Traditional Chinese medicine composition for treating lung cancer bone metastasis and application thereof

Abstract

The application belongs to the field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine composition for treating lung cancer bone metastasis and application thereof. The main active ingredients of the traditional Chinese medicine composition include, in mass parts, 20-40 parts of radix codonopsis, 20-40 parts of poria, 20-40 parts of astragalus, 10-30 parts of atractylodes, 10-20 parts of licorice, 10-30 parts of curcuma, 10-20 parts of pinellia, 5-10 parts of dried tangerine or orange peel, 20-40 parts of oldenlandia, 10-30 parts of psoralea, 10-30 parts of drynaria, 10-30 parts of epimedium, and 10-20 parts of jackinthepulp. Animal experiments show that the traditional Chinese medicine composition can not only inhibit primary tumor growth, but also slow down tumor progression of bone metastasis. When combined with a chemotherapy drug, the traditional Chinese medicine composition can not only significantly enhance the tumor inhibition effect of the chemotherapy drug, but also significantly prolong the survival time of mice, relieve weight loss and organ toxic side effects caused by the chemotherapy drug.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for treating lung cancer bone metastasis and application thereof. BACKGROUND

[0002] Lung cancer is the highest mortality rate of malignant tumor in the world, about 30-40% of patients have bone metastasis at the time of diagnosis, and most of them are osteolytic lesions, often combined with severe pain, pathological fracture and other bone-related events, which seriously threaten the quality of life of patients. The median survival time of lung cancer bone metastasis is only 6-10 months, even after active treatment such as radiotherapy, chemotherapy, immunotherapy and bone protective agents, the one-year survival rate is only 40-50%. At present, there is still a lack of effective intervention strategies for refractory lung cancer bone metastasis.

[0003] At present, lung cancer bone metastasis has made certain progress in traditional Chinese medicine treatment, and more and more traditional Chinese medicine has achieved good effect in the treatment of lung cancer bone metastasis, for example: the HuGuXiao Ji Fang which is based on "tonifying kidney and strengthening bone" can improve bone pain of patients with bone metastasis in cooperation with zoledronic acid, but there is no clear conclusion on tumor inhibition rate and patient survival (Chen Xian, Zhang Haibo, Liu Yihong, et al. The efficacy of HuGuXiao Ji Fang combined with zoledronic acid in the treatment of bone metastasis and the correlation between NTx level and TCM kidney deficiency syndrome [J]. New Chinese Medicine, 2017, 49(10): 117-120. DOI: 10.13457 / j.cnki.jncm.2017.10.037).

[0004] At present, there is still an urgent need for a traditional Chinese medicine composition which can effectively inhibit tumor growth, prolong survival and improve quality of life of patients. SUMMARY

[0005] The first object of the present application is to provide a traditional Chinese medicine composition for treating lung cancer bone metastasis, and the second object of the present application is to provide the application of the traditional Chinese medicine composition.

[0006] According to the first aspect of the present application, a traditional Chinese medicine composition for treating lung cancer bone metastasis is provided, the main active ingredients of which include, by mass fraction: 20-40 parts of radix codonopsis, 20-40 parts of poria cocos, 20-40 parts of radix astragali, 10-30 parts of atractylodes, 10-20 parts of licorice, 10-30 parts of curcuma, 10-20 parts of pinellia, 5-10 parts of dried tangerine or orange peel, 20-40 parts of belamcanda chinensis, 10-30 parts of psoralea, 10-30 parts of drynaria, 10-30 parts of epimedium, and 10-20 parts of arisaema.

[0007] The application considers that lung cancer is caused by deficiency, local excess and systemic deficiency. The pathogenic toxin invades the lung and causes damage to lung collaterals, leading to qi stagnation and blood stasis and accumulation of mass. Blood stasis and heat burn body fluid, causing deficiency of lung yin and kidney yin. Spleen is the source of phlegm, and its dysfunction causes internal water and dampness, accumulation of dampness into phlegm. Lung is the organ for storing phlegm, and phlegm easily blocks lung collaterals and causes accumulation of mass. Therefore, lung cancer is a disease of deficiency in origin and excess in superficiality, and the pathogenesis is deficiency, phlegm, toxin and stasis. The treatment is to combine syndrome differentiation, disease differentiation and symptomatic treatment.

