CN111558045A - Medicine composition for treating lung cancer - Google Patents
Medicine composition for treating lung cancer Download PDFInfo
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- CN111558045A CN111558045A CN202010602230.0A CN202010602230A CN111558045A CN 111558045 A CN111558045 A CN 111558045A CN 202010602230 A CN202010602230 A CN 202010602230A CN 111558045 A CN111558045 A CN 111558045A
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- lung cancer
- pharmaceutical composition
- aucubin
- small cell
- cell lung
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention provides a pharmaceutical composition for the treatment of lung cancer, preferably small cell lung cancer. The pharmaceutical composition comprises an immune checkpoint inhibitor and aucubin. Related formulations of the pharmaceutical compositions and uses thereof are also provided. The pharmaceutical composition can obviously inhibit the growth of the transplanted tumor of the lung cancer nude mouse and obviously improve the survival period of the nude mouse, and the effect is obviously better than that of the independent medication of the same dose of the immune check point inhibitor and aucubin, which shows that the pharmaceutical composition has obvious synergistic effect and good clinical application prospect after the combination.
Description
Technical Field
The invention relates to a pharmaceutical composition for treating lung cancer. In particular to a medicine composition for treating small cell lung cancer.
Background
Lung cancer is a common malignant tumor, and both the prevalence and the mortality rate of lung cancer are among the top of the malignant tumors in the world. According to the histological classification of lung tumors proposed by the World Health Organization (WHO), lung cancer can be classified into two main categories: small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC). The small cell lung cancer accounts for 15% -20% of primary bronchogenic carcinoma and belongs to neuroendocrine tumors. Compared with non-small cell lung cancer, small cell lung cancer has the pathophysiological characteristics of low differentiation degree, high malignancy degree, early occurrence of distal metastasis and the like, the prognosis is poor, and the average five-year survival rate is not more than 10%. Unfortunately, small cell lung cancer research is slow and clinical treatment regimens are extremely limited. For a long time, first-line therapy for small cell lung cancer is generally systemic chemotherapy based on platinum drugs in combination with etoposide. Although small cell lung cancer is sensitive to chemotherapy, the vast majority of patients relapse quickly and die within two years.
In recent years, immune checkpoint inhibitors (immune checkpoint inhibitors) have made a great breakthrough in the treatment of small cell lung cancer, and the overall layout of the treatment methods for small cell lung cancer is being changed. Alemtuzumab (atezolizumab) for first line therapy, nivolumab (nivolumab) and pembrolizumab (pembrolizumab) for third line therapy have received formal approval by the U.S. Food and Drug Administration (FDA). Attrituximab is currently the only approved immunotherapeutic approach for the initial treatment of extensive small cell lung cancer. Is also a major breakthrough in the treatment of small cell lung cancer in recent 20 years. Immune checkpoint inhibitors are becoming a research hotspot in the field of small cell lung cancer which has long been considered as "forbidden regions of research" (see, for example, the book Juanpsis, et al, "Current State of clinical research of immune checkpoint inhibitors in the treatment of small cell lung cancer", J. Clinoperaceae, Vol. 25, 5 th, 2020, 5 th, 788, 793).
However, in clinical studies and clinical applications, it has been found that despite their strong therapeutic effect, immune checkpoint inhibitors suffer from a number of disadvantages, for example, PD-1/PD-L1 mab, which is very expensive, is prone to severe adverse reactions in the skin, endocrine, liver and lung systems, and even in some patients, is resistant. The above-mentioned deficiencies of immune checkpoint inhibitors, such as tumor resistance, production of synergistic effects and reduction of toxic side effects, appear to be overcome by the use of combinations. However, how to select a combination from a large number of drugs that can produce synergistic effects with immune checkpoint inhibitors and reduce their toxicity has become a new challenge for scientists in the field of drug development. The research shows that the natural product has unique advantages in the aspects of regulating the tumor microenvironment, inhibiting tumor metastasis and improving tumor drug resistance. Therefore, the search for natural products capable of enhancing the curative effect of the immune checkpoint inhibitor and reducing the toxic and side effects of the immune checkpoint inhibitor has important clinical significance for improving the treatment outcome and the survival period of patients with lung cancer (especially, small cell lung cancer).
