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

Abstract

The invention 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 traditional Chinese medicine composition comprises the following main active ingredients in parts by mass: 20-40 parts of codonopsis pilosula, 20-40 parts of poria cocos, 20-40 parts of astragalus membranaceus, 10-30 parts of bighead atractylodes rhizome, 10-20 parts of liquorice, 10-30 parts of curcuma zedoary, 10-20 parts of pinellia ternate, 5-10 parts of pericarpium citri reticulatae, 20-40 parts of oldenlandia diffusa, 10-30 parts of fructus psoraleae, 10-30 parts of rhizoma drynariae, 10-30 parts of herba epimedii and 10-20 parts of rhizoma arisaematis. Animal experiments show that the traditional Chinese medicine composition not only can inhibit the growth of primary lesion tumors, but also can slow down the progression of bone metastatic lesion tumors, and when the traditional Chinese medicine composition is combined with chemotherapeutics for application, the tumor inhibition effect of the chemotherapeutics can be obviously enhanced, the survival time of mice can be obviously prolonged, and the curative effect of the mice is improved. And weight loss and visceral toxic and side effects caused by chemotherapeutic drugs are relieved.

Description

Technical Field

[0001] The invention 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 Art

[0002] Lung cancer is the malignant tumor with the highest mortality rate in the world. About 30-40% of patients have bone metastasis at the time of diagnosis, and most of them present with osteolytic lesions, often accompanied by severe pain, pathological fractures 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 with multiple regimens such as radiotherapy, chemotherapy, immunotherapy and bone protective agents, the one-year survival rate is only 40-50%. There is still a lack of effective intervention strategies for refractory lung cancer bone metastasis.

[0003] At present, certain progress has been made in the treatment of lung cancer bone metastasis in traditional Chinese medicine. More and more traditional Chinese medicines have achieved good results in the treatment of lung cancer bone metastasis. For example, the Hugu Xiaoji prescription, which focuses on "tonifying the kidney and strengthening the bones", can cooperate with zoledronic acid to improve bone pain in patients with bone metastasis, but there is no clear conclusion on its tumor inhibition rate and patient survival (Chen Xian, Zhang Haibo, Liu Yihong, et al. Study on the efficacy of Hugu Xiaoji prescription combined with zoledronic acid in the treatment of bone metastasis cancer pain 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] Currently, there is still an urgent need for a Chinese medicine composition that can effectively inhibit tumor growth and prolong the patient's survival period and quality of life. Summary of the invention

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

[0006] According to a first aspect of the present invention, a traditional Chinese medicine composition for treating bone metastasis of lung cancer is provided, wherein the main active ingredients thereof include, by weight: 20-40 parts of Codonopsis pilosula, 20-40 parts of Poria cocos, 20-40 parts of Astragalus membranaceus, 10-30 parts of Atractylodes macrocephala, 10-20 parts of Licorice root, 10-30 parts of Curcuma zedoaria, 10-20 parts of Pinellia ternata, 5-10 parts of Citrus reticulatae, 20-40 parts of Hedyotis diffusa, 10-30 parts of Psoralea corylifolia, 10-30 parts of Drynaria fortunei, 10-30 parts of Epimedium, and 10-20 parts of Arisaema consanguineum.

[0007] The present invention believes that lung cancer is mostly caused by deficiency, local part is real, systemic part is deficient, evil toxin invades lung, stubbornly does not go, damages lung network, causes qi stagnation and blood stasis to form agglomeration. And blood stasis turns into heat to burn body fluid, causing lung yin and kidney yin deficiency. Spleen is the source of phlegm, and its healthy transport is disordered, then water and dampness are blocked, and moisture is gathered to form phlegm. Lung is the device for storing phlegm, and phlegm easily blocks lung network and forms agglomeration. Therefore, lung cancer is a disease of deficiency in essence and excess in superficiality, and the pathogenesis lies in "deficiency", "phlegm", "toxicity" and "stasis". During treatment, syndrome differentiation, disease differentiation and combined with symptomatic treatment are adopted.