[0008] The TCM syndrome differentiation of bone metastasis mainly belongs to the categories of bone tumor, bone erosion, bone fistula, bone impediment and bone caries in TCM, and the basic pathogenesis is considered to be deficiency of vital qi and excess of pathogenic factors. Deficiency of vital qi is the root, and the lung, spleen and kidney are deficient. Excess of pathogenic factors is the branch, and phlegm and stasis, cancer toxin and impediment of muscles and bones are the branch. Kidney dominates bone, and deficiency of kidney leads to weakness of bone. Cancer toxin easily invades bone along with collaterals and blood. Lung cancer bone metastasis belongs to the late stage of disease, and the disease course is long. Deficiency of kidney leads to deficiency of essence in kidney, and bone loses nourishment. "Where there is deficiency, pathogenic factors will stay there". Cancer toxin stays in the body due to deficiency, and accumulates for a long time to cause bone tumor. Therefore, deficiency of kidney is particularly prominent in lung cancer bone metastasis.

[0009] The prescription mainly supplements kidney and strengthens spleen, and uses Fructus Psoraleae and Herba Epimedii to supplement kidney and strengthen bone, to strengthen the congenital origin. Radix Paeoniae Albus and Radix Codonopsis strengthen spleen and tonify qi, to supplement acquired qi. Fructus Psoraleae, Herba Epimedii, Radix Paeoniae Albus and Radix Codonopsis are the monarch herbs. Rhizoma Arisaematis removes blockage of collaterals, resolves phlegm, and Atractylodes Rhizome removes blood stasis, and stops pain. Radix Dipsaci supplements kidney and strengthens bone, and promotes blood flow and stops pain. Atractylodes Rhizome strengthens spleen and tonifies qi, dries dampness and promotes diuresis. Poria promotes diuresis and removes dampness, and Rhizoma Pinelliae and Pericarpium Citri Reticulatae dry dampness and resolve phlegm, to strengthen spleen and resolve phlegm. Licorice strengthens spleen and tonifies qi, stops cough and relieves asthma, and harmonizes all herbs. Herba Oldenlandiae clears heat and resolves toxin, removes stasis and resolves mass, to attack cancer toxin in lung cancer patients. All the herbs are combined to supplement without stagnation, clear without attacking, attack and supplement together, treat the branch and the root, and together strengthen the body resistance to cancer, strengthen spleen and supplement kidney, resolve phlegm, remove stasis and resolve toxin.

[0010] The raw materials of the prescription are as follows:

[0011] Codonopsis: the root of Codonopsis pilosula (Franch.) Nannf., Codonopsis pilosula Nannf. var. (Nannf.) L.T.Shen or Codonopsis tangshen Oliv.

[0012] Poria: the dried sclerotium of Poria cocos (Schw.) Wolf of the family Polyporaceae.

[0013] Radix Astragali: The dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or A. membranaceus (Fisch.) Bge.

[0014] Radix Atractylodis Macrocephalae: The dried rhizome of Atractylodes macrocephala Koidz.

[0015] Radix Glycyrrhizae: The dried root and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat., or Glycyrrhiza glabra L.

[0016] Rhizoma Curcumae Wenyujin: The rhizome of Curcuma aeruginosa Roxb. [C. zedoaria non Rosc.], Curcuma kwangsiensis S.G. Lee et C.F. Ling, or Curcuma wenyujin Y.H. Chen et C.Ling.

[0017] Rhizoma Pinelliae: The dried tuber of Pinellia ternata (Thunb.) Breit.

[0018] Pericarpium Citri Reticulatae: The dried mature fruit skin of Citrus reticulata Blanco and its cultivated varieties.

[0019] Herba Oldenlandiae Diffusae: The whole herb of Oldenlandia diffusa (Willd.) Roxb.

[0020] Fructus Psoraleae: The mature fruit of Psoralea corylifolia L.

[0021] Rhizoma Drynariae: The rhizome of Drynaria fortunei (Kunze) J. Sm.

[0022] Epimedium: stems and leaves of Epimedium brevicornum Maxim., Epimedium sagittatum, Epimedium wushanense, Epimedium koreanum Nakai, Epimedium pubesens Maxim. and the like.

[0023] Arisaema: dried tuber of Arisaema erubescens (Wall.) Schott., Arisaema heterophyllum BI. or Arisaema amurense Maxim.

[0024] In some embodiments, the main active ingredients include, in parts by mass: Radix Codonopsis 30 parts, Poria cocos 30 parts, Radix Astragali 30 parts, Atractylodes 20 parts, Radix Glycyrrhizae 15 parts, Curcuma 20 parts, Rhizoma Pinelliae 15 parts, Pericarpium Citri Reticulatae 5 parts, Oldenlandia 30 parts, Fructus Psoraleae 20 parts, Drynaria 20 parts, Epimedium 20 parts, Arisaema 15 parts.

