KR101693828B1 - Compostion comprising Yukmijihwangtang extract for treatment of renal cell carcinoma or liver cancer - Google Patents
Compostion comprising Yukmijihwangtang extract for treatment of renal cell carcinoma or liver cancer Download PDFInfo
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Abstract
Description
The present invention provides a composition for treating renal cancer or liver cancer, which comprises an anti-cancer agent and a cyphosanthanthin extract.
Sorafenib is a typical oral anticancer drug that is frequently used for advanced renal cancer and liver cancer through inhibition of tyrosine protein kinases and Raf kinases. Recently, Sorafenib has been widely used for non-reactive thyroid cancer, squamous cell carcinoma of the lung, and recurrent glioblastoma. However, various unintended side effects such as skin rash, hand-foot skin reactions, diarrhea, hypertension, reversible posterior leukoencephalopathy syndrome, and erythropoiesis are caused by the clinic and hypersensitivity to sorafenib is also reported have.
In addition, drugs affecting the liver microsomal enzymes such as dexamethasone, ketoconazole, rifampin and doxorubicin, drugs metabolized by hepatic microsomal enzymes, insecticides, uridine diphosphate -glucuronosyltransferase) with a drug metabolized by the drug.
On the other hand, Shihosangan-tang is a representative prescription to stop the pain by restoring the metabolic function of the liver damaged by anger, stress and overwork, improving blood circulation, relieving tension of smooth muscle, and so on. It is a combined prescription consisting of seven natural products, namely, 芎 芎, 藥药, 枳), 香 子 子 and licorice, and is currently prescribed for liver damage [Zhang et al, 2007] Various inflammatory gastrointestinal disorders through modulation [Ao et al., 2007; Zhong and Gong, 2007; Zhang et al., 2010; Qiu et al., 2011] is well known.
Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a composition for the treatment of kidney cancer or liver cancer using Shihosangan hot-water extract.
However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
In order to achieve the above object, the present invention provides a composition for treating renal cancer or liver cancer, which comprises an anti-cancer agent and a cyphosanthanthin extract.
In one embodiment of the present invention, the anticancer agent is sorapenib.
In another embodiment of the present invention, the Shihosangan hot-water extract is characterized in that it contains Shiho, Dermis, Taisho, Peony, Crust, Fragrant and Licorice.
In another embodiment of the present invention, the anticancer agent and Shihosanthanthanthin extract may be pre-mixed and formulated or separately formulated.
In another embodiment of the present invention, the anticancer agent and the citric acid extract are administered parenterally, orally, locoregionally, or percutaneously.
In another embodiment of the present invention, the administration of the Shihosan hot-water extract is started within 30 minutes to 4 hours after administration of the anticancer drug.
The kidney cancer or the composition for treating liver cancer containing the Shihosangan hot water extract as an active ingredient provided in the present invention is administered in combination with an anticancer agent to improve the efficiency of treating renal cancer or liver cancer, .
Fig. 1 is a graph showing the change in the concentration of sorapanib in blood for a group administered with sorafenib alone and a group administered with shofosan gang within 5 minutes after the administration of sorafenib.
FIG. 2 is a graph showing changes in body weight and body weight for a group administered with sorafenib alone in Example 2, and a group administered with Sorafenib in combination with Shihosangan hot water for 5 minutes or less.
FIG. 3 is a graph showing changes in blood sorapenib concentration according to each group in Example 2. FIG.
4 is a view schematically showing the experimental design of the third embodiment. 5 to 20 relate to the third embodiment.
FIG. 5 is a graph showing the change in the survival rate observed to examine the effect of Shihosangan-tang on HepG2 cells.
6 is a graph showing the change in survival rate observed to examine the effect of sorapenib on HepG2 cells.
FIG. 7 is a graph showing the results of changes in body weight and weight gain according to each group.
FIG. 8 is a photograph showing the difference in volume of tumors according to each group. FIG.
9 is a graph showing the change in tumor volume according to each group.
FIG. 10 is a graph showing changes in blood IL-6 and IFN-y contents according to each group.
11 is a graph showing changes in NK cell activity according to each group.
Fig. 12 is a diagram showing the histopathological changes of masses according to each group.
FIG. 13 is a graph showing the results of observing changes in caspase-3 immunoreactive cells in the mass in each group.
Fig. 14 is a graph showing the results of observing the changes of PARP-immunoreactive cells in the mass in each group.
FIG. 15 is a graph showing the results of observing changes in intracellular COX-2-immunoreactive cells in each group. FIG.
16 is a graph showing the results of observing the changes of iNOS immunoreactive cells in the mass in each group.
FIG. 17 is a graph showing the results of observing changes in TNF-a immunoreactive cells in the mass in each group.
18 is a diagram showing the results of observing histopathological changes of spleen according to each group.
FIG. 19 is a diagram showing the results of observing histopathological changes of submandibular glands according to each group.
20 is a diagram showing the results of observing histopathological changes of the ovarian fats according to each group.
FIG. 20 is a graph showing the results of observing changes in MDA, a change in GSH content, catalase and SOD activity, which are indicators of lipid peroxidation in kidney tissues, in order to confirm the effect of inhibiting renal antioxidation.
21 is a view schematically showing the experimental design of the fourth embodiment. 22 to 30 all relate to the fourth embodiment.
FIG. 22 is a graph showing the results of changes in body weight and weight gain according to each group. FIG.
23 is a graph showing changes in NK cell activity according to each group.
24 is a diagram showing the results of observing histopathological changes of spleen white water quality according to each group.
25 is a diagram showing the results of observing histopathological changes of submandibular glands according to each group.
FIG. 26 is a graph showing the histopathological changes of the testicular tubule according to each group. FIG.
FIG. 27 is a diagram showing the results of observation of histopathological changes of epididymal duct according to each group. FIG.
28 is a diagram showing the results of observation of histopathological changes of the lungs according to each group.
29 is a diagram showing the results of histopathological changes of the kidney according to each group.
FIG. 30 is a diagram showing the results of observing histopathological changes on the main body according to each group. FIG.
The present inventors paid attention to herbal medicines in order to develop a composition capable of further enhancing the effect of chemotherapeutic treatment while alleviating various adverse effects of administration of an anticancer agent for the treatment of kidney cancer or liver cancer, The present inventors have completed the present invention by confirming that they have excellent chemotherapeutic effect and side effect reduction effect.
Accordingly, it is an object of the present invention to provide a composition for treating renal cancer or liver cancer, which comprises an anticancer agent and a cyphosanthanthin extract.
The term " Sihosoganthan tang extract " used in the present invention means an extract extracted from seven medicinal materials. The seven medicinal materials include seven medicinal materials such as Shiho, dermis, cingulate, peony, crust, rosemary and licorice.
In one embodiment of the present invention, the anticancer agent and the cyphosanthin water extract may be mixed beforehand or separately formulated.
The administration time of the Soshosangan hot water extract may be performed within 30 minutes to 4 hours after the administration of the anticancer agent, preferably within 1 hour to 3 hours, most preferably from 1 hour and 30 minutes to 2 hours Min, and may be administered 2 hours after the administration of the anticancer drug as in the embodiment of the present invention, but the present invention is not limited thereto.
The anticancer agent used in the present invention is sorapenib, but it is not limited thereto.
The anticancer agent and the citric acid extract can be administered parenterally, orally, locoregionally, or transdermally. The Shihosangan hot-water extract is preferably orally administered, but may be appropriately selected by those skilled in the art depending on the condition and the weight of the patient, the degree of disease, and the period of time.
In the present invention, an 'individual' refers to a subject in need of treatment for diseases, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, And the like.
In addition, the present invention can provide a composition for treating renal cancer or liver cancer, which comprises Shihosangan hot-water extract.
The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include, but is not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate.
In one embodiment of the present invention, the preferred dosage of the pharmaceutical composition varies depending on the condition and the weight of the patient, the degree of disease, the drug form, the administration route, and the period, but can be appropriately selected by those skilled in the art. However, it is preferably administered at a daily dose of 0.001 to 300 mg / kg body weight, more preferably 0.01 to 200 mg / kg body weight.
The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. The method of administration is not limited and can be administered, for example, orally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine, or intra-cerebroventricular injection.