[0008] The TCM syndrome differentiation of bone metastasis mainly belongs to the categories of bone tumor, bone erosion, bone fistula, bone arthritis, and bone carbuncle in TCM. Its basic pathogenesis is considered to be deficiency of the body and excess of pathogenic factors. Deficiency of the body is the root, and the lung, spleen, and kidney are damaged; excess of pathogenic factors is the symptom, and phlegm and blood stasis, cancer toxins block the tendons and bones. The kidney governs the bones, and kidney deficiency leads to weak bones. Cancer toxins can easily invade the bones along the meridians and blood. Bone metastasis of lung cancer is a late stage of the disease with a long course of disease. Long-term illness affects the kidney or the mother's disease affects the child, resulting in the depletion of kidney essence and qi, and the bones are not nourished. "Where there is the greatest deficiency, there is the place for the pathogenic factors." Cancer toxins take advantage of the deficiency to stay, gather over time, and develop into bone tumors. Therefore, kidney deficiency syndrome is particularly prominent in bone metastasis of lung cancer.

[0009] This prescription focuses on tonifying the kidney and strengthening the spleen. It uses a lot of Psoralea corylifolia and Epimedium to tonify the kidney and strengthen the bones to strengthen the innate foundation. Astragalus and Codonopsis pilosula to tonify the spleen and replenish qi to tonify the acquired qi. Psoralea corylifolia, Epimedium, Astragalus mulberry and Codonopsis pilosula are the main medicines; and Arisaema consanguineum is used to travel through the meridians, open up knots and resolve phlegm, Curcuma zedoaria promotes qi and breaks blood, eliminates accumulation and relieves pain, and Drynaria fortunei tonifies the kidney and strengthens bones, promotes blood circulation and relieves pain; the adjuvant Atractylodes macrocephala strengthens the spleen and replenishes qi, dries dampness and promotes diuresis, Poria promotes diuresis and eliminates dampness, strengthens the spleen and resolves phlegm, Pinellia ternata and Citrus reticulata dry dampness and resolves phlegm, together they have the effects of tonifying qi and strengthening the spleen, removing dampness and resolving phlegm; the guiding medicine Licorice strengthens the spleen and replenishes qi, relieves cough and asthma, harmonizes all the medicines, and Hedyotis diffusa clears away heat and detoxifies, breaks up blood stasis and disperses knots, and together they attack the evil toxins in patients with lung cancer. The combination of these medicines can nourish without stagnation, clear without destroying, attack and supplement at the same time, treat both the symptoms and the root cause, and together play the role of strengthening the body to fight cancer, strengthening the spleen and kidneys, resolving phlegm, removing blood stasis and detoxifying.

[0010] The sources of raw materials for this recipe are as follows:

[0011] Codonopsis: The root of Codonopsis pilosula (Franch.) Nannf., C.pilosula Nannf.var. (Nannf.) LTShen or C.tangshen Oliv. of the Campanulaceae family.

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

[0013] Astragalus: The root of Astragalus memeranaceus (Fisch.) Bge. Var. mongholicus (Bge.) Hsiao or A. membranaceus (Fisch.) Bge. of the genus Astragalus in the Leguminosae family.

[0014] Atractylodes: The rhizome of Atractylodes macrocephala, a plant of the genus Atractylodes in the Asteraceae family.

[0015] Licorice: The dried roots and rhizomes of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. or Glycyrrhiza glabra L., plants of the genus Glycyrrhiza in the Leguminosae family.

[0016] Curcuma: The rhizome of Curcuma aeruginosa Roxb. [C.zedoaria nonRosc.], Curcuma kwang siensis SGLee et CFLiang and Curcuma wenyujin YHChen et C.Ling of the Zingiberaceae family.

[0017] Pinellia: The dried tuber of Pinellia ternata (Thunb.) Breit., a plant of the Araceae family.

[0018] Tangerine peel: the dried mature peel of Citrus reticulata Blanco and its cultivated varieties.