[0025] In some embodiments, the Radix Glycyrrhizae is Radix Glycyrrhizae Preparata, the Rhizoma Pinelliae is Rhizoma Pinelliae Preparatum, the Fructus Psoraleae is Fructus Psoraleae Preparatum, and the Arisaema is Arisaema Preparatum. The Radix Glycyrrhizae has the effects of tonifying the center and benefiting qi and clearing heat and detoxifying, and the raw Radix Glycyrrhizae is more effective in clearing heat and detoxifying than the honey-fried Radix Glycyrrhizae; the Rhizoma Pinelliae is pungent and toxic, and the toxicity is reduced after being prepared with ginger, and the Rhizoma Pinelliae can then warm the center and reduce phlegm; the Fructus Psoraleae has the functions of tonifying the kidney and filling essence and strengthening the bone and benefiting qi, and the Fructus Psoraleae is further prepared with salt, and the mechanism of "salty and cold entering the kidney" is used to guide the drug into the kidney, and the prepared Fructus Psoraleae has better kidney-tonifying performance; the Arisaema is bitter, pungent and warm, and toxic, and the toxicity is reduced after being prepared, and the prepared Arisaema can be used internally to dry dampness and reduce phlegm.

[0026] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Specifically, the excipient used is a carrier or excipient commonly used in the art, including but not limited to starch, lactose, glucose, sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose, malt, gelatin, polyols (such as propylene glycol, glycerol, mannitol), tablet pressing agents and the like, to help improve the stability or activity of the drug, or produce an acceptable taste or smell in the case of oral administration.

[0027] In some embodiments, the dosage form of the traditional Chinese medicine composition is a decoction, an oral solution, granules, powder, tablets, pills or capsules. Thus, the clinical administration is facilitated.

[0028] According to a second aspect of the present application, the use of the traditional Chinese medicine composition for treating lung cancer bone metastasis described above in the preparation of a drug for treating lung cancer is provided.

[0029] According to a third aspect of the present application, there is provided use of the Chinese medicine composition for treating lung cancer bone metastasis as described above in the preparation of a medicament for treating distant metastasis of lung cancer.

[0030] In some embodiments, the distant metastasis of lung cancer is lung cancer bone metastasis.

[0031] The beneficial effects of the present application include:

[0032] (1) The present application is based on the fact that patients with advanced lung cancer bone metastasis have deficiency in the origin, and deficiency in the lung, spleen and kidney; and the fact that the patients have excess in the symptoms, and phlegm, blood stasis and cancer toxin blocking the bones. The Chinese medicine composition of the present application is mainly used for tonifying the kidney and strengthening the bones, and for invigorating the spleen and replenishing qi, and is combined with the treatment methods of resolving phlegm, removing blood stasis and detoxification to improve the survival of patients with advanced lung cancer bone metastasis. Not only can the survival period be prolonged, but also the quality of life can be improved by reducing the toxic and side effects of chemotherapy drugs, and the treatment effect is good and the safety is reliable.

[0033] (2) The Lewis lung cancer tumor-bearing mouse model and lung cancer bone metastasis model animal experiments show that the Chinese medicine composition of the present application not only can inhibit the growth of primary tumor, but also can slow down the progression of bone metastasis tumor, and when combined with chemotherapy drugs, not only can significantly enhance the tumor inhibition effect of chemotherapy drugs, but also can significantly prolong the survival time of mice, and relieve the weight loss and organ toxic and side effects caused by chemotherapy drugs. Thus, it is shown that the Chinese medicine composition of the present application can directly slow down the progression of lung cancer primary tumor and bone metastasis, thereby improving the quality of life of patients and prolonging the survival time. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 is the HE staining diagram of the main organs of mice in each group in the Lewis lung cancer tumor-bearing mouse model animal experiment of the present application.

[0035] Figure 2 is the metastatic bone live imaging and fluorescence quantitative statistical results of mice in each group in the mouse lung cancer bone metastasis model animal experiment of the present application.

[0036] Figure 3 is the total survival time and body weight change of mice in each group in the mouse lung cancer bone metastasis model animal experiment of the present application.

[0037] Figure 4 is the lung live imaging and fluorescence quantitative statistical results and lung HE staining diagram of mice in each group in the mouse lung cancer bone metastasis model animal experiment of the present application. DETAILED DESCRIPTION

[0038] The present application will be further described in detail below in combination with specific examples. Unless otherwise specified, the raw materials and reagents used in the present application are commercially available.

[0039] Example 1

[0040] The traditional Chinese medicine decoction for treating lung cancer bone metastasis of the embodiment is prepared from the following raw medicinal materials: Radix Codonopsis 30g, Poria 30g, Radix Astragali 30g, Atractylodes 20g, Glycyrrhiza 15g, Curcuma 20g, Pinellia 15g, Tangerine Peel 5g, Oldenlandia 30g, Fructus Psoraleae 20g, Herba Epimedii 20g, Rhizoma Arisaematis 15g.

