof, but is not limited thereto. The anticancer agent includes all anticancer agents that can be used clinically, pharmacologically, or biomedically, including, but not limited to, antitumor antibiotics, phagosomal enzyme inhibitors, or taxane drugs. The disease caused by the side effect of the anticancer agent is characterized in that it is at least one selected from the group consisting of hematopoietic toxicity, anemia and neutropenia.
The health food of the present invention can be used as it is or can be used with other food or food ingredients, and can be suitably used according to conventional methods. There is no particular limitation on the kind of the health food. Examples of the food to which the seedling extract can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, soups, drinks, tea, , An alcoholic beverage and a vitamin complex, and includes all the health foods in a conventional sense. The health drink containing the composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as a conventional beverage. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 g of the composition of the present invention.
The health food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin , Alcohols, carbonating agents used in carbonated drinks, and the like. And may further contain flesh for the production of fruit juice or vegetable beverages. These components may be used independently or in combination. Although the ratio of such additives is not critical, it is generally selected in the range of 0.01 to 2 parts by weight based on 100 parts by weight of the composition of the present invention.
The present invention also relates to anticancer adjuvants containing an extract for breeding as an active ingredient. The anticancer adjuvant is characterized by inhibiting one or more side effects of anticancer drugs selected from hematopoietic toxicity, anemia and neutropenia induced by administration of an anticancer drug.
The anticancer adjuvant may further contain one or more active ingredients which exhibit the same or similar functions in addition to the extract for breeding. The anticancer adjuvant can be administered orally or parenterally at the time of clinical administration and can be administered orally or parenterally at the time of parenteral administration and can be administered by intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intrauterine injection, And can be used in the form of a general pharmaceutical preparation.
The anticancer adjuvant may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers. The daily dose of the anticancer adjuvant is about 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg, preferably administered once to several times a day. However, The range varies depending on diet, time of administration, method of administration, excretion rate, and severity of the disease. The anticancer adjuvant of the present invention can be administered in various forms of parenteral administration at the time of actual clinical administration. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, It is prepared. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited thereto.
Example 1. Preparation of seed extract
In order to produce an extract for breeding, which is an effective ingredient of the present invention, a seedling was purchased from Kwang Myung Dang Pharmaceutical Co. (Ulsan, Korea). 100 g of the purchased seedlings were pulverized and then mixed with 2 L of water in a round flask. The water bath connected to the reflux condenser equipped with a cooling tube was heated and repeated twice for 2 hours each time. The extracted extract was filtered under reduced pressure using a paper filter paper (Whatman No. 2) and a vacuum pump (Vacuum pump, GAST). The filtered liquid extract was concentrated under reduced pressure using a rotary evaporator (EYELA), and the concentrated extract was lyophilized and homogenized with a mortar to obtain a hot water extract for breeding. This was stored in a sealed plastic container at 4 ° C in a low temperature storage tank until the experiment.
Example 2. Docetaxel Check hematopoietic toxicity
To examine the hematopoietic effect of docetaxel, an anticancer drug currently in clinical use, the effect of docetaxel on the growth and differentiation of hematopoietic stem cells in mouse bone marrow cells was examined using ex vivo , in vivo experiments.
One) In bone marrow cells of mice, Hematopoietic toxicity Effect verification ( ex vivo )
Bone marrow cells were isolated from mouse femurs. Then, recombinant murine stem cell factor (rm) stem cell factor, rm IL-3, human-derived recombinant IL-6 (recombinant human IL-6, rhIL-6 ) And rh erythropoietin (methocult GF M3434) medium for 7-10 days to induce the growth of hematopoietic stem cells. And the effect of anticancer drugs on growth and differentiation of hematopoietic stem cells was observed by performing a colony forming unit assay (CFU assay).
As a result, hematopoietic toxicity was shown at a low concentration as shown in FIG. 1, and in particular, hematopoietic toxicity was found to be very severe at a concentration of 50 nM or more.
2) In mice injected with anticancer drugs Hematopoietic toxicity Effect verification ( in vivo )
C57BL6 mice were intraperitoneally injected with 50, 100 and 150 mg / kg of docetaxel. After 3 and 7 days, bone marrow cells were isolated from the femur of the mouse, counted, and the survival rate was measured.