The composition for treating renal cancer or liver cancer comprising the Shihosangan hot-water extract of the present invention can increase the blood-sugar-enhancing effect and alleviate various side effects that have been caused when the anticancer agent is administered alone .
Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
[ Example ]
In this Example, the absorption and excretion of the anticancer drug according to the combination administration of Shihosangan-tang, that is, the effect on the pharmacokinetics, and the like, were selected and a combination administration method without affecting the pharmacokinetics was selected, And the synergistic effect on the drug efficacy was evaluated.
Sorafenib tosylate (Hangzhou Tacon Co., Ltd., Hangzhou, China) was selected for use as an anticancer agent used in this example, and Shihosanggang (hereinafter referred to as SHSGT) was purchased from HANZUNG PHARM. Respectively.
Example One. Sorafenib's Pharmacokinetics ( pharmacokinetics ) On Shihosangan hot spring : Single-dose oral administration within 5 minutes
In this example, single oral administration of
1.1. Experimental Method
Male Sprague-Dawley (SD) male rats (OrientBio, Seungnam, Korea) were used as the experimental animals after 29 days of purification for SPF.VAF Outbred Crl: CD.
The experimental method is as follows:
Group separation (total 2 groups: 5 per group)
Frequency: Single oral administration
Medium: Sterile distilled water (5 ml / kg)
Administration: 50 mg / kg of sorafenib (Hangzhou Tacon Co., Ltd., Hangzhou, China) was dissolved in sterilized distilled water and was administered orally at a dose of 5 ml / kg.
Blood collection: About 0.5 ml of whole blood from orbital veins was infused with 50 IU of heparin (Sigma, St. Louis, MO, USA) for 30 minutes before, 30 minutes after, 1, 2, 3, 4, 6, ), And the plasma was separated by centrifugation at 13000 rpm for 10 minutes immediately after collection. The separated plasma was stored at -150 ° C until LC-MS / MS analysis.
Sorafenib blood level analysis: for Carbamazepine (Sigma, St. Louise, MO , USA) in the plasma was separated using a internal standard, was measured, the concentration of sorafenib by LC-MS / MS method. Chromatographic analysis was performed using Agilent 1100 Series HPLC (Agilent Technologies, Santa Clara, Calif., USA) and column effluent was analyzed using an
HPLC Condition
Column: Waters Symmetry 占 C18 (2.1 占 50 mm, 3.5 占 퐉) (Waters Corp., Milford, MA, USA)
Column Oven: 30 ° C
Mobile phase: 25% distilled water (0.1% formic acid) / 75% acetonitrile
Flow rate: 0.30 ml / min
Injection Volume: 5.0μl
LC- MS / MS
Ion source: Turbo Ion Spray (300 ° C)
Polarity: Positive
Carbamazepine (IS) = m / z 237 > 194 (Retention time: 0.64 min), sorafenib = 465 > 252 (Retention time: 0.85 min)
Standard Curve: Analyst 1.4.1, Quadratic (1 / x 2 , no Iterate)
Observations: Serum sorafenib concentrations (μg / ml), pharmacokinetic parameters - Cmax, Tmax, AUC, and serum levels of the serum at 30 minutes before, 30 minutes after, and 1, 2, 3, 4, 6, t 1/2 and MRT were compared using noncompartmental pharmacokinetics data analyzer program (PK solutions 2.0; Summit, Montrose, CO, USA).
1.2. Blood sorafenib Change in concentration
In sorafenib alone or in sorafenib + Shihosangan tang group, sorafenib was detected in the
Serum sorafenib concentrations in the Sorafenib + Shihosengantang group were 30 minutes after administration, and 1, 2, 3, 4, 6, 8, and 24 hours after administration of sorafenib compared with sorafenib alone in the administration group of 5520.69, 264.39, 17.99, -10.85, 24.47, 75.43, 14.48 and 82.58%, respectively.
1.3. Tmax (time to become the highest blood concentration) change
In sorafenib + Shihosangan-tang group, the serum Tmax of sorafenib was 4.60 ± 2.30hr, showing a mild decrease of -17.86% compared to 5.60 ± 2.51hr of sorafenib alone (Table 3).
Values are expressed as mean ± SD. of five rats
Tmax: Time to reach Cmax
AUC 0 -t : The total area under the plasma concentration-time curve from time to zero
AUC 0 - inf : The total area under the plasma concentration-time curve from time zero to time infinity
t 1/2 : half life
MRT inf : mean residence to time infinity
1.4. Cmax (peak blood concentration) change
The sorafenib serum Cmax was 10.49 ± 3.94 μg / ml in Sorafenib + Shihosangan-tang group and 33.79% in sorafenib alone (7.84 ± 1.34 μg / ml) (Table 3).
1.5. AUC ( The total area under the plasma concentration - time curve from time zero to time measured
In the Sorafenib + Shihosangan-tang group, the serum sorafenib AUC 0 -t was 184.90 ± 84.28 hr · μg / ml and the AUC 0-t was 61.42% higher than the 114.54 ± 48.56hr · μg / ml of sorafenib alone The serum sorafenib AUC 0 - inf In the case of sorafenib + Shihosangan-tang treatment group, 471.04 ± 257.36hr · μg / ml showed a 95.05% increase compared with 241.50 ± 154.69hr · μg / ml of sorafenib alone group (Table 3).
1.6. t 1/2 Change of
Sorafenib + Shiho sogan bath treated in a plasma t 1/2 of sorafenib 29.40 ± 11.14hr, exhibited no significant increase of 38.57% compared with 21.22 ± 10.08hr of sorafenib alone group (Table 3).
1.7. MRT inf of change
In the Sorafenib + Shihosangan-tang group, serum MRT inf of 44.06 ± 16.50hr was significantly higher than that of sorafenib alone (31.41 ± 16.11hr, 40.26%) (Table 3).
As a result of this Example 1, it was observed that single oral administration of Shihosangan hot water within 5 minutes showed a tendency to increase the oral bioavailability of sorafenib as a whole, but the serum concentration of sorafenib and change of pharmacokinetic parameters Was not observed in the group administered with Shihosangan hot water. Therefore, it was observed that single - dose combination administration of Shihosogan - tang for 5 minutes did not significantly affect the absorption and excretion of sorafenib, that is, oral bioavailability.
In the result, sorafenib alone administration group of Example 1 Tmax was observed in the 5.60 ± 2.51hr, Cmax, AUC 0 -t, AUC 0 - inf,
Example 2. Sorafenib's Pharmacokinetics pharmacokinetics ) On Shihosangantan Effect evaluation: repeated oral administration for 7 days every 5 minutes
In Example 2, sorafenib and Shihosangan-tang were repeatedly orally administered for 7 days in 5 minutes. Then, the effect of sorafenib on the pharmacokinetics of the sorafenib was evaluated using normal male rats, and the drug interaction between sorafenib and Shihosangantang To make it more clear. The patients were divided into two groups: sorafenib 50 mg / kg and Shihosogan hotpot 100 mg / kg for 7 days and repeatedly for 7 days, 30 minutes before the last 7 times, 30 minutes, 1, 2, 3, 4, Twenty-four hours later, the serum sorafenib concentration was measured and noncompartmental pharmacokinetics data (Cmax, Tmax, AUC, t 1/2 and MRT) were calculated and compared with sorafenib alone.
2.1. Experimental Method
Male Sprague-Dawley (SD) male rats (OrientBio, Seungnam, Korea) were used as the experimental animals after 8 days of sterilization with SPF.VAF Outbred Crl: CD.
Group separation (total 2 groups: 10 per group)
Frequency: 7 days repeated oral administration (within 5 minutes)
Medium: Sterile distilled water (5 ml / kg)
Dose: 50 mg / kg of sorafenib (Hangzhou Tacon Co., Ltd., Hangzhou, China) was dissolved in sterilized distilled water and orally administered at 5 ml / kg. Within 5 minutes after sorafenib administration, 100 mg / kg of Shihosangan was dissolved in sterile distilled water And then orally administered at the same dose. Sorafenib and Shihosangan-tang were orally administered once a day for 7 days. In the case of sorafenib alone, sterilized distilled water of the same volume was orally administered in 5 minutes instead of Shihosanggang instead of Shihosanggang (Table 4).