[0041] The above components are taken to prepare the traditional Chinese medicine decoction according to the existing traditional Chinese medicine decoction preparation method. The ratio is one dose, and one dose is about 300mL.

[0042] Illustratively, the preparation method of the traditional Chinese medicine decoction is specifically as follows: the above traditional Chinese medicinal materials are mixed according to the ratio, to obtain a mixture, then water is added according to the solid-liquid ratio of 1:10 for soaking for 0.5h, followed by decocting for 0.5h, the first filtrate and the filter residue are obtained by filtration, the filter residue is decocted once, the filtrate obtained by filtration is combined with the first filtrate, sterilized, cooled to room temperature, and then packaged.

[0043] Example 2

[0044] The traditional Chinese medicine oral liquid for treating lung cancer bone metastasis of the embodiment is prepared from the following raw medicinal materials: Radix Codonopsis 30g, Poria 30g, Radix Astragali 30g, Atractylodes 20g, Glycyrrhiza 15g, Curcuma 20g, Pinellia 15g, Tangerine Peel 5g, Oldenlandia 30g, Fructus Psoraleae 20g, Herba Epimedii 20g, Rhizoma Arisaematis 15g.

[0045] The above components are taken to prepare the traditional Chinese medicine oral liquid according to the existing traditional Chinese medicine oral liquid preparation method. The ratio is one dose, and one dose is about 300mL.

[0046] Illustratively, the preparation method of the traditional Chinese medicine oral liquid is specifically as follows: the above traditional Chinese medicinal materials are mixed according to the ratio, to obtain a mixture, then water is added according to the solid-liquid ratio of 1:15 for soaking for 20min, followed by decocting for 1h, the first filtrate and the filter residue are obtained by filtration, the filter residue is decocted once, the filtrate obtained by filtration is combined with the first filtrate, sterilized, cooled to room temperature, and then packaged.

[0047] Example 3

[0048] The traditional Chinese medicine granules for treating lung cancer bone metastasis of the embodiment are prepared from the following raw medicinal materials: Radix Codonopsis 30g, Poria 30g, Radix Astragali 30g, Atractylodes 20g, Glycyrrhiza 15g, Curcuma 20g, Pinellia 15g, Tangerine Peel 5g, Oldenlandia 30g, Fructus Psoraleae 20g, Herba Epimedii 20g, Rhizoma Arisaematis 15g.

[0049] The above components are taken to prepare the traditional Chinese medicine granules by adding carriers or excipients according to the existing traditional Chinese medicine granule preparation method.

[0050] Illustratively, the traditional Chinese medicine granules can be prepared by the following method:

[0051] The filtrate obtained according to the method of preparing the decoction of Example 1 was concentrated under reduced pressure to obtain a clear extract, then maltodextrin was added to the clear extract, followed by spray drying to obtain a dry extract powder; then maltodextrin was added to the dry extract powder to obtain a mixed powder; then a 90% (by volume) ethanol-water solution was added to the mixed powder to obtain a soft material, which was sieved to obtain wet granules; finally, the wet granules were dried to obtain the granules. The granules were packaged into each package of about 10 g for clinical use and administration.

[0052] Example 4

[0053] The Chinese medicine powder for treating lung cancer bone metastasis of this example is prepared from the following raw medicinal materials: Radix Codonopsis 30 g, Poria 30 g, Radix Astragali 30 g, Atractylodes 20 g, Glycyrrhiza 15 g, Curcuma 20 g, Pinellia 15 g, Tangerine Peel 5 g, Oldenlandia 30 g, Fructus Psoraleae 20 g, Drynaria 20 g, Epimedium 20 g, Rhizoma Dioscoreae 15 g.

[0054] The above components were crushed and uniformly mixed with suitable carriers or excipients to form a dry powder to form a powder, which can be taken by washing with water.

[0055] Example 5

[0056] The Chinese medicine tablet for treating lung cancer bone metastasis of this example is prepared from the following raw medicinal materials: Radix Codonopsis 30 g, Poria 30 g, Radix Astragali 30 g, Atractylodes 20 g, Glycyrrhiza 15 g, Curcuma 20 g, Pinellia 15 g, Tangerine Peel 5 g, Oldenlandia 30 g, Fructus Psoraleae 20 g, Drynaria 20 g, Epimedium 20 g, Rhizoma Dioscoreae 15 g.

[0057] The above components were crushed and uniformly mixed with suitable carriers or excipients to form a dry powder to form a powder, which can be taken by washing with water.