Aucubin (aucubin) belongs to iridoid compounds, and is widely present in plants of Plantaginaceae, Scrophulariaceae, Polulariaceae, Eucommiaceae, etc., wherein the content of herba plantaginis is the highest. The aucubin has effects of protecting liver, removing toxic substance, resisting inflammation, resisting oxidation, and resisting osteoporosis. The oral administration bioavailability of aucubin is low, and the administration modes of the oral administration of aucubin from high bioavailability to low bioavailability are intravenous administration, intraperitoneal administration and oral administration. Studies show that aucubin has obvious cytotoxicity on human myeloid leukemia K562 cells and can induce apoptosis. In addition, studies show that aucubin can increase the amount of p53 and p21 proteins in a549 cell line of human non-small cell lung cancer, and further block cells at the stage of G0/G1, and finally cause apoptosis of A549 cells (see, for example, Hanmanfei et al, "research on chemical structures and pharmacological actions of natural aucubin and derivatives thereof" Chinese herbal medicines, Vol.19, No. 2017, No. 4105-one 4113). However, there is no study on the combination of aucubin and an immune checkpoint inhibitor in the treatment of lung cancer (especially small cell lung cancer).
Disclosure of Invention
The invention aims to provide a pharmaceutical composition with synergistic effect for treating lung cancer (especially small cell lung cancer) patients, and provides a new idea for safely, effectively and economically treating lung cancer (especially small cell lung cancer) clinically.
The technical scheme for realizing the purpose of the invention is as follows:
the first aspect of the invention provides a pharmaceutical composition for treating lung cancer, which comprises an immune checkpoint inhibitor and aucubin, wherein the weight ratio of the immune checkpoint inhibitor to the aucubin is 1: 0.1-1.
In one embodiment, the immune checkpoint inhibitor is selected from one or more of ipilimumab, nivolumab, pembrolizumab, astuzumab, avilimumab, and desvolumab.
In another embodiment, the weight ratio of immune checkpoint inhibitor to aucubin is 1: 0.2-0.8.
In a preferred embodiment, the immune checkpoint inhibitor is selected from altritizumab, and the weight ratio of altritizumab to aucubin is 1: 0.2.
in one embodiment, the pharmaceutical composition further comprises a chemotherapeutic agent, and the immune checkpoint inhibitor, aucubin, and the chemotherapeutic agent are in a weight ratio of 1: 0.1-1:0.1-1.
In another embodiment, the chemotherapeutic agent is selected from one or more of cisplatin, carboplatin, paclitaxel, docetaxel, etoposide, pemetrexed.
In a preferred embodiment, the immune checkpoint inhibitor is selected from alt-rubimab, the chemotherapeutic agent is selected from etoposide, and the weight ratio of alt-rubimab, aucubin, and etoposide is 1: 0.2: 0.4.
the second aspect of the invention provides a pharmaceutical preparation for treating lung cancer, which is prepared from the pharmaceutical composition and a pharmaceutically acceptable carrier.
In one embodiment, the pharmaceutical formulation is an injection.
In another embodiment, the injectable formulation is selected from the group consisting of an injectable solution, a sterile powder for injection, and a concentrated solution for injection.
The route of administration may be parenteral, including but not limited to intravenous, subcutaneous, intramuscular, and the like.
The active ingredients (e.g., alemtuzumab, aucubin, and/or etoposide) in the pharmaceutical composition of the invention may be administered simultaneously or separately in sequential order. The active ingredients of the pharmaceutical compositions of the present invention may be administered in combination in the same pharmaceutical formulation or in separate and distinct formulations.
A third aspect of the invention provides the use of a pharmaceutical composition or pharmaceutical formulation as described above in the manufacture of a medicament for the treatment of lung cancer.
In a preferred embodiment, the lung cancer is small cell lung cancer.
In a more preferred embodiment, the small cell lung cancer is a limited-term small cell lung cancer or a broad-term small cell lung cancer.
In a more preferred embodiment, the extensive small cell lung cancer is post-chemotherapy extensive small cell lung cancer.