Blood collection: About 0.5 ml of whole blood from the orbital venous cannula was infused with 50 IU of heparin (Sigma, St. Louis, MO) for 30 minutes before the last 7 times sorafenib, 30 minutes after administration, 1, 2, 3, 4, 6, , MO, USA), and the plasma was separated by centrifugation at 13000 rpm for 10 minutes immediately after collection. The separated plasma was stored at -150 ° C until LC / MS / MS analysis.
Sorafenib blood level analysis: for Carbamazepine (Sigma, St. Louise, MO , USA) in the plasma was separated using a internal standard, was measured, the concentration of sorafenib by LC-MS / MS method. Chromatographic analysis was performed using Agilent 1100 Series HPLC (Agilent Technologies, Santa Clara, Calif., USA) and column effluent was analyzed using an
HPLC Condition
Column: Waters Symmetry ( TM) C18 (2.1 x 50 mm, 3.5 m) (Waters Corp., Milford, Mass., USA)
Column Oven: 30 ° C
Mobile phase: 25% distilled water (0.1% formic acid) / 75% acetonitrile
Flow rate: 0.30 ml / min
Injection Volume: 5.0μl
LC- MS / MS
Ion source: Turbo Ion Spray (300 ° C)
Polarity: Positive
Carbamazepine (IS) = m / z 237 > 194 (Retention time: 0.64 min), sorafenib = 465 > 252 (Retention time: 0.85 min)
Standard Curve: Analyst 1.4.1, Quadratic (1 / x 2 , no Iterate)
Observations: Serum sorafenib concentration (μg / ml), pharmacokinetic index - Cmax, Tmax (mg / ml), serum concentration of serum in the last 7 hours, 30 minutes before the administration of sorafenib, 1, 2, 3, 4, 6, , AUC, t 1/2 and MRT were compared and analyzed using a noncompartmental pharmacokinetics data analyzer program (PK solutions 2.0; Summit, Montrose, CO, USA).
2.2. Change in weight
Significant changes in body weight and body weight were observed in patients treated with Sorafenib and Shihosangan baths within 5 minutes, as compared with patients treated with sorafenib alone (p <0.05) (Table 5, Fig. 2).
(Distilled water)
(100 mg / kg)
Values are expressed as mean ± SD. of five rats, g
2.3. Blood sorafenib Change in concentration
In sorafenib or sorafenib and Shihosangan baths, sorafenib was detected in the blood from 30 minutes before the last 7 times of sorafenib administration, and was continuously detected until 24 hours after administration. On the other hand, no significant change in the serum sorafenib level was observed in sorafenib and cyphosanthan tablets administered orally seven times in 5 minutes compared to sorafenib alone (FIG. 3).
After sorafenib was administered in combination with sorafenib and cyphosanthan for 5 minutes, the serum sorafenib concentration was increased to 30 minutes before, 30 minutes after, and 1, 2, 3, 4, 6, -0.54, -6.33, 1.08, 12.11, -3.47, -16.24, -8.90 and -39.29%, respectively, compared with the control group.
2.4. Of Tmax change
The serum Tmax of sorafenib was 6.20 ± 9.86hr in the sorafenib and cyphosanthan gang administration group, which was repeated 7 times within 5 minutes. The sorafenib group showed the same Tmax as 6.20 ± 9.96hr in sorafenib alone group (Table 6).
Average + standard deviation
2.5. Cmax change
The sorafenib serum Cmax was 3.12 ± 0.87 μg / ml in the sorafenib and cyphosanthan gum administration group, which was repeatedly administered within 7 min within 5 min, and -9.67% in the sorafenib group (Table 6).
2.6. AUC change
The sorafenib AUC 0 -t and AUC 0 - inf in the serum were 47.04 ± 7.56 and 61.74 ± 16.65hr · μg / ml, respectively, in the sorafenib and cyphosanthan gang administration group, AUC 0 -t and AUC 0 - inf showed a mild decrease with -16.16 and -21.42%, respectively, compared to ± 19.86 and 78.57 ± 46.57 hr · μg / ml (Table 6).
2.7. t 1/2 Change of
In the group administered with sorafenib and cyphosanthan gum for 7 consecutive times within 5 min, the serum t 1/2 of sorafenib was 11.07 ± 2.62 hr, which was slightly less than -21.09% compared to 14.03 ± 2.48 hr of sorafenib alone (Table 6).
2.8. MRT inf of change
The serum MRT inf of sorafenib was 15.98 ± 3.61 hr in sorafenib and cyphosanthan gang in combination with 7 times repeated oral administration in 5 minutes and showed a slight decrease of -21.72% compared with 20.41 ± 4.10 hr in sorafenib alone group (Table 6).
In this Example 2, sorafenib and Shihosogan tang were administered repeatedly orally for 7 days within 5 minutes, and the effect on the drug power of sorafenib was evaluated by using normal male rats, and the drug interaction of sorafenib and Shihosogan tang To make it more clear. The patients were divided into two groups: sorafenib 50 mg / kg and Shihosangan hotpot 100 mg / kg for 5 days and repeatedly orally for 7 days and 30 minutes before the last 7 times sorafenib, 30 minutes, 1, 2, 3, 4, Twenty-four hours later, blood samples were collected and serum sorafenib levels were measured and noncompartmental pharmacokinetics data were calculated and compared with sorafenib alone.
In this Example 2, oral administration of Shihosangan hot water for 7 days in sorafenib and sorafenib for 7 days resulted in no significant change in serum sorafenib level compared to sorafenib alone and significant changes in pharmacokinetic parameters were also recognized I did. Therefore, as a result of the repeated administration for 7 days in Example 1 and Example 2, it was observed that administration of Shihosogangan for 5 minutes or less did not affect the absorption and excretion of sorafenib, that is, the bioavailability. Therefore, it is expected that there will be no interference with the bioavailability when the concomitant administration of sorafenib in combination with Shihosangantang for liver cancer is administered within 5 minutes in the pharmacodynamics experiment.
All of the experimental animals used in the administration of
The results of this Example 2, sorafenib alone 7 days was observed in repeat group is a Tmax 6.20 ± 9.96hr, Cmax, AUC 0 -t, AUC 0 - inf,
In other words, when the results of Example 1 and Example 2 are taken into consideration, it was observed that the administration of salbutamol in the interval of 5 minutes or less did not significantly affect the absorption and excretion of sorafenib, that is, oral bioavailability Conjugation of sorafenib with Shihosangan tang for liver cancer In the pharmacodynamics experiment, it is expected that there will be no interference with bioavailability when administered within 5 minutes.
Example 3. Liver cancer treatment Sorafenib ( Nexvar TM )Wow Shiho Conjugated administration experiment: Shihosangantang HepG2 In liver cancer cell transplantation nude mice sorafenib To antitumor effect Mitch Influence
In Example 3, the effect of Sihosoganthang on sorafenib anticancer effect was investigated by using HepG2, a representative hepatocellular carcinoma cell line, as a part of integrated medical research of sorafenib and Shihosoganthang for liver cancer patients .
In Example 3, the cytotoxicity of Shihosangan hot-water and sorafenib to HepG2 cell line was evaluated by a general MTT method. After 21 days of HepG2 lung cancer cell transplantation, Shihosangan hot-water extract was administered to athymic
3.1. Experimental Method
The experimental results in this Example 3 were compared with that of the sorafenib 20 mg / kg alone group. All the test materials were dissolved in sterilized distilled water, and the dose of 10 ml / kg, which is the general oral dose of rodents, was measured once a day for 35 days (Table 7, Fig. 4).
Cytotoxicity assays : Hepa2 cells (0, 0.5, 1, 5, 10, 50, 100 and 500 mg / kg) and sorafenib (0, 0.1,1,2,4,6,8 and 10 μM) to the (1 × 10 4 cell) survival in a concentration of IC 50 to 50% inhibition was evaluated using the general method MTT.
Experimental animals : A total of 145 SPF / VAF Hsd: Athymic Nude-Foxn1nu mice (6-week old female, Harlan Lab., Udine Italy) [ANNEX I, II] were obtained from a total of 145 animals, , HepG2 cells were transplanted into the subcutaneous area of the right hind paw, and the tumor volume was 205.28 ± 51.66 mm 3 (138.79 ~ 351.51 mm 3 ) were selected again, and 7 mice per group were used in this experiment. Eight normal control mediums were also prepared based on body weight (weight: normal group - 25.24 ± 2.36 g, 22.70 ~ 30.10 g; tumor transplantation group - 25.33 ± 1.62 g, 22.20 ~ 29.40 g) (Table 8, Fig.