[0019] Oldenlandia diffusa: the whole herb of Oldenlandia diffusa (Willd.) Roxb., a plant of the genus Hedyotis in the Rubiaceae family.

[0020] Psoralea: The ripe fruit of Psoralea corylifolia L., a plant of the genus Psoralea in the leguminous family.

[0021] Drynaria fortunei: The rhizome of Drynaria fortunei (Kunze) J.Sm., a plant of the genus Drynaria in the family Quercetinaceae.

[0022] Epimedium: the stems and leaves of Epimedium brevicornum Maxim., Epimedium sagittatum., Epimedium wushanense., Epimedium koreanum Nakai., and Epimedium pubesens Maxim., etc., which are plants of the genus Epimedium in the Berberidaceae family.

[0023] Arisaema: The dried tubers of Arisaema erubescens (Wall.) Schott., Arisaema heterophyllum BI. or Arisaema amurense Maxim. of the Araceae family.

[0024] In some embodiments, its main active ingredients include, by mass: 30 parts of Codonopsis pilosula, 30 parts of Poria cocos, 30 parts of Astragalus membranaceus, 20 parts of Atractylodes macrocephala, 15 parts of Licorice, 20 parts of Curcuma zedoaria, 15 parts of Pinellia ternata, 5 parts of Citrus reticulata, 30 parts of Hedyotis diffusa, 20 parts of Psoralea corylifolia, 20 parts of Drynaria fortunei, 20 parts of Epimedium, and 15 parts of Arisaema.

[0025] In some embodiments, licorice is roasted licorice, pinellia is ginger pinellia, psoralea corylifolia is salt psoralea corylifolia, and aranemia is processed aranemia. Licorice has the effects of tonifying the middle qi and clearing away heat and detoxifying. Raw licorice is more effective in clearing away heat and detoxifying. After roasting with honey, the effect of tonifying the middle qi and invigorating qi is better; raw pinellia is pungent and toxic, but its toxicity is reduced after ginger processing, and it can warm the middle qi and resolve phlegm; psoralea corylifolia has the functions of tonifying the kidney, replenishing essence, strengthening bones and invigorating qi. After further processing with salt, it takes the "salty and cold enter the kidney" mechanism in the nature and taste of the meridians to guide the drug into the kidney, and the kidney tonifying performance is better; aranemia is bitter, pungent, warm, and toxic. After processing, the toxicity is reduced and it can be used internally, which can dry dampness and resolve phlegm.

[0026] In some embodiments, pharmaceutically acceptable adjuvants are also included. Specifically, the adjuvants used are carriers or excipients 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), compressed tablets, etc., 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 Chinese medicine composition is decoction, oral solution, granules, powder, tablet, pill or capsule, so as to facilitate clinical administration.

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

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

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

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

[0032] (1) The present invention is based on the fact that the root cause of patients with advanced lung cancer bone metastasis is deficiency of the body's vital energy, and the lung, spleen, and kidney are impaired; the symptom is excess of pathogenic factors, and phlegm and blood stasis, cancer toxins block the tendons and bones. The Chinese medicine composition of the present invention mainly uses the methods of tonifying the kidney and strengthening bones, strengthening the spleen and replenishing qi, and also removing phlegm, removing blood stasis, and detoxifying to improve the survival of patients with advanced lung cancer bone metastasis. It can not only prolong the survival period, but also improve the quality of life by reducing the toxic and side effects of chemotherapy drugs, and has good therapeutic effect and reliable safety.

[0033] (2) Animal experiments on Lewis lung cancer tumor-bearing mouse model and lung cancer bone metastasis model showed that the Chinese medicine composition of the present invention can not only inhibit the growth of primary tumor, but also slow down the progression of bone metastasis tumor, and when used in combination with chemotherapeutic drugs, it can not only significantly enhance the tumor inhibition effect of chemotherapeutic drugs, but also significantly prolong the survival time of mice and alleviate the weight loss and organ toxicity caused by chemotherapeutic drugs. This shows that the Chinese medicine composition of the present invention can directly slow down the progression of primary lung cancer and bone metastasis, thereby improving the quality of life of patients and prolonging their survival time. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0035] Figure 2 These are the in vivo imaging and fluorescence quantitative statistical results of metastatic bones of each group of mice in the animal experiment of the mouse lung cancer bone metastasis model of the present invention.