By "localized small cell lung cancer" is meant a patient whose tumor is confined to one thoracic cavity, including metastasis to the pre-mediastinal, ipsilateral supraclavicular and anterior oblique horn lymph nodes. By "extensive small cell lung cancer" is meant the development of a tumor that exceeds the range of the limited stage.
The aucubin used in the pharmaceutical composition of the present invention can be extracted and separated from plants of plantago, scrophulariaceae, globulariaceae, eucommia ulmoides, etc. containing the active ingredient by a biological purification method, or can be purchased from commercially available products.
In the above-mentioned medical applications, the administration time, administration frequency, etc. of the composition of the present invention are required depending on the specific diagnosis result of the disease state, which is within the technical scope of those skilled in the art.
The therapeutic regimen for mice is applied to human body, and the effective dose of all drugs to human body can be converted by the effective dose of the drugs to mice, which is also easy to be realized by the ordinary skilled person in the art.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention combines the advantages of China in the aspect of natural product research, screens out a pharmaceutical composition with synergistic effect in the aspect of treating lung cancer (especially small cell lung cancer), remarkably enhances the effect of the immune checkpoint inhibitor in treating lung cancer (especially small cell lung cancer) by combining aucubin and the immune checkpoint inhibitor, and further makes it possible to increase the effectiveness and safety of the drugs by reducing the dosage of the immune checkpoint inhibitor.
(2) The plant containing aucubin (such as plantain herb, figwort root, eucommia bark and the like) has wide sources in China, and the aucubin has simple preparation method, mature industrial production method and lower cost. Therefore, the curative effect is enhanced by adding aucubin into the expensive immune check point inhibitor, so that the medicine cost of lung cancer (especially small cell lung cancer) patients in China can be greatly reduced, and the economic burden of the patients is really reduced.
Detailed Description
The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.
Example (b):
1. purpose of experiment
Investigating the influence of the pharmaceutical composition on the H446 mouse transplantation tumor model
2. Experimental Material
2.1 animals: SPF-grade BALB/c female nude mice, 6-8 weeks old, 18-22g in weight, purchased from Beijing Huafukang Biotechnology GmbH, Inc., license number SCXK (Jing) 2018-.
2.2 Instrument: an analytical balance, an electronic balance, a 1mL syringe, a gavage needle, an animal cage, picric acid, and the like.
2.3 main drugs and reagents: a human small cell lung cancer cell line H446 purchased from cell banks of Chinese academy of sciences; aucubin was purchased from Sigma company of usa (purity over 99.5%); etoposide injection (20mg/mL) was purchased from zilu pharmaceuticals; abitlizumab injection (60mg/mL) was purchased from Roche Gentam.
3. Experimental methods
3.1 establishment and administration of transplantable tumor model
BALB/c female nude mice were bred at room temperature, and after acclimatization, were inoculated with H446 cells, and each nude mouse was injected with 5 × 107And (4) cells. After one week of inoculation, the subcutaneous tissues of the left armpits of the nude mice are observed, and the nude mice are found to have nodule generation in the size of rice grains at the inoculation part. And (4) continuously feeding, when the diameter of the tumor is about 5mm, removing the nude mice with large tumor size and weight difference, and randomly grouping the rest nude mice.
The experiment was divided into the following groups of 10 tumor-bearing mice per group: (1) a model group; (2) attrituximab (5 mg/kg); (3) aucubin (1 mg/kg); (4) etoposide (2mg/kg) group; (5) attrituximab (5mg/kg) + aucubin (1 mg/kg); (6) attrituximab (5mg/kg) + aucubin (1mg/kg) + etoposide (2 mg/kg).
The tumor-bearing mice of the model group were administered with 0.9% physiological saline by intraperitoneal injection, and the other groups were administered with intraperitoneal injection according to the body weight of the tumor-bearing mice, once per week, and continuously for 4 weeks. After 4 weeks, half of the mice in each group were sacrificed and the tumor mass was detached. The remaining mice were continued on the previous dosing schedule and the survival of each group was calculated.