[0058] Example 6

[0059] The Chinese medicine capsule for treating lung cancer bone metastasis of this example is prepared from the following raw medicinal materials: Radix Codonopsis 30 g, Poria 30 g, Radix Astragali 30 g, Atractylodes 20 g, Glycyrrhiza 15 g, Curcuma 20 g, Pinellia 15 g, Tangerine Peel 5 g, Oldenlandia 30 g, Fructus Psoraleae 20 g, Drynaria 20 g, Epimedium 20 g, Rhizoma Dioscoreae 15 g.

[0060] The above components were crushed and uniformly mixed with suitable carriers or excipients to form a dry powder to form a powder, which can be taken by washing with water.

[0061] Example 7

[0062] The traditional Chinese medicine decoction for treating lung cancer bone metastasis of the present embodiment is prepared from the following raw medicinal materials: Radix Codonopsis 40 g, Poria 40 g, Radix Astragali 40 g, Rhizoma Atractylodis Macrocephalae 30 g, Radix Glycyrrhizae Preparata 20 g, Curcuma 30 g, Rhizoma Pinelliae Preparatum 20 g, Pericarpium Citri Reticulatae 10 g, Herba Belamcandae 40 g, Fructus Aurantii Immaturus 30 g, Radix Drynariae 30 g, Herba Epimedii 30 g, Rhizoma Arisaematis Preparatum 20 g.

[0063] The preparation method is the same as that of Embodiment 1.

[0064] Embodiment 8

[0065] The traditional Chinese medicine granules for treating lung cancer bone metastasis of the present embodiment are prepared from the following raw medicinal materials: Radix Codonopsis 20 g, Poria 20 g, Radix Astragali 20 g, Rhizoma Atractylodis Macrocephalae 10 g, Radix Glycyrrhizae Preparata 10 g, Curcuma 10 g, Rhizoma Pinelliae Preparatum 10 g, Pericarpium Citri Reticulatae 7 g, Herba Belamcandae 20 g, Fructus Aurantii Immaturus 10 g, Radix Drynariae 10 g, Herba Epimedii 10 g, Rhizoma Arisaematis Preparatum 10 g.

[0066] The preparation method is the same as that of Embodiment 3.

[0067] Next, to illustrate the therapeutic effect of the traditional Chinese medicine composition for treating lung cancer bone metastasis of the present application on lung cancer primary lesions and bone metastatic lesions, the traditional Chinese medicine decoction prepared in Embodiment 1 is concentrated and used for animal experiments and evaluation of the therapeutic effect. It should be noted that the drug concentration for animals is not the same as that for humans, and the drug concentration for mice is about 9 times that for humans, so the traditional Chinese medicine decoction prepared in Embodiment 1 is concentrated and administered to mice.

[0068] I. Lewis lung cancer tumor-bearing mouse model

[0069] 1. Experimental method

[0070] 1×10 6 Lung cancer cells of Lewis mice were injected subcutaneously into the hind limbs of C57BL / 6 mice, and the long and short diameters of the tumor were measured every other day using a vernier caliper, and the tumor size volume (mm 3 ) was calculated according to the formula: tumor volume = 0.5 × L × W 2 , where L is the long diameter size and W is the short diameter size. On days 7-10 after tumor implantation, the mice were randomly divided into 6 groups according to the tumor formation of the mice: control group, low-dose group, medium-dose group, high-dose group, cisplatin group, medium-dose + cisplatin group (i.e., combination group), with 4-5 mice in each group.

[0071] Each group was administered according to the following scheme:

[0072] ① Control group: 0.36 mL of pure water was administered orally once a day;

[0073] ② Low-dose group: the concentrated solution (concentration of 0.965g crude drug / mL) obtained by concentrating the traditional Chinese medicine decoction of Example 1 was given, and 17.55g of crude drug per kg of mouse body weight was administered by gavage once a day;

[0074] ③ Medium-dose group: the concentrated solution (concentration of 1.93g crude drug / mL) obtained by concentrating the traditional Chinese medicine decoction of Example 1 was given, and 35.1g of crude drug per kg of mouse body weight was administered by gavage once a day;

[0075] ④ High-dose group: the concentrated solution (concentration of 3.86g crude drug / mL) obtained by concentrating the traditional Chinese medicine decoction of Example 1 was given, and 70.2g of crude drug per kg of mouse body weight was administered by gavage once a day;

[0076] ⑤ Cisplatin group: cisplatin aqueous solution (concentration of 0.3mg / mL) 0.2mL was administered by intraperitoneal injection, twice a week;

[0077] ⑥ Medium-dose + cisplatin group (i.e. combination group): the concentrated solution (concentration of 1.93g crude drug / mL) obtained by concentrating the traditional Chinese medicine decoction of Example 1 was given, and 35.1g of crude drug per kg of mouse body weight was administered by gavage once a day, and cisplatin aqueous solution (concentration of 0.3mg / mL) 0.2mL was administered by intraperitoneal injection, twice a week.