Group separation (total 7 groups; 8 per group)
(1) Intact control: Normal medium control
(2) TB control: treated with sterile distilled water after HepG2 tumor cell transplantation
3) SF20: administration of
(4) SHSGT400: Shihosangan-tang after
(5) SF + SHSGT400: 20 mg / kg of sorafenib and 400 mg / kg of Shihosangan bath after tumor cell transplantation
(6) SF + SHSGT200: 20 mg / kg of sorafenib and 200 mg / kg of Shihosangan bath after tumor cell transplantation
(7) SF + SHSGT100: 20 mg / kg of sorafenib and 100 mg / kg of Shihosangan bath after tumor cell transplantation
Tumor cell transplantation: 37 ℃ using HepG2 (American Type Culture Collection Center, Manassas, VA, USA) a 10% fetal bovine serum (FBS) RPMI 1640 with the addition of (Gibco, Grand Island, NY, USA) cell culture medium, The cells were maintained in a 5% CO 2 incubator and maintained at a density of 1.0 × 10 8 cells / ml. Subsequently, 0.2 mL (2 × 10 7 cells / mouse) of HepG2 tumor cell suspension was injected subcutaneously into the dorsal hind paw of the mouse To form a solid mass. In this study, oral administration of sorafenib or Shihosangan tang was started from the day 21 (tumor volume; 205.28 ± 51.66 mm 3 , 138.79 ~ 351.51 mm 3 ) of HepG2 lung cancer cell transplantation.
Drug administration: From 21 days after HepG2 lung cancer cell transplantation, 400, 200, or 100 mg / kg of Sihosogan Tang were orally administered to
Observations: IC 50 (cytotoxicity), a concentration that inhibits the survival rate of HepG2 cells by 50%, was evaluated by the general MTT method, and HepG2 hepatoma cell transplantation mice were treated with anti-cancer and immunosuppressive effects and tumor- (Tables 8 and 9, Fig. 4).
* All antisera were raised in rabbits.
PARP = Cleaved poly (ADP-ribose) polymerase
ABC = A
(1) Antitumor effect: Changes in tumor cell volume and apoptotic cell percentages in tumor volume, tumor weight, forming mass, changes in caspase-3, PARP, COX-2, iNOS and TNF-α immunoreactivity in mass
(2) Immunological activity: Changes in immunoglobulin (thymic and submandibular) weights, serum IFN-γ content, NK cell activity, splenic TNF-α, IL-1β and IL-10 content, , Changes in TNF-α immunoreactivity in the masses and subcutaneous lymph nodes,
(3) Tumor-related cachexia-inhibiting effects: Changes in body weight, ovarian fat mass, blood IL-6 content,
3.2. Cytotoxicity Cytotoxicity )
(1) Influence on survival rate of HepG2 cells in Shihosangan-tang
The decrease in HepG2 cell viability was significantly (p <0.01) lower than that of the vehicle control group (0 mg / ml treated group), and the IC 50 was 9.21 ± 2.75 mg / ml (Fig. 5).
(-0.4 mg / ml), and -30 mg / kg, respectively, compared with the untreated control group (0 mg / ml treated group) at 0.5, 1, 5, 10, 50, 100 and 500 mg / -96.31, -97.24, and -98.10% points of HepG2 cell survival rate.
(2) Effect of Sorafenib on HepG2 cell viability
A decrease in HepG2 cell survival rate (p < 0.01 or p < 0.05) as compared to the vehicle control group (0 μM treated group) began to be recognized from the
(-0.82, -8.92, -37.20, -48.70, -59.33, -79.13 and -0.92, respectively) in Sorafenib 0.1, 1, 2, 4, 6, 8 and 10 μM treatment groups -89.75% point of HepG2 cell survival rate.
3.3. Weight and Weight gain change
A significant (p < 0.01) decrease in body weight during the administration period was also observed in the tumor-transplant control group at 14 days after the start of administration, (P <0.01 or p <0.05) in the sorafenib alone group compared to the tumor control group, and the body weight gain during the administration period was also significantly higher than that of the tumor control group (p <0.01 or p <0.05) ≪ 0.01). On the other hand, the body weight gain was significantly increased (p <0.01 or p <0.05) in the shihojangan tang alone group compared with the tumor control group, and the increase in body weight was significantly (p <0.01 (P <0.01 or p <0.05) in
[B-A]
Single formula treated
Sorafenib and SHSGT co-administered within 5
a p <0.01 and b p <0.05 compared with intact control by LSD test
c p <0.01 as compared with TB control by LSD test
d p <0.01 as compared with sorafenib single formula mice by LSD test
The weight gain during the administration period (35 days; body weight at the end of sacrifice - body weight at the start of administration) showed a change of -151.20% point compared with the normal medium control group in the tumor graft control group, and sorafenib 20 mg / In the group treated with 400 mg / kg hot water, 400 mg / kg, 200 mg / kg and
3.4. tumor volume change
(P <0.01 or p <0.05) in the Sorafenib-treated group compared with the tumor-grafted control group after 14 days from the start of administration, and the change in the tumor volume during the administration period was also significant <0.01). In the group administered with 400 mg / kg of Shiho Sangan-tang alone, the tumor volume was significantly decreased (p <0.01) from 14 days after the administration of the tumor graft control, 200 and 100 mg / kg, and sorafenib 20 mg / kg for 5 min, the tumor volume was significantly (p <0.01) lower than that of the sorafenib alone group from 21 days after the start of administration and the tumor volume (P < 0.01) reduction compared to sorafenib alone (Table 11, Figures 8 and 9).
[BA]
a p <0.01 as compared with TB control by LSD test
b p <0.01 as compared with sorafenib single formula mice by LSD test
Changes in tumor volume during the drug administration period (5 weeks; tumor volume at the end of the sacrifice day - tumor volume at the start of the administration) were determined by sorafenib 20 mg / kg and
3.5. Change in tumor weight
(P <0.01) decreased relative to tumor and absolute weight in all drug - administered groups, including 400 mg / kg monotherapy group, compared with the tumor - grafted control group. On the other hand, the decrease in tumor weight was significantly (p <0.01 or p <0.05) significantly higher than the sorafenib 20 mg / kg alone administration group in all of
a p <0.01 compared with intact control by LSD test
b p <0.01 as compared with TB control by LSD test
c p <0.01 and d p <0.05 as compared with sorafenib single formula mice by LSD test
e p <0.01 and f p <0.05 as compared with intact control by MW test
g p <0.01 compared with TB control by MW test
h p <0.01 as compared with sorafenib single formula mice by MW test
Single formula treated
Sorafenib and SHSGT co-administered within 5
a p <0.01 compared with intact control by LSD test
b p <0.01 and c p <0.05 as compared with TB control by LSD test
d p <0.01 as compared with sorafenib single formula mice by LSD test
e p <0.01 and f p <0.05 as compared with intact control by MW test
g p <0.01 compared with TB control by MW test
h p <0.01 as compared with sorafenib single formula mice by MW test
, -64.15, -90.75, respectively, compared with the tumor-grafted control group in the combination therapy of
3.6. Change in spleen weight
In the tumor-grafted control group, there was a significant (p <0.01) decrease in spleen absolute and relative weight compared to the normal medium control group. However, in the 400 mg / kg monotherapy group and 400 mg / kg group, (p <0.01) weight gain was observed in
Absolute weight of spleen showed -53.16% point change in tumor-grafted control group compared with normal medium control group, sorafenib 20 mg / kg and 400 mg / kg saline alone, 400 mg, 200 mg and 100 mg / kg and 20 mg / kg of sorafenib showed -29.04, 58.23, 90.27, 72.01 and 61.08% points of change compared to the tumor control group, respectively.
The relative weight of spleen showed a change of -41.08% point compared to the normal medium control group in tumor graft control group, sorafenib 20 mg / kg and 400 mg / kg saline alone, 400 mg / / kg and 20 mg / kg of sorafenib showed a -20.36, 39.12, 55.44, 39.07 and 38.98% points of change compared with the tumor-grafted control, respectively.