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

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

[0038] The present invention is further described in detail below in conjunction with specific examples. Unless otherwise specified, the raw materials and reagents used in the present invention are all purchased from the market.

[0039] Example 1

[0040] The Chinese herbal decoction for treating bone metastasis of lung cancer in this embodiment is prepared from the following raw materials: 30g of Codonopsis pilosula, 30g of Poria cocos, 30g of Astragalus membranaceus, 20g of Atractylodes macrocephala, 15g of Licorice root, 20g of Curcuma zedoaria, 15g of Pinellia ternata, 5g of Citrus reticulata, 30g of Hedyotis diffusa, 20g of Psoralea corylifolia, 20g of Drynaria fortunei, 20g of Epimedium, and 15g of Arisaema consanguineum.

[0041] The above components are taken and a Chinese medicine decoction is prepared according to an existing Chinese medicine decoction preparation method. The ratio is one dose of medicine, and one dose of medicine is about 300 mL.

[0042] Exemplarily, the preparation method of the Chinese herbal decoction is specifically as follows: the above-mentioned Chinese medicinal materials are mixed according to a ratio to obtain a mixture, and then added into water at a solid-liquid ratio of 1:10, soaked for 0.5h, and then decocted for 0.5h, filtered to obtain a first filtrate and a filter residue, decocted the filter residue once, filtered the obtained filtrate, combined with the first filtrate and sterilized, cooled to room temperature, and packaged.

[0043] Example 2

[0044] The Chinese medicine oral liquid for treating bone metastasis of lung cancer in this embodiment is prepared from the following raw materials: 30g of Codonopsis pilosula, 30g of Poria cocos, 30g of Astragalus membranaceus, 20g of Atractylodes macrocephala, 15g of Licorice, 20g of Curcuma zedoaria, 15g of Pinellia ternata, 5g of Tangerine peel, 30g of Hedyotis diffusa, 20g of Psoralea corylifolia, 20g of Drynaria fortunei, 20g of Epimedium, and 15g of Arisaema consanguineum.

[0045] The above components are taken and a Chinese medicine oral liquid is prepared according to an existing Chinese medicine oral liquid preparation method. The ratio is one dose of medicine, and one dose of medicine is about 300 mL.

[0046] Exemplarily, the preparation method of the Chinese medicine oral liquid is specifically as follows: the above-mentioned Chinese medicinal materials are mixed according to a ratio to obtain a mixture, and then added into water at a material-liquid ratio of 1:15, soaked for 20 minutes, and then decocted for 1 hour, filtered to obtain a first filtrate and a filter residue, decocted the filter residue once, filtered the obtained filtrate, combined with the first filtrate and sterilized, cooled to room temperature, and packaged.

[0047] Example 3

[0048] The Chinese medicine granules for treating bone metastasis of lung cancer in this embodiment are prepared from the following raw materials: 30g of Codonopsis pilosula, 30g of Poria cocos, 30g of Astragalus membranaceus, 20g of Atractylodes macrocephala, 15g of Licorice, 20g of Curcuma zedoaria, 15g of Pinellia ternata, 5g of Citrus reticulata, 30g of Hedyotis diffusa, 20g of Psoralea corylifolia, 20g of Drynaria fortunei, 20g of Epimedium, and 15g of Arisaema consanguineum.

[0049] The above components are taken, a carrier or an excipient is added, and the Chinese medicine granules are prepared according to the existing Chinese medicine granule preparation method.