[0078] The mental state, food intake, activity, etc. of the mice were observed every day to monitor the vital signs. The mice were recorded as dead when the mice died or the tumor volume ≥2000mm 3 The end point was the 21st day of administration, and the mouse organs were collected for paraffin embedding, etc.

[0079] 2. Experimental results

[0080] (1) Effect of traditional Chinese medicine composition on general condition of Lewis lung cancer mice

[0081] The changes in body weight of mice in each group before and after treatment are shown in Table 1.

[0082] Table 1 Changes in body weight of mice before and after treatment

[0083]

[0084] Note: 1) P<0.05 compared with the control group at the 1st week of treatment; 2) P<0.05 compared with the control group at the 2nd week of treatment; 3) P<0.05 compared with the cisplatin group at the 2nd week of treatment.

[0085] As shown in Table 1, compared with the control group, the body weight of mice in the cisplatin group decreased significantly with treatment time, while the body weight of mice in the low, medium, and high dose groups and the combined group did not change significantly; and compared with the cisplatin group, the body weight of mice in the combined group increased, with statistically significant differences (P<0.05). This suggests that the traditional Chinese medicine composition of the present invention can reduce the weight loss caused by the side effects of chemotherapy drugs.

[0086] (2) Effects of traditional Chinese medicine composition on tumor volume, tumor inhibition rate and survival time in Lewis lung cancer mice

[0087] The changes in tumor volume, tumor inhibition rate, and average survival time of mice in each group are shown in Table 2.

[0088] Table 2. Changes in tumor volume, tumor inhibition rate, and average survival time of mice in each group.

[0089] Group Tumor volume (mm3 3 ) Tumor inhibition rate (%) Average survival time (d) Control group 1835.22±50.34 / 14.2±2.05 Low-dose group 1151.36±575.37 37.26 18.0±3.08 Medium-dose group 1100.56 ± 391.65 1) ]] 40.03 21.2 ± 3.77 1) ]]> High-dose group 897.90 ± 155.73 1) ]] 51.07 21.4 ± 2.61 1) ]] Cisplatin group 868.85 ± 286.34 1) ]] 52.65 15.8±3.03 Combined group 487.63 ± 64.27 1)2)3) ]] 73.43 26.6 ± 3.21 1)2)3) ]]

[0090] Note: 1) Compared with the control group, P<0.05; 2) Compared with the medium-dose group, P<0.05; 3) Compared with the cisplatin group, P<0.05.

[0091] As shown in Table 2, compared with the control group, the tumor inhibition rate of the low, medium, and high dose groups increased with increasing dosage, and the medium and high dose groups showed statistically significant differences in prolonging the average survival time of mice compared with the control group (P<0.05). While the cisplatin group significantly inhibited tumor volume, it did not prolong the survival time of mice. Compared with the control group, the medium dose group, and the cisplatin group, the tumor inhibition rate and mouse survival time of the combined group were significantly increased, with statistically significant differences (P<0.05). This suggests that the traditional Chinese medicine composition of the present invention can directly reduce lung cancer growth and prolong survival time.

[0092] (3) Effects of traditional Chinese medicine composition on the pathological morphology of various organs in Lewis lung cancer mice

[0093] HE staining images of major organs of mice in each group are shown below. Figure 1 As shown in the figure, each group of organs has two smaller images, one above the other. The upper image is a panoramic scan of the organ slice, and the lower image is a 20x magnified image.

[0094] from Figure 1It can be seen that the structural morphology of the heart, liver and spleen of the mice in each group has no obvious difference. Lung HE staining shows that lung metastasis occurs in 1 mouse in the cisplatin group, and no lung metastasis occurs in the other groups. In the kidney staining, the renal tubules of the mice in the cisplatin group show mild swelling and a small amount of degeneration and necrosis, and the renal interstitial inflammatory cell infiltration, while no obvious change occurs in the other groups. It is indicated that cisplatin may have certain nephrotoxicity, and the combination of the traditional Chinese medicine composition of the application can reduce the toxic side effects of cisplatin.