3.7. Subconsciousness Change in weight
(P <0.01) in the tumor transplantation control group compared with the normal medium control group. However, in the tumor transplantation control group, the absolute and relative weight of the subcutaneous lymph node were decreased, And sorafenib were significantly higher (p <0.01) than those of the transplant control group, respectively. In particular, sorafenib was significantly increased compared with sorafenib alone at 400, 200 and 100 mg / Significant (p < 0.01) subtle lymph node Absolute and relative weight gain was admitted dose-dependently. In contrast, sorafenib 20 mg / kg alone was significantly (p <0.01 or p <0.05) lower than that of the tumor-grafted control group in absolute and relative weight reduction (Table 12 and 13).
The absolute weight of the sublingual lymph node showed a -67.53% point change in the tumor-grafted control group compared to that of the normal medium control group.
The relative weight of the subcutaneous lymph nodes was -58.82% in the tumor control group compared to the normal control group, and sorafenib 20 mg / kg and 400 mg / kg saline alone, and 400, 200 and 100 mg / kg and
3.8. Change of fat weight around ovary
(P <0.01) in the tumor transplantation group compared to the normal medium control group. However, in the group treated with Shihosangan bath and all three doses of Shihosangan bath and sorafenib, the tumor transplantation control group (100 mg / kg) and
Absolute and relative weights of the ovarian adipose tissues were -66.29 and -57.97%, respectively, in the transplant control group compared with the normal control group.
3.9. Blood IL -6 and IFN -γ content change
In the tumor-grafted control group, serum IL-6 and IFN-γ contents were significantly (p <0.01) lower than those of the normal medium control group. / kg and sorafenib were significantly (p <0.01) lower in serum IL-6 and IFN-γ levels than the tumor-grafted control, respectively. Especially, all three doses of serotonin and sorafenib (P <0.01), respectively, as compared with those treated with sorafenib alone, and the increase of IFN-γ content was dose-dependently recognized. In the sorafenib alone group, serum IL-6 and serum IFN-γ levels were significantly (p <0.01) lower than those of the transplant control group (FIG. 10).
Serum IL-6 levels were 543.72% in the tumor control group compared to the normal control group, and sorafenib 20 mg / kg and 400 mg / kg of saline alone, 400 and 200 and 100 mg / kg and
Serum IFN-γ levels were -50.21% in the tumor control group compared to the normal control group, and sorafenib 20 mg / kg and 400 mg / kg saline alone, In the group treated with 100 mg / kg and
3.10. NK cell Change in activity
Significant (p <0.01) decrease in spleen and peritoneal NK cell activity was observed in the tumor transplantation control group compared to the normal medium control group, but significantly higher than that in the tumor transplantation control group (p <0.01 ) Increased in spleen and peritoneal NK cell activity. Especially, the increase in spleen and peritoneal NK cell activity was significantly (p <0.01) significantly higher than that of sorafenib alone . On the other hand, sorafenib alone showed a significant decrease in spleen and peritoneal NK cell activity (p <0.01) as compared with the tumor graft control group (FIG. 11).
The splenic NK cell activity was -64.07% in the tumor control group compared to the normal control group, and sorafenib 20 mg / kg and 400 mg / kg of Sihosogan tang alone,
Peritoneal NK cell activity showed a -69.58% point change in the tumor-grafted control group compared to the normal medium control group.
3.11. spleen cytokine Change in content
In the tumor-grafted control group, spleen TNF-α, IL-1β and IL-10 contents were significantly decreased (p <0.01) compared with the normal medium control group. (p <0.01 or p <0.05), respectively, in the group treated with salmeterol / mg / kg and sorafenib, respectively. Especially, all three doses of saline group (400, 200 and 100 mg / kg) and sorafenib (p <0.01), respectively, as compared with those treated with sorafenib alone, the increase in the levels of spleen TNF-α, IL-1β and IL-10 was dose-dependent. In the sorafenib-treated group, the levels of spleen TNF-α, IL-1β and IL-10 were significantly decreased (p <0.01 or p <0.05).
a p <0.01 and b p <0.05 compared with intact control by MW test
c p <0.01 and d p <0.05 compared with TB control by MW test
e p <0.01 as compared with sorafenib single formula mice by MW test
In the tumor-grafted control group, the spleen TNF-α content was -61.21% as compared with the normal control group, and sorafenib 20 mg / kg and
In the tumor-grafted control group, splenic IL-1β content was -73.15% as compared with the normal medium control group.
The amount of splenic IL-10 in the tumor-transplanted control group was -63.34% higher than that in the normal control group, and sorafenib 20 mg / kg and
3.12. Histological change
3.12.1. Histopathological change of mass
Undifferentiated polymorphic hepatocellular carcinoma (HepG2) cells were strongly constituted in the tumor-grafted control group. In some cells, apoptosis caused an increase in cytoplasmic acidity and nuclear enrichment, and mitosis was also frequently observed. On the other hand, apoptotic cells were significantly increased (p <0.01) in the sorafenib and serotonin-treated groups, and all of the three doses of Shihosangan-tang and sorafenib-treated groups were significantly increased (p <0.01) (P <0.01 or p <0.05), respectively, compared with sorafenib alone (p <0.01 or p <0.05) in the combination of 400, 200 and 100 mg / kg of sorafenib and 20 mg / kg of sorafenib volume reduction and apoptotic cell number increase were administrated dose-dependent (Table 15, Figure 12).
a p <0.01 as compared with TB control by LSD test
b p <0.01 and c p <0.05 as compared with sorafenib single formula mice by LSD test
In addition, there was a significant (p <0.01) increase in the number of caspase-3 and PARP-immunoreactive cells in the mass compared with that in the tumor-grafted control group in all the treatment groups including 400 mg / (P <0.01), respectively, compared with sorafenib alone (p <0.01), but the number of caspase-3 and PARP-immunoreactive cells increased significantly Was recognized dose-dependently with the decrease in the number of COX-2 immunoreactive cells (Table 15, Figs. 13-15). Significant increases in the number of iNOS and TNF-α immunoreactive cells in the mass were significant (p <0.01) in the group treated with Shihosangan tang alone or in all groups treated with Shihosangan, The number of iNOS and TNF-α immunoreactive cells was significantly (p <0.01) significantly higher than sorafenib alone (100 mg / kg and
The proportion of tumor cells in the tumor tissues was significantly higher in the sorafenib group treated with
The proportion of apoptotic cells in the tumor tissues was significantly higher in
The proportion of caspase-3 immunoreactive cells in the tumor tissues was significantly higher in
The proportion of PARP-immunoreactive cells in the tumor tissues was significantly higher in
The proportion of COX-2 immunoreactive cells in tumor tissues was significantly higher in
The proportion of iNOS-immunoreactive cells in the tumor tissues was significantly higher in
The proportion of TNF-α immunoreactive cells in the tumor tissues was significantly higher in
3.12.2. Histopathological changes of the spleen
In the tumor-grafted control group, atrophy characterized by significant lymphocyte reduction in the spleen white water quality portion was recognized and a significant (p < 0.01) reduction in spleen thickness, white water quality diameter and number were recognized, respectively. Significant increases (p <0.01 or p <0.05) in spleen thickness, white water quality diameter and number were recognized in the histopathologically significant group compared with the tumor graft control group in the combination of Shihosangan bath alone and all three doses, In particular, the increase in spleen thickness, white water diameter, and number of sorafenib treated rats treated with
(mm / central regions)
a p <0.01 and b p <0.05 compared with intact control by LSD test
c p <0.01 and d p <0.05 as compared with TB control by LSD test
e p <0.01 as compared with sorafenib single formula mice by LSD test
The total thickness of the spleen showed a change of -38.54% point in the tumor-transplanted control group compared to the normal medium control group, and sorafenib 20 mg / kg and 400 mg / kg saline alone, 400 mg, 200 mg and 100 mg / kg and
The number of spleen white water was -57.83% in the tumor control group compared with the normal medium control group, and sorafenib 20 mg / kg and 400 mg / kg of saline alone, 400, 200 and 400 mg / 100 mg / kg and
The diameter of the spleen white water showed a -45.45% point change in the tumor-transplanted control group compared with the normal medium control group.