As a result, even if all injected the 50, 100 and docetaxel in 150㎎ / ㎏ As shown in Figure 2, three days after and 7 days after, by significantly decreased the number of separated bone marrow cells, stem from in vivo animal models Toxicity.
Example 3. In docetaxel For bone marrow toxicity induced by Heat number Identify the effect of recovering the bone marrow toxicity of the extract
In order to confirm the effect of hydrothermal extract for breeding on bone marrow cells to reduce the hematopoietic toxicity induced by docetaxel, the effect of reducing the bone marrow toxicity was confirmed by treating docetaxel with hot water extract for breeding.
Specifically, the bone marrow cells were separated from the femur of a mouse, and then subjected to hematopoietic stem cell transplantation in a medoculture GF M3434 medium containing recombinant stem cell factor derived from rat, rm IL-3, human recombinant IL-6 and rh erythropoietin Toxin-induced 15 nM docetaxel was treated. Then, the 25, 50 and 100 μg / ml of the hot water extract for breeding prepared in Example 1 was added, and the growth of the hematopoietic stem cells was induced by culturing for 7 days. After 7 days, grown hematopoietic stem cells were obtained and CFU analysis was performed to confirm the growth of hematopoietic stem cells. As a negative control, PBS containing 0.5% DMSO instead of the seedling extract was treated as a vehicle and the same method as described above was performed.
As a result, it was confirmed that the reduction of hematopoietic stem cell colony induced by docetaxel was significantly restored by the hot water extract for breeding as shown in FIG. 3 and FIG. 4 (FIGS. 3 and 4).
Example 4. For breeding Heat number Extract Doclex Bone marrow suppression in guided myelosuppressive animal models Mitigability Confirm
In order to determine whether hematopoietic toxicity reduction effect was exerted in the animal model for inducing myelosuppression, mice were injected intraperitoneally with docetaxel to induce bone marrow suppression, and then the change by the seedling extract was confirmed.
Specifically, C57BL6 mice were divided into four groups: Group 1 was a control group, which was treated with saline containing 5% ethanol and 2
As a result, as shown in FIG. 5, the number of bone marrow mononuclear cells was significantly decreased in the docetaxel-treated group, and the bone marrow suppression was restored in the group administered with the extract for sarcoma.
Histological analysis of the mouse femur in each of the above administration groups revealed hypocellularity due to reduction of hematopoietic cells and abnormality of cell structure in the bone marrow (yellow arrow) in the group treated with docetaxel alone, (Fig. 6), and histopathological analysis of the thymus showed that the tissue shrinkage by docetaxel administration and the loss of functional lymphatic system were restored by the combined administration for sarcoma (Fig. 6) 7).
Thereafter, mice were weighed every day for weight change of mice in the control group, docetaxel-treated group, 125 mg / kg of extract of sarcocarcinoma group administered with dog extract and 250 mg / kg of extract for sarcoma extract group, Weights of spleen and thymus, which play an important role in number changes and hematopoiesis, were measured.
As a result, as shown in Table 1, the weight of spleen and thymus sharply decreased in docetaxel treated group, whereas in the group administered docetaxel and 125 and 250 mg / kg of sarcomeric extract, The weight of the thymus was similar to that of the normal control group, and the weight of the thymus was less than that of the docetaxel group.
In Table 1, the spleen and thymus indices were obtained from the following formula.
Organ index (mg / g) = tissue weight (mg) / individual weight (g)
On the other hand, mRNA was obtained from spleen tissues of mice, and the expression of cytokines involved in hematopoiesis was confirmed. The administration of docetaxel significantly reduced the expression of IL-3, which is deeply involved in the differentiation and proliferation of hematopoiesis, particularly myeloid progenitor cells. When combined with docetaxel and sarcoma extract, reduced IL -3 (Fig. 8).
Claims (7)
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| Saisai Wang 외. Echinacoside improves hematopoietic function in 5-FU-induced myelosuppression mice. Life Sciences. 123. pp.86~92. (2015) |
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