3.2 evaluation index
3.2.1 tumor weight and tumor inhibition rate:
after 4 weeks of dosing, half of the mice in each group were sacrificed and weighed after the tumor mass had been detached.
Tumor inhibition (%) is ═ average tumor weight in model group-average tumor weight in administered group)/average tumor weight in model group x 100%
3.2.2 survival: in assessing survival, tumor-bearing animals at moribund status were euthanized for animal welfare considerations.
3.3 statistical methods
Results were analyzed using SPSS 13.0 statistical software and data are presented as mean ± standard deviation. The comparison among multiple groups adopts one-factor analysis of variance, the comparison between two groups adopts t test, and P <0.05 indicates that the difference has statistical significance.
4. Results of the experiment
4.1 the pharmaceutical composition of the invention has the effect of inhibiting tumor of tumor-bearing mice
In the experiment, after the nude mice were inoculated with H446 cells, the tumors grew rapidly after a 5-day incubation period. As shown in Table 1 below, the results show that Atizumab (5mg/kg) alone is effective in inhibiting tumor growth (p < 0.05). After the aucubin is singly administrated once every week for 4 weeks, the aucubin hardly shows the inhibition effect on tumors, and the tumor inhibition rate is only 0.05%. Etoposide (2mg/kg) alone has a certain effect of inhibiting the growth of H446 tumor, but the tumor inhibition rate of the etoposide is not statistically significant compared with that of a model group. After the group of the astuzumab (5mg/kg) and the aucubin (1mg/kg) is administrated once a week for 4 weeks, the tumor weight of the nude mice is remarkably reduced (p is less than 0.01), and the tumor inhibition rate reaches 43.42%. Surprisingly, after etoposide (2mg/kg) is further added into the pharmaceutical composition, the effect of the pharmaceutical composition on inhibiting the growth of H446 tumor is further enhanced, and the tumor inhibition rate can reach 53.95% (p < 0.01).
The results show that when the astuzumab and aucubin are combined according to a certain proportion, the tumor inhibition effect of the combined drug is obviously superior to the effect of the independent use of the astuzumab and aucubin, and the addition of etoposide in the composition can further improve the anti-tumor effect of the astuzumab, which indicates that the combined drug exerts a synergistic anti-tumor effect.
Table 1: the pharmaceutical composition of the invention has the effect of inhibiting tumor of tumor-bearing mice 4 weeks after administration
Note: p <0.05, p <0.01, compared to model groups.
4.2 Effect of the pharmaceutical composition of the invention on the survival time of tumor-bearing mice
As shown in Table 2 below, the results show that alt-Veruzumab (5mg/kg) alone is effective in prolonging survival (p <0.05) of tumor-bearing mice. Aucubin (1mg/kg) alone had no improvement in survival in tumor bearing mice compared to the model group. Etoposide (2mg/kg) alone has a certain prolongation effect (40.4 +/-5.1 days) on the survival period of tumor-bearing mice, but has no statistical significance compared with a model group, which is probably related to the stronger toxicity of the chemotherapeutic drug etoposide. The age of survival of tumor-bearing mice is remarkably prolonged after the group of the Atzhuzumab (5mg/kg) and the aucubin (1mg/kg) is administrated (59.2 +/-3.7 days, and p is less than 0.01). After etoposide (2mg/kg) is further added into the pharmaceutical composition, the survival period of tumor-bearing mice is not further prolonged compared with the combination of the two drugs (54.3 +/-2.4 days, p is less than 0.05). As mentioned above, this may be associated with the strong toxicity of the chemotherapeutic drug etoposide itself.
The results show that when the astuzumab and the aucubin are combined according to a certain proportion, the effect of improving the life cycle of tumor-bearing mice is obviously better than the effect of singly using the astuzumab and the aucubin, and the synergistic antitumor effect of the medicines is shown. However, the addition of etoposide to the above pharmaceutical composition did not further extend the survival of tumor-bearing mice.
The tumor inhibition effect of the pharmaceutical composition on H446 transplantation tumor nude mice shows a trend which is substantially consistent with the influence on the survival time of experimental animals.
Table 2: influence of the pharmaceutical composition on survival time of tumor-bearing mice
Note: p <0.05, p <0.01, compared to model groups.