3.12.3. The Lymphatic Histopathological change
In the tumor-grafted control group, significant atrophy of the lymph node was observed in the lymph node compared with the normal medium control, and significant decrease (p <0.01) in the total lymph node, cortical thickness and the number of follicles in the cortex were recognized. On the other hand, the total number of lymph nodes, cortical thickness, and the number of follicles in the cortex were significantly increased (p <0.01 or p <0.05) The administration of sorafenib (100 mg / kg) and sorafenib (20 mg / kg) significantly increased the total number of lymph nodes and the number of follicles in the cortex (p <0.01) . On the other hand, sorafenib alone was significantly (p <0.01) significantly lower than that of the tumor-transplanted control group, and the cortical thickness and the number of follicles in the cortex were decreased (Table 17, Fig. 19).
(μm / central regions)
a p <0.01 compared with intact control by LSD test
b p <0.01 and c p <0.05 as compared with TB control by LSD test
d p <0.01 as compared with sorafenib single formula mice by LSD test
e p <0.01 as compared with intact control by MW test
f p <0.01 and g p <0.05 compared with TB control by MW test
h p <0.01 as compared with sorafenib single formula mice by MW test
The total thickness of the submandibular glands was -55.35% compared to the normal control group in the tumor-grafted control group, and sorafenib 20 mg / kg and 400 mg / kg saline alone, mg / kg and
The number of follicles in the submandibular cortex was -66.31% compared to the normal control group in the transplant control group, and sorafenib 20 mg / kg and 400 mg / kg saline alone, 200, and 100 mg / kg, and sorafenib 20 mg / kg, respectively, showed a change of -44.44, 90.48, 171.43, 144.44, and 90.48% points, respectively, compared with the tumor graft control group.
The thickness of subcortical cortical cortex showed a -74.57% point change in the tumor-transplanted control group, and sorafenib 20 mg / kg and 400 mg / kg of Shiho Sangan-tang alone,
11.4. Histopathological changes in the ovarian fats: In the tumor-grafted control group, atrophy characterized by a marked decrease in the size of white adipocytes was observed, and significant (p <0.01) accumulation fat thickness and white fat cell mean Respectively. On the other hand, cumulative fat thickness and mean diameter of white adipocytes (p <0.01 or p <0.05) were significantly (p <0.01 or p <0.05) higher in the group treated with Shihosangan tang and Shihosangan tang at 400, 200 and 100 mg / kg and sorafenib (P <0.01), respectively, and the mean diameter of white adipocytes was significantly increased in sorafenib - treated group compared with sorafenib - treated group. (P <0.01 or p <0.05), respectively, in sorafenib alone group (Table 18, Fig. 20).
Values are expressed mean ± S.D. of eight mice
SHSGT = Shihosogan - tang purchase from HANZUNG PHARM. CO. LTD. (Daejeon, Korea)
TB = tumor-bearing
a p <0.01 compared with intact control by LSD test
b p <0.01 and c p <0.05 as compared with TB control by LSD test
d p <0.01 as compared with sorafenib single formula mice by LSD test
e p <0.01 and f p <0.05 as compared with intact control by MW test
g p <0.01 and h p <0.05 compared with TB control by MW test
i p <0.01 as compared with sorafenib single formula mice by MW test
The thickness of the accumulated fat around the ovaries was -66.48% compared with the normal control group in the transplantation control group, and sorafenib 20 mg / kg and 400 mg / kg of Shiho Sangan-tang alone, And 100 mg / kg and
The average diameter of ovarian white adipocytes was -57.61% in the transplantation group compared to the normal control group, and sorafenib 20 mg / kg and 400 mg / kg saline alone, , -29.00, 47.38, 88.25, 67.27, and 47.09%, respectively, in the group treated with 200 and 100 mg / kg of sorafenib and 20 mg / kg of sorafenib compared with the control group of the tumor.
As a result of Example 3, the IC 50 values for HepG2 cells were calculated to be 9.21 ± 2.75 mg / ml and 3.51 ± 0.72 μM (1.63 ± 0.33 μg / ml), respectively, and HepG2 cell transplantation Histopathologic atrophy due to decreased lymphocyte counts of spleen and nasopharyngeal lymph nodes, serum IFN-γ content, spleen TNF-α, IL-1β and IL-10 content, , Decreased body weight and body weight gain, increased serum IL-6 levels, decreased ovarian fat mass, and histopathologic evidence of atrophy of surrounding fat tissue around the ovaries. Thus, after tumor transplantation, typical tumor-associated immunosuppression and cachexia are thought to have been induced. In addition, the reduction of volume and weight of sorafenib by 20 mg / kg of sorafenib was associated with a decrease in the percentage of tumor cells due to an increase in apoptotic cells in the histopathologic examination, and that of caspase-3 and PARP immunoreactivity (IL-6) and immunosuppression (weight of spleen and subcutaneous lymph nodes, serum IFN-? Levels, and serum IL-6 levels) NK cell activity, changes in the intracellular TNF-α, IL-1β and IL-10 levels, and histological changes in the immunological organs) were observed to be significantly exacerbated and the iNOS and TNF- Were observed to have no effect. On the other hand, in the group treated with Shihosangan tang alone, significant immunological activity and decrease of tumor - associated cachexia were observed compared with the tumor graft control group. However, anticancer effect on the mass itself was relatively lower than that of the sorafenib treated group. On the other hand, all of the three doses of Shihosangan tang and sorafenib treated group showed significant inhibition of anti-cancer, immunological activity, and tumor-associated cachexia compared to the tumor-transplant control group. Especially, all three doses of
In addition, a significant increase in the tumor-associated cachexia-suppressing effect and the anticancer activity due to the remarkable immunological activity was recognized in the group of sorafenib-treated group, which was the lowest dose used in Example 3, as compared with sorafenib alone group, When combined with 100 mg / kg or more of Shihosangan water, the anticancer effect of sorafenib is clearly increased by immunological activity, and it is considered that it can control tumor related cachexia.
Sihosoganthang and sorafenib were calculated as the IC 50 of 9.21 ± 2.75 mg / ml and 3.51 ± 0.72 μM (1.63 ± 0.33 μg / ml), respectively, for HepG2 cells, and Shihosangan tang had relatively low cytotoxicity against HepG2 cells While sorafenib showed relatively strong cytotoxicity. On the other hand, the IC 50 of sorafenib against HepG2 cells is known to be about 5 μM (2.32 μg / ml), depending on the experiment [Blivet-Van Eggelpoel et al., 2012].
As a result of Example 3, a remarkably superior reduction in tumor volume and tumor weight was observed in the combination treatment with sorafenib at a dose of 400 mg / kg, 200 mg, and 100 mg / kg, compared with sorafenib alone at 20 mg / kg. The anticancer effect of sorafenib was significantly increased. On the other hand, the anti-cancer synergistic effect according to the combination of Shihosangan bath was relatively low cytotoxicity in the cytotoxicity test for HepG2 cells, but the increase of apoptotic cells in the mass and the immunoreactivity were confirmed in various tests In conclusion, it seems to be due to immune activity rather than cytotoxicity to direct tumor cells.
As a result of this Example 3, the transplantation of human hepatocarcinoma HepG2 cells resulted in reduction of the immunoreactive cytokines TNF-α and IL-1β in the spleen and IFN-γ blood levels, and T lymphocyte and immunosuppression Of IL-10, an immunosuppressive cytokine, was also recognized. In addition, the decrease in the intracellular level of TNF-α, IL-1β and IL-10 and the decrease of IFN-γ in blood were remarkably inhibited by all the administration of Shihosangan-tang, And 100 mg / kg, respectively, the levels of TNF-α, IL-1β and IL-10 spleen and the serum level of IFN-γ were significantly increased in comparison with sorafenib alone.
As a part of tumor-related immunosuppression, it is known that the function of immunocompetent cells such as NK cells and macrophages is inhibited during tumorigenesis, and the activity of these immunocompetent cells is currently attracted to the development of another concept of anti-cancer agent [Ha et al. , 2004; Yu and Hwang, 2004]. In the results of this experiment, it was observed that the activity of splenocytes and abdominal macrophages was decreased in the tumor transplant control group, and the activity of the NK cell was significantly reduced in sorafenib alone group compared with the tumor graft control group. However, , The dose-dependent abdominal and spleen NK cell activity was observed. In the combination of 400, 200 and 100 mg / kg of Shiho Sangan-tang, the increase in NK cell activity was significantly higher than sorafenib alone .