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

[0051] According to the method for preparing a decoction in Example 1, a filtrate is obtained, the filtrate is concentrated under reduced pressure to obtain a clear paste, maltodextrin is added to the clear paste, and then spray-dried to obtain a dry paste powder; then maltodextrin is added to the dry paste powder to obtain a mixed powder; then a 90% volume fraction ethanol-water solution is added to the mixed powder to prepare a soft material, the soft material is sieved to obtain wet granules; finally, the wet granules are dried to obtain the obtained granules. The obtained granules are packaged into about 10g per package for easy clinical use and administration.

[0052] Example 4

[0053] The Chinese medicine powder for treating bone metastasis of lung cancer in this embodiment is prepared from the following raw materials: 30g of Codonopsis pilosula, 30g of Poria cocos, 30g of Astragalus membranaceus, 20g of Atractylodes macrocephala, 15g of Licorice, 20g of Curcuma zedoaria, 15g of Pinellia ternata, 5g of Tangerine peel, 30g of Hedyotis diffusa, 20g of Psoralea corylifolia, 20g of Drynaria fortunei, 20g of Epimedium, and 15g of Arisaema consanguineum.

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

[0055] Example 5

[0056] The Chinese medicine tablets for treating bone metastasis of lung cancer in this embodiment are prepared from the following raw materials: 30g of Codonopsis pilosula, 30g of Poria cocos, 30g of Astragalus membranaceus, 20g of Atractylodes macrocephala, 15g of Licorice root, 20g of Curcuma zedoaria, 15g of Pinellia ternata, 5g of Tangerine peel, 30g of Hedyotis diffusa, 20g of Psoralea corylifolia, 20g of Drynaria fortunei, 20g of Epimedium, and 15g of Arisaema consanguineum.

[0057] The above components were taken and wet granules were first prepared according to the method of Example 3, and then the wet granules were tableted and dried to obtain tablets.

[0058] Example 6

[0059] The Chinese medicine capsule for treating bone metastasis of lung cancer in this embodiment is prepared from the following raw materials: 30g of Codonopsis pilosula, 30g of Poria cocos, 30g of Astragalus membranaceus, 20g of Atractylodes macrocephala, 15g of Licorice, 20g of Curcuma zedoaria, 15g of Pinellia ternata, 5g of Tangerine peel, 30g of Hedyotis diffusa, 20g of Psoralea corylifolia, 20g of Drynaria fortunei, 20g of Epimedium, and 15g of Arisaema consanguineum.

[0060] The above components are taken, crushed and uniformly mixed with suitable carriers or excipients to form dry powder, granulated, and then filled into capsules to prepare capsules.

[0061] Example 7

[0062] The traditional Chinese medicine decoction for treating bone metastasis of lung cancer in this embodiment is prepared from the following raw materials: 40g of Codonopsis pilosula, 40g of Poria cocos, 40g of Astragalus membranaceus, 30g of Atractylodes macrocephala, 20g of Radix Glycyrrhizae Preparata, 30g of Curcuma zedoariae, 20g of Pinellia ternata, 10g of Citrus reticulatae, 40g of Hedyotis diffusa, 30g of Psoralea corylifolia, 30g of Drynaria fortunei, 30g of Epimedium, and 20g of processed Arisaema.

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

[0064] Example 8

[0065] The Chinese medicine granules for treating bone metastasis of lung cancer in this embodiment are prepared from the following raw materials: 20g of Codonopsis pilosula, 20g of Poria cocos, 20g of Astragalus membranaceus, 10g of Atractylodes macrocephala, 10g of Radix Glycyrrhizae Preparata, 10g of Curcuma zedoariae, 10g of Pinellia ternata, 7g of Citrus reticulatae, 20g of Hedyotis diffusa, 10g of Psoralea corylifolia, 10g of Drynaria fortunei, 10g of Epimedium, and 10g of processed Arisaema.