[0095] II. Mouse lung cancer bone metastasis model

[0096] 1. Experimental method

[0097] First, a left ventricular injection bone metastasis model simulating clinical metastasis is constructed: 5x10 5 GFP-Luc stably expressed Lewis mouse lung cancer cells are injected into the left ventricle of C57BL / 6J mice, and about 2-3 weeks later, small animal live imaging is performed. The fluorescence signal is distributed in the bone, brain, etc. The complete leg bone of the mouse with bone metastasis is taken and the bone marrow cavity cells are separated. Tumor cells are screened by flow sorting, which are bone metastasis tumor cells through hematogenous metastasis. 1x10 5 Bone metastasis tumor cells are taken, and the suspension is sucked up with a microsyringe. After the C57BL / 6J mouse is properly anesthetized, the mouse's left lower limb knee joint is flexed, a sterile insulin needle is first used to puncture at the tibial plateau, the needle is slowly inserted into the bone marrow cavity along the direction of the tibia, the needle is pulled out, and then a microsyringe is replaced along the drilling path to enter the bone marrow cavity, and the suspension is slowly injected. After standing for a few moments, the needle is punctured out. About 1-2 weeks later, live imaging is performed, and it can be seen that the mouse lung cancer cells grow locally in the left tibia, i.e. a mouse lung cancer bone metastasis model is constructed.

[0098] The mice are randomly divided into 4 groups: a control group, a cisplatin group, a middle dose group, and a middle dose + cisplatin group (i.e. a combination group), each group having 4-5 mice.

[0099] Each group is administered according to the following scheme:

[0100] ① The control group: 0.36 mL of pure water is administered by gavage once a day;

[0101] ② The cisplatin group: 0.2 mL of a cisplatin aqueous solution (concentration of 0.3 mg / mL) is administered by intraperitoneal injection, twice a week;

[0102] ③ The middle dose group: the concentrated solution (concentration of 1.93 g of crude drug / mL) obtained by concentrating the traditional Chinese medicine decoction of Example 1 is administered by gavage, according to 35.1 g of crude drug / kg of mouse body weight, once a day;

[0103] (4) Medium dose + cisplatin group (i.e. combination group): the concentrated solution (concentration of 1.93 g crude drug / mL) obtained by concentrating the traditional Chinese medicine decoction of Example 1 was administered by gavage at 35.1 g crude drug / kg body weight of the mice, once a day, and cisplatin aqueous solution (concentration of 0.3 mg / mL) was administered by intraperitoneal injection at 0.2 mL, twice a week.

[0104] The mental state, food intake, activity, etc. of the mice were observed every day to monitor the vital signs, and the mice were treated for 21 days. After the administration was completed, the mice were dissected, the changes in the tumors were monitored using live imaging, and the survival time of the mice was counted.

[0105] 2. Experimental results

[0106] (1) Effect of the traditional Chinese medicine composition on the growth of lung cancer bone metastasis tumors in mice

[0107] The live imaging of the metastatic bones of the mice in each group and the results of the fluorescence quantification are shown in Figure 2 , in which the left graph is a representative graph of the live imaging of the metastatic bones of the mice, and the right graph is a fluorescence quantification graph; *P<0.05; **P<0.01; ***P<0.001.

[0108] As can be seen from Figure 2 , in the lung cancer bone metastasis model, the live imaging of the metastatic bones and the results of the fluorescence quantification showed that, compared with the control group, the average fluorescence value of the cisplatin group had no significant change (P>0.05), while the average fluorescence value of the medium dose group and the combination group significantly decreased (P<0.01), and compared with the cisplatin group, the average fluorescence value of the combination group significantly decreased (P<0.01). This indicates that cisplatin has no obvious improvement effect on metastatic bone tumors, while the traditional Chinese medicine composition of the present application can reduce the growth of metastatic bone tumors, and the traditional Chinese medicine composition of the present application combined with a chemotherapeutic drug can achieve a better therapeutic effect.

[0109] (2) Effect of the traditional Chinese medicine composition on the survival time and body weight of lung cancer bone metastasis mice

[0110] The total survival time and body weight changes of the mice in each group are shown in Figure 3 , in which the left graph is a survival time graph of the mice, and the right graph is a body weight change graph of the mice; **P<0.01; ***P<0.001.

[0111] As can be seen from Figure 3As shown in the left graph of FIG. 1, compared with the control group, the cisplatin group did not prolong the survival time of mice, while the medium-dose group and the combination group significantly prolonged the average survival time of mice, and the survival time of the combination group was significantly prolonged compared with the cisplatin group, with a statistically significant difference (P<0.01), but there was no statistically significant difference in the survival time between the combination group and the medium-dose group (P=0.1135). Thus, it is shown that the traditional Chinese medicine composition of the present application can prolong the survival time of lung cancer bone metastasis mice, and the traditional Chinese medicine composition of the present application combined with a chemotherapeutic drug can achieve a better therapeutic effect.