In Example 3, caspase-3 and PARP immunoreactivity associated with administration of sorafenib or Shihosangan-tang was increased, and in particular, the combination of 400, 200 and 100 mg / kg of Shihosangan tang was significantly higher than that of sorafenib alone The increase in caspase-3 and PARP immunoreactivity in the tumor was observed in a dose-dependent manner, and the anticancer effect of sorafenib was significantly increased by administration of 100 mg / kg or more of salbutamol and 100 mg / kg of prostaglandins And inhibition of COX-2 immunoreactivity, which is known to be involved in angiogenesis in tumors, was observed in all drug-administered groups, including sorafenib alone, and these inhibitors also inhibited COX-2 immunoreactivity at 400, 200 and 100 mg / kg Of patients treated with sorafenib compared with sorafenib alone. In general, the increase in iNOS activity is associated with endotoxin, IL-1β, TNF-α, and IFN-γ, resulting in shock and excessive inflammatory responses, and is known to exacerbate tumors such as angiogenesis. However, It is also known that iNOS secreted from cells induces apoptosis of tumor cells, resulting in inhibition of tumor growth [Xie et al., 1995]. In Example 3, a significant increase in iNOS immunoreactivity in HepG2 cell transplantation mass was observed in all experimental groups except
Cachexia, one of the most important side effects in tumors, is the most important cause of poor quality of life in malignant tumors and is known to cause various chronic complications including marked malnutrition, dehydration, weight loss, etc. [Oka et al., 1996; Tisdale, 1997; Inui, 1999]. Various studies to date [Strassmann et al., 1992; Fujita et al., 1996; According to Kurebayashi et al., 1999, IL-6 secreted by tumor cells is known to be the cause of tumor cachexia, and it is known that there is a significant increase in blood IL-6 level in actual tumor patients [Oka et al. , 1996]. In the results of this experiment, although decrease in body weight and atrophy and decrease in accumulated fat tissue were recognized after tumor transplantation with a remarkable increase in serum IL-6 content, these tumor-associated cachexia phenomena were remarkably suppressed in the group treated with Shihosangan tang , Especially
In other words, administration of
Example 4. Liver cancer treatment Sorafenib ( Nexvar TM )Wow Shiho Conjugated administration experiment: Shihosangantan sorafenib Toxicity-reducing effect
4.1. Experimental Method
Experimental animal name:
Male ICR mice (Male ICR mice)
SPF / VAF Outbred CrljOri: CD1 [ICR] Male mice (OrientBio, Seungnam, Korea) were purified for 9 days and then weighed 7 mice per group based on body weight (mean: 33.69 ± 1.41 g, 31.30 ~ 36.80 g) (Table 19, Figure 21).
Experimental group and use number : sufficient number of interpretation of experimental results
Total 6 groups (including medium control group); Seven grains per group (total 42 used)
(G3M) sorafenib 100 mg / kg, and 400 mg / kg sorbenib (G1M) sorafenib alone, (G2M) 400 mg / kg alone group, G4M) sorafenib 100 mg / kg and
Experimental purpose · Method of administration · Administration dose : Experimental purpose Clinical application route / Approach to obtain lethal dose in outline
Oral administration ( oral gavage ; Sterile distilled water is used as a solvent for oral dosing once a day for 28 days at a dose of 10 ml / kg.) - 400, 200 or 100 mg / kg of Sihosogan bath is administered to
Shiho Sanggantang It is a typical prescription for restoring the metabolic function of liver damaged by anger, stress and overwork, improving blood circulation, relieving tension of smooth muscle and stopping pain, and is a combination prescription consisting of 7 kinds of natural products (Table 1 ), sorafenib is tyrosine protein kinases and Raf kinases inhibitor, which are typical oral anticancer drugs frequently used in advanced kidney cancer and liver cancer, immunosuppression due to extreme lymphopenia, serious interaction with other drugs, Such as hypersensitivity reactions to the use of various side effects are questionable. The purpose of this study was to evaluate the sorafenib toxicity reduction effect of Shiho Sangan - tang as a part of an integrated medical study of sorafenib and Shihosogan tang in patients with liver cancer using a mouse. The dose of sorafenib is 125 mg / kg, which is known to show death and irreversible toxicity in repeated oral administration in rats [European Medicines Agency, 2006; Mellor et al., 2011] was set at a relatively low dose of 100 mg / kg. In Example 4, Shihosangan water or sorafenib was dissolved in sterilized distilled water and orally administered at a dose of 10 ml / kg, which is a general oral dose of rodents, once a day for 28 days at an interval of 5 minutes or less (Table 19; 21).
Observation period and items : 4 weeks; Mortality, clinical symptoms, weight change, autopsy findings
28 days; Table 3) and changes in blood chemistry (20 items; Table 4), histopathologic changes (23 organ: brain-cerebral, cerebellum and training) Esophagus, Gastrointestinal tract, Lung, Testicular, Epididymal, Kidney, Adrenal gland, Spleen, Liver, Pancreas, Gastrointestinal tract, Esophagus, Cell activity.
4.2. death rate
As a result of this experiment, mortality associated with the administration of the test substance was not recognized during the 28-day experimental period, and final autopsy was performed on all the experimental animals (7/7; 100%) in all experimental groups (Table 22).
a treatment day
* Total mortalities during 28 days of observation periods - died animals / total observed animals (percentages; seven mice per group)
4.3. Clinical symptoms
As a result of Example 4, the clinical symptoms associated with the administration of the test substance were not observed during the 28-day experimental period (Table 23).
4.4. Weight and Weight gain change
In the sorafenib group treated with
* Day of treatment after overnight fasted
** Days of sacrifice after overnight fasted
a p <0.01 and b p <0.05 compared with vehicle control by LSD test
c p <0.01 and d p <0.05 as compared with sorafenib single-treated mice by LSD test
4.5. Change in long-term weight
In the case of
a p <0.01 compared with vehicle control by LSD test; b p <0.01 and c p <0.05 as compared with sorafenib single-treated mice by LSD test
d p < 0.01 and e p < 0.05 compared to vehicle control by MW test; f p <0.01 and g p <0.05 as compared with sorafenib single-treated mice by MW test
L, left sides; S, splenic lobes; G, gland; LN, submandibular lymph node
a p <0.01 and b p <0.05 compared with vehicle control by LSD test; c p <0.01 and d p <0.05 as compared with sorafenib single-treated mice by LSD test
4.6. Hematological change
As a result of 14 hematologic tests, sorafenib alone showed a significant decrease (p <0.01) in WBC and a decrease in lymphocyte ratio and associated neutrophil leukocyte ratio compared to the medium control group. However, Or 400 mg / kg and sorafenib, respectively, were significantly (p <0.01 or p <0.05) higher than those of
a p <0.01 compared with vehicle control by LSD test; b p <0.01 as compared with sorafenib single-treated mice by LSD test
c p <0.01 compared with vehicle control by MW test; d p <0.01 and e p <0.05 as compared with sorafenib single-treated mice by MW test
4.7. Blood biochemical change
Twenty blood biochemical tests showed no significant biochemical changes in serum biochemical changes compared to the vehicle control group in sorafenib and salbutamol alone, all three doses of salbutamol and sorafenib (Table 28).