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

[0067] Next, to illustrate the therapeutic effect of the Chinese medicine composition for treating lung cancer bone metastasis of the present invention on primary lung cancer lesions and bone metastases, the Chinese medicine decoction prepared in Example 1 was concentrated and then subjected to the following animal experiment and its therapeutic effect was evaluated. It should be noted that the drug concentration used in animal experiments is different from that used in humans, and the drug concentration used in mice is about 9 times that of humans, so the Chinese medicine decoction prepared in Example 1 was concentrated and then administered to mice.

[0068] 1. Lewis lung cancer tumor-bearing mouse model

[0069] 1. Experimental Methods

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

[0071] Each group was given medication according to the following regimen:

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

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

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

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

[0076] ⑤ Cisplatin group: 0.2 mL of cisplatin aqueous solution (concentration 0.3 mg / mL) was intraperitoneally injected twice a week;

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

[0078] The mice’s mental state, eating habits, and activities were observed daily to monitor their vital signs. 3 The death was recorded, and the survival time of the mice was counted. The 21st day of administration was taken as the end point, and the mouse organs were collected for paraffin embedding.

[0079] 2. Experimental results

[0080] (1) Effect of Chinese herbal medicine combination on the 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 mouse body weight before and after treatment

[0083]

[0084] Note: 1) Compared with the control group at the first week of treatment, P<0.05; 2) Compared with the control group at the second week of treatment, P<0.05; 3) Compared with the cisplatin group at the second week of treatment, P<0.05.

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

[0086] (2) Effects of Chinese herbal medicine combination on tumor volume, tumor inhibition rate and survival time of 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 <![CDATA[Tumor volume (mm 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 <![CDATA[1100.56±391.65 1) ]]> 40.03 <![CDATA[21.2±3.77 1) ]]> High dose group <![CDATA[897.90±155.73 1) ]]> 51.07 <![CDATA[21.4±2.61 1) ]]> Cisplatin group <![CDATA[868.85±286.34 1) ]]> 52.65 15.8±3.03 Joint Group <![CDATA[487.63±64.27 1)2)3) ]]> 73.43 <![CDATA[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 can be seen from Table 2, compared with the control group, the inhibition rate of the tumor in the low, medium and high dose groups increased with the increase of the prescription dosage, and the difference in the average survival time of the mice in the medium and high dose groups was statistically significant compared with the control group (P<0.05); while the cisplatin group could significantly inhibit the tumor volume, but did not prolong the survival time of the mice. Compared with the control group, the medium dose group and the cisplatin group, the tumor inhibition rate and the survival time of the mice in the combined group were significantly increased, and the difference was statistically significant (P<0.05). This suggests that the Chinese medicine composition of the present invention can play a role in directly reducing the growth of lung cancer and prolonging the survival time.

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

[0093] HE staining of the main organs of mice in each group is shown in Figure 1 As shown in the figure, each group and each organ has two small pictures, the upper picture is a panoramic scan of the organ slice, and the lower picture is a 20-fold magnified picture.

[0094] from Figure 1It can be seen that there is no significant difference in the structural morphology of the mouse heart, liver and spleen in each group. HE staining of the lungs showed that one mouse in the cisplatin group had lung metastasis, while no other group had. In kidney staining, the renal tubules of the mice in the cisplatin group showed mild swelling and a small amount of degeneration and necrosis, and inflammatory cell infiltration in the renal interstitium, while there was no significant change in other groups. It is suggested that cisplatin may have certain nephrotoxicity, and the combination of the Chinese medicine composition of the present invention can reduce the toxic and side effects of cisplatin.