[0112] From Figure 3 As shown in the right graph of FIG. 1, there was no significant difference in the overall body weight of mice, and only the cisplatin group showed a trend of weight loss at the end of administration. Thus, it is shown that the traditional Chinese medicine composition of the present application can alleviate the body weight loss mediated by the side effects of chemotherapeutic drugs.

[0113] (3) Effect of the traditional Chinese medicine composition on distant lung metastasis of lung cancer bone metastasis mice

[0114] After the administration of the lung cancer bone metastasis model was completed, it was found that many mice had distant lung metastasis when the organs of the mice were collected. The lungs of the mice were taken for live imaging and fixed and embedded for HE staining. The live imaging and fluorescence quantification of the lungs of mice in each group and the lung HE staining diagram are shown in Figure 4 , in which the upper left graph is a representative diagram of live imaging of the lungs of mice, the lower left graph is a fluorescence quantification diagram, and the right graph is a lung HE staining diagram of mice; *P<0.05.

[0115] From Figure 4 As shown in FIG. 2, compared with the control group, the average fluorescence value of the cisplatin group had no significant change (P>0.05), while the average fluorescence value of the medium-dose group and the combination group significantly decreased (P<0.05), and compared with the cisplatin group, the average fluorescence value of the combination group significantly decreased (P<0.05). The results show that compared with the control group, the cisplatin group did not reduce the incidence of distant lung metastasis, while the traditional Chinese medicine composition of the present application can reduce the occurrence and progression of distant lung metastasis, and the traditional Chinese medicine composition of the present application combined with a chemotherapeutic drug can achieve a better therapeutic effect. The above results suggest that the traditional Chinese medicine composition of the present application not only can reduce the tumor growth of bone metastasis foci, but also can reduce the occurrence of distant lung metastasis.

[0116] In summary, the Lewis lung cancer tumor-bearing mouse model and the lung cancer bone metastasis model show that the traditional Chinese medicine composition of the present application not only can inhibit the growth of primary tumor, but also can slow down the progression of bone metastasis tumor, and when combined with a chemotherapeutic drug, it can not only significantly enhance the tumor inhibition effect of the chemotherapeutic drug, but also can significantly prolong the survival time of mice and alleviate the body weight loss and organ toxicity side effects caused by the chemotherapeutic drug. Thus, it is shown that the traditional Chinese medicine composition of the present application can directly slow down the progression of lung cancer primary tumor and bone metastasis tumor, thereby improving the quality of life of patients and prolonging the survival time.

Claims

1. A traditional Chinese medicine composition for treating lung cancer bone metastasis, characterized in that, It is prepared from the following raw materials: 20-40 parts of radix codonopsis, 20-40 parts of poria, 20-40 parts of radix astragali, 10-30 parts of atractylodes, 10-20 parts of licorice, 10-30 parts of curcuma, 10-20 parts of pinellia, 5-10 parts of dried tangerine or orange peel, 20-40 parts of hedyotis, 10-30 parts of psoralea, 10-30 parts of drynaria, 10-30 parts of epimedium, and 10-20 parts of arisaema.

2. The Chinese medicine composition for treating lung cancer bone metastasis according to claim 1, characterized in that, It is prepared from the following raw materials: 30 parts of radix codonopsis, 30 parts of poria, 30 parts of radix astragali, 20 parts of atractylodes, 15 parts of licorice, 20 parts of curcuma, 15 parts of pinellia, 5 parts of dried tangerine or orange peel, 30 parts of hedyotis, 20 parts of psoralea, 20 parts of drynaria, 20 parts of epimedium, and 15 parts of arisaema. 3.The traditional Chinese medicine composition for treating lung cancer bone metastasis according to claim 1 or 2, characterized in that, The licorice is fried licorice, the pinellia is ginger pinellia, the psoralea is salted psoralea, and the arisaema is processed arisaema.

4. The Chinese medicine composition for treating lung cancer bone metastasis according to claim 1 or 2, characterized in that, It also includes pharmaceutically acceptable adjuvants.

5. The Chinese medicine composition for treating lung cancer bone metastasis according to claim 1 or 2, characterized in that, The dosage form of the traditional Chinese medicine composition is a decoction, an oral liquid, granules, powder, tablets, pills, or capsules.

6. Use of the traditional Chinese medicine composition for treating lung cancer bone metastasis according to any one of claims 1-5 in the preparation of a drug for treating lung cancer.

7. Use of the traditional Chinese medicine composition for treating lung cancer bone metastasis according to any one of claims 1-5 in the preparation of a drug for treating lung cancer bone metastasis.

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