4.8. Autopsy findings
In the case of
Single
Normal
Congestion
1+
2/7
2/7
1/7
1/7
1/7
1/7
1/7
1/7
0/7
0/7
0/7
0/7
Normal
Atrophy
1+
2+
0/7
0/7
0/7
7/7
3/7
4/7
0/7
0/7
0/7
3/7
3/7
0/7
3/7
3/7
0/7
3/7
3/7
0/7
Normal
Atrophy
1+
2+
Hypertrophy
1+
0/7
0/7
0/7
2/7
2/7
7/7
3/7
4/7
0/7
0/7
0/7
0/7
0/7
0/7
0/7
2/7
2/7
0/7
0/7
0/7
3/7
3/7
0/7
0/7
0/7
3/7
3/7
0/7
0/7
0/7
Normal
a) Bilateral submandibular lymph node
1+ = slight; 2+ = moderate
4.8. NK cell Change in activity
In
Spleen NK cell activity was significantly (-74.62%) higher in the
Peritoneal NK cell activity showed a -76.80% point change in
4.9. Histopathological observation
In
Single
Single
400 mg /
Normal
1/7
1/7
1/7
1/7
0/7
0/7
Normal
1/7
0/7
0/7
0/7
0/7
0/7
Normal
wDE †
1+
2+
0/7
0/7
0/7
7/7
3/7
4/7
0/7
0/7
0/7
3/7
3/7
0/7
4/7
4/7
0/7
3/7
3/7
0/7
Normal
DS-VO †
1+
2+
0/7
0/7
0/7
7/7
4/7
3/7
0/7
0/7
0/7
3/7
3/7
0/7
3/7
3/7
0/7
4/7
4/7
0/7
Normal
AS-DS †
1+
2+
0/7
0/7
0/7
7/7
4/7
3/7
0/7
0/7
0/7
3/7
3/7
0/7
3/7
3/7
0/7
4/7
4/7
0/7
Normal
dDE †
1+
2+
5/7
2/7
0/7
0/7
0/7
0/7
0/7
7/7
3/7
4/7
7/7
0/7
0/7
0/7
0/7
5/7
0/7
2/7
2/7
0/7
4/7
0/7
3/7
3/7
0/7
5/7
0/7
2/7
2/7
0/7
Normal
1/7
1/7
1/7
1/7
1/7
1/7
Normal
a) Bilateral submandibular lymph node
† CG = congestion spots; CY, focal cyst formation; decrease in white pulp lymphoid cells; rHP = hyperplasia of splenic red pulp cells; DS-VO = reduction of spermatogonia in the seminiferous tubules with vacuole; AS-DS = Decreased spermatozoa and abnormal spermatozoa in the lumen of the epididymal tubules; dHP = diffused hyperplasia of lymphoid cells; dDE = diffused less of lymphoid cells; fCY = focal cyst formation in the mucosa of the fundus; 1+ = slight; 2+ = moderate; 3+ = severe degrees.
In Example 4, Shihosangan water or sorafenib was dissolved in sterilized distilled water and orally administered at a dose of 10 ml / kg, a general oral dose of rodents [Flecknell, 1996], once daily for 28 days at an interval of 5 minutes .
As a result of Example 4, blood biochemical changes, deaths, and clinical symptoms associated with administration of sorafenib or Shihosangan tang were not recognized during the pre-experiment period, but in
On the other hand, in the group administered with 400 mg / kg Shihosangan tang alone, significant weight, clinical symptoms, hematology, blood biochemistry, gross autopsy and histopathological changes were not observed compared with the medium control group.
The mice in the group administered with the medium control group, sorafenib and Shihosanthang alone group, all three doses of Shihosangan
The histopathological examination of the spleen and submandibular ganglion atrophy observed in
Most target-oriented anticancer drugs including sorafenib, which have been developed so far, not only inhibit the growth differentiation of the tumor cells themselves, but also have various effects on various immunocompetent cells including normal cells other than the target, especially T lymphocytes, NK cells, monocytes and dendritic cells , And is known to induce inhibition mainly [Hipp et al., 2008; Zhao et al., 2008; Alfaro et al., 2009; Krusch et al., 2009]. NK cells are known to be one of the most important immunocompetent cells in the innate immune system and are known to inhibit growth and disseminated metastasis of various tumor cells [Vivier et al., 2008], with T and B lymphocytes In contrast, it exhibits cytotoxicity directly against tumor cells [Levy et al., 2011], without the secretion of immunoreactive cytokines such as interferon-γ (IFN-γ), which regulate basic sensitization processes and tumor metastasis and local growth, Inhibition of NK cell activity has been accepted as directly implicating an increased likelihood of tumorigenesis [Imai et al., 2000]. Therefore, the activity of NK cells is currently attracting attention as another concept of cancer drug development [Ha et al., 2004; Yu and Hwang, 2004]. The NK cell activity is inhibited by sorafenib in vitro [Krusch et al., 2009] and in In vivo [Zhang et al., 2013] experiments, it is well known that the results of this experiment also showed a significant decrease in spleen and abdominal NK cell activity in the sorafenib monotherapy group compared to the medium control group. On the other hand, the increase in peritoneal and spleen NK cell activity, which was significantly higher in sorafenib-treated group than in sorafenib-treated group, was found to be dose-dependent in all three doses of Shihosangan-tang and sorafenib-treated group. This is a direct proof of the marked reduction in immunosuppression. On the other hand, no significant change in NK cell activity was observed in the 400 mg / kg single dose group of Shihosangan bath compared to the medium control group. The immunoregulatory effect of Shihosangantang has been well known [Ao et al., 2007; Zhong and Gong, 2007; Zhang et al., 2010; Qiu et al., 2011].
Sorafenib inhibits tyrosine protein kinases and Raf kinases [Wilhelm et al., 2008; Smalley et al., 2009], a representative oral anticancer agent frequently used in advanced kidney cancer and liver cancer [Bayer, 2007; Keating and Santoro, 2009], are known to induce apoptosis of tumor cells through various methods [Cervello et al., 2012; Huang et al., 2013; Kim et al., 2013; Liu et al., 2013], may also promote apoptosis in rapidly dividing normal cells such as testicular and epididymal rather than target tumor cells. In conclusion, we concluded that the reduction of testicular spermatogonial cells and the decrease of testicular and epididymal weights associated with the presence of sorafenib in the testis, . In addition, since sorafenib-induced testicular and epididymal damage was significantly inhibited by the administration of all three doses of saline, saline administration of sorafenib at a dose of 100 mg / kg or more, It is expected to significantly suppress. On the other hand, significant inhibition of testicular and epididymal weight, visual and histopathological changes was not observed in the 400 mg / kg administration group of Shihosangan tang compared to the medium control group.
No significant changes in RBC, HGB, HCT, MCV, MCH, MCHC, PLT, MON%, EOS% and BAS% were observed in sorafenib alone or in all groups treated with sorafenib As a result of blood biochemical tests, significant blood biochemical changes were not observed in the sorafenib and serotonergic monotherapy groups, all three doses of serotonin and sorafenib combination groups compared with the medium control group.
On the other hand, mild pulmonary hypertrophy and subcutaneous lymph node enlargement confirmed by gross autopsy, mild pulmonary hypertrophy observed during histopathological examination, renal cyst formation, diffuse lymphocytic enlargement of lymph node and supratentorial cystic function were all included in the experimental group , And it is thought to be an accidental lesion, not a toxic symptom due to the administration of the test substance. These symptoms are rarely observed in normal mice [Roh and Ku SK, 2010; Lee et al., 2011; Choi et al., 2014; Kim et al., 2015].
In other words, administration of
Claims (6)
Characterized in that the sorafenip and the cyphosanthanthin extract are formulated prior to mixing or separately formulated.
Wherein the sorapenip and the cyphosanate extract are administered parenterally, orally, locoregionally, or transdermally.
Wherein the administration of the Soshosangan hot water extract is started from 1 minute to 30 minutes after administration of the anticancer agent.
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| WO2019168388A1 (en) * | 2018-02-28 | 2019-09-06 | 중앙대학교 산학협력단 | Composition for preventing, alleviating, or treating cachexia and muscle loss |
| WO2022098192A1 (en) * | 2020-11-09 | 2022-05-12 | 경희대학교 산학협력단 | Composition for preventing or treating cachexia comprising medicinal herb complex extract |
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| KR101833036B1 (en) | 2017-09-05 | 2018-02-28 | 재단법인 통합의료진흥원 | Compostion comprising Lonicera japonica extract for treatment of kidney cancer |
| WO2019168388A1 (en) * | 2018-02-28 | 2019-09-06 | 중앙대학교 산학협력단 | Composition for preventing, alleviating, or treating cachexia and muscle loss |
| US11684650B2 (en) | 2018-02-28 | 2023-06-27 | Chung-Ang University Industry Academic Cooperation Foundation | Composition for preventing, alleviating, or treating cachexia and muscle loss |
| WO2022098192A1 (en) * | 2020-11-09 | 2022-05-12 | 경희대학교 산학협력단 | Composition for preventing or treating cachexia comprising medicinal herb complex extract |
| KR20220063029A (en) * | 2020-11-09 | 2022-05-17 | 경희대학교 산학협력단 | Composition for preventing or treating cachexia comprising medicinal herb complex extract |
| KR102477343B1 (en) * | 2020-11-09 | 2022-12-13 | 경희대학교 산학협력단 | Composition for preventing or treating cachexia comprising medicinal herb complex extract |
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