[0095] 2. Mouse lung cancer bone metastasis model

[0096] 1. Experimental Methods

[0097] First, a bone metastasis model was constructed by injecting 5×10 5 Lewis mouse lung cancer cells stably expressing GFP-Luc were injected into C57BL / 6J mice through the left ventricle. About 2 to 3 weeks later, in vivo imaging of the small animals was performed, and fluorescent signals were seen distributed in the bones and brain. The complete leg bones of mice with bone metastasis were taken and the bone marrow cavity cells were separated. Tumor cells were selected by flow cytometry. These were bone metastasis tumor cells that metastasized through the blood. 1×10 5 Bone metastasis tumor cells were collected and the suspension was aspirated with a microinjector. The C57BL / 6J mice were properly anesthetized and fixed, and the left lower limb knee joint of the mice was flexed. A sterile insulin needle was first used to puncture the tibial plateau, and the needle was slowly inserted into the bone marrow cavity along the direction of the tibia. The needle was pulled out, and then replaced with a microinjector to enter the bone marrow cavity along the drilling path, and the suspension was slowly injected. After standing for a while, the needle was punctured and removed. About 1 to 2 weeks later, in vivo imaging was performed, and mouse lung cancer cells were seen growing locally in the left tibia, which constituted a mouse lung cancer bone metastasis model.

[0098] The mice were randomly divided into 4 groups: control group, cisplatin group, medium-dose group, medium-dose + cisplatin group (ie, combination group), with 4 to 5 mice in each group.

[0099] Each group was administered medication according to the following regimen:

[0100] ① Control group: 0.36 mL of pure water was given intragastrically once a day;

[0101] ②Cisplatin group: 0.2 mL of cisplatin aqueous solution (concentration 0.3 mg / mL) was intraperitoneally injected twice a week;

[0102] ③ Medium dose group: The mice were given the concentrated solution obtained by concentrating the traditional Chinese medicine decoction of Example 1 (concentration: 1.93 g crude drug / mL), and gavage was performed at 35.1 g crude drug / kg mouse body weight, once a day;

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

[0104] The mice's mental state, eating, activities, etc. were observed every day to monitor vital signs. The drugs were administered for 21 days. After the drug administration, the mice were dissected, and tumor changes were monitored using in vivo imaging, and the survival time of the mice was calculated.

[0105] 2. Experimental results

[0106] (1) Effect of Chinese herbal medicine combination on tumor growth in mice with lung cancer bone metastasis

[0107] The results of in vivo imaging and fluorescence quantitative statistics of metastatic bone in each group of mice are shown in the figure. Figure 2 As shown in the figure, the left picture is a representative picture of in vivo imaging of metastatic bone in dissected mice, and the right picture is a fluorescence quantitative statistical picture; *P<0.05; **P<0.01; ***P<0.001.

[0108] from Figure 2 It can be seen that in the lung cancer bone metastasis model, the in vivo imaging and fluorescence quantitative statistical results of the metastatic bone showed that compared with the control group, the fluorescence average value of the cisplatin group did not change significantly (P>0.05), while the fluorescence average values ​​of the medium-dose group and the combined group decreased significantly (P<0.01). At the same time, compared with the cisplatin group, the fluorescence average value of the combined group decreased significantly (P<0.01). This shows that cisplatin has no significant improvement effect on metastatic bone tumors, while the Chinese medicine composition of the present invention can reduce the growth of metastatic bone tumors, and the Chinese medicine composition of the present invention combined with chemotherapeutic drugs can achieve better therapeutic effects.

[0109] (2) Effect of Chinese herbal medicine combination on survival time and body weight of mice with lung cancer bone metastasis

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

[0111] from Figure 3As can be seen from the left figure, 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 could significantly prolong 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 statistical difference in survival time between the combination group and the medium-dose group (P=0.1135). This shows that the Chinese medicine composition of the present invention can prolong the survival time of mice with lung cancer bone metastasis, and the Chinese medicine composition of the present invention combined with chemotherapeutic drugs can achieve better therapeutic effects.

[0112] from Figure 3 As can be seen from the right figure, there is no significant difference in the weight of the whole mice, and only the cisplatin group showed a trend of weight loss at the end of the administration period. This shows that the Chinese medicine composition of the present invention can slow down the weight loss mediated by the side effects of chemotherapy drugs.

[0113] (3) Effect of Chinese herbal medicine combination on distant lung metastasis in mice with lung cancer bone metastasis

[0114] After the administration of the lung cancer bone metastasis model was completed, the organs of the mice were collected and it was found that many mice had distant lung metastasis. The lungs of the mice were taken for in vivo imaging and fixed and embedded for HE staining. The results of in vivo imaging and fluorescence quantitative statistics of the lungs of each group of mice and the lung HE staining are shown in the figure. Figure 4 As shown in the figure, the upper left picture is a representative picture of in vivo imaging of dissected mouse lungs, and the lower left picture is a fluorescence quantitative statistical picture; the right picture is a HE staining picture of mouse lungs; *P<0.05.

[0115] from Figure 4 It can be seen that compared with the control group, the fluorescence mean value of the cisplatin group did not change significantly (P>0.05), while the fluorescence mean values ​​of the medium-dose group and the combination group decreased significantly (P<0.05), and compared with the cisplatin group, the fluorescence mean value of the combination group decreased significantly (P<0.05). The results show that compared with the control group, the incidence of distant lung metastasis in the cisplatin group did not decrease, while the Chinese medicine composition of the present invention can reduce the occurrence and progression of distant lung metastasis, and the Chinese medicine composition of the present invention combined with chemotherapeutic drugs can achieve better therapeutic effects. The above results suggest that the Chinese medicine composition of the present invention can not only reduce the tumor growth of bone metastases, but also reduce the occurrence of distant lung metastasis.

[0116] The Lewis lung cancer tumor-bearing mouse model and the lung cancer bone metastasis model show that the Chinese medicine composition of the present invention can not only inhibit the growth of primary tumors, but also slow down the progression of bone metastasis tumors, and when used in combination with chemotherapeutic drugs, it can not only significantly enhance the tumor inhibition effect of chemotherapeutic drugs, but also significantly prolong the survival time of mice, and alleviate the weight loss and organ toxicity caused by chemotherapeutic drugs. This shows that the Chinese medicine composition of the present invention can directly slow down the progression of primary lung cancer and bone metastasis, thereby improving the quality of life of patients and prolonging their survival time.

Claims

1. A Chinese medicine composition for treating bone metastasis of lung cancer, characterized in that: The main active ingredients include, by weight, 20-40 parts of Codonopsis pilosula, 20-40 parts of Poria cocos, 20-40 parts of Astragalus membranaceus, 10-30 parts of Atractylodes macrocephala, 10-20 parts of Licorice root, 10-30 parts of Curcuma zedoariae, 10-20 parts of Pinellia ternata, 5-10 parts of Tangerine peel, 20-40 parts of Oldenlandia diffusa, 10-30 parts of Psoralea corylifolia, 10-30 parts of Drynaria fortunei, 10-30 parts of Epimedium, and 10-20 parts of Arisaema consanguineum.

2. The Chinese medicine composition for treating lung cancer bone metastasis according to claim 1, characterized in that: Its main active ingredients, measured by weight, include: 30 parts of Codonopsis pilosula, 30 parts of Poria cocos, 30 parts of Astragalus membranaceus, 20 parts of Atractylodes macrocephala, 15 parts of Licorice root, 20 parts of Curcuma zedoariae, 15 parts of Pinellia tuber, 5 parts of Tangerine peel, 30 parts of Oldenlandia diffusa, 20 parts of Psoralea corylifolia, 20 parts of Drynaria fortunei, 20 parts of Epimedium, and 15 parts of Arisaema consanguineum.

3. The Chinese medicine composition for treating lung cancer bone metastasis according to claim 1 or 2, characterized in that: The licorice is roasted licorice, the pinellia is ginger pinellia, the psoralea is salt 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: Pharmaceutically acceptable excipients are also included.

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 Chinese medicine composition is decoction, oral solution, granules, powder, tablet, pill or capsule.

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

7. Use of the Chinese medicinal composition for treating bone metastasis of lung cancer according to any one of claims 1 to 5 in the preparation of a medicament for treating distant metastasis of lung cancer.

8. The use according to claim 7, characterized in that: The distant metastasis of lung cancer is bone metastasis of lung cancer.

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