5. Conclusion of the experiment
The experimental results show that when the astuzumab and the aucubin are combined according to a certain proportion, the tumor inhibition effect and the survival time improvement effect of the astuzumab and the aucubin on the human small cell lung cancer H466 transplanted tumor mouse are remarkably superior to the effect of the independent use of the astuzumab and the aucubin, and the pharmaceutical composition disclosed by the invention has a synergistic effect on treating lung cancer (particularly small cell lung cancer).
The further addition of other chemotherapeutic drugs (e.g., etoposide) to the above pharmaceutical composition may further synergistically improve the tumor suppression effect and survival time of tumor-bearing mice, but the overall anti-tumor effect exhibited by the pharmaceutical composition may also be related to the toxicity of the chemotherapeutic drugs.
In addition, in the above animal experiments, no significant phenomenon of panic, restlessness or food refusal was observed in the nude mice of the pharmaceutical composition group (groups 5 and 6) of the present invention. No obvious adverse reaction exists in the pharmaceutical composition, and experimental animals have good tolerance to the pharmaceutical composition.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (10)
1. A pharmaceutical composition for treating lung cancer, which comprises an immune checkpoint inhibitor and aucubin, wherein the weight ratio of the immune checkpoint inhibitor to the aucubin is 1: 0.1-1.
2. The pharmaceutical composition of claim 1, wherein the immune checkpoint inhibitor is selected from one or more of ipilimumab, nivolumab, pembrolizumab, astuzumab, avizumab, and devolizumab.
3. The pharmaceutical composition of claim 1 or 2, wherein the weight ratio of immune checkpoint inhibitor to aucubin is 1: 0.2-0.8.
4. The pharmaceutical composition of any one of claims 1-3, wherein the immune checkpoint inhibitor is selected from the group consisting of astuzumab, and the weight ratio of astuzumab to aucubin is 1: 0.2.
5. the pharmaceutical composition of any one of claims 1-4, further comprising a chemotherapeutic agent, wherein the immune checkpoint inhibitor, aucubin, and the chemotherapeutic agent are present in a weight ratio of 1: 0.1-1:0.1-1.
6. The pharmaceutical composition of any one of claims 1-5, wherein the chemotherapeutic agent is selected from one or more of cisplatin, carboplatin, paclitaxel, docetaxel, etoposide, pemetrexed.
7. The pharmaceutical composition of any one of claims 1-6, wherein the immune checkpoint inhibitor is selected from astuzumab, the chemotherapeutic agent is selected from etoposide, and the weight ratio of astuzumab, aucubin, and etoposide is 1: 0.2: 0.4.
8. a pharmaceutical preparation for treating lung cancer, wherein the pharmaceutical preparation is prepared from the pharmaceutical composition of any one of claims 1-7 and a pharmaceutically acceptable carrier, and preferably the pharmaceutical preparation is an injection.
9. Use of the pharmaceutical composition of any one of claims 1-7 or the pharmaceutical formulation of claim 8 in the manufacture of a medicament for the treatment of lung cancer.
10. The use of claim 9, wherein the lung cancer is small cell lung cancer, preferably the small cell lung cancer is restricted small cell lung cancer or extensive small cell lung cancer, more preferably the extensive small cell lung cancer is extensive small cell lung cancer after chemotherapy.
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| CN202010602230.0A CN111558045A (en) | 2020-06-29 | 2020-06-29 | Medicine composition for treating lung cancer |
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| CN202010602230.0A CN111558045A (en) | 2020-06-29 | 2020-06-29 | Medicine composition for treating lung cancer |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115381847A (en) * | 2022-09-20 | 2022-11-25 | 上海市第六人民医院 | Application of aucubin in preventing or treating cisplatin ototoxicity |
-
2020
- 2020-06-29 CN CN202010602230.0A patent/CN111558045A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115381847A (en) * | 2022-09-20 | 2022-11-25 | 上海市第六人民医院 | Application of aucubin in preventing or treating cisplatin ototoxicity |
| CN115381847B (en) * | 2022-09-20 | 2023-12-19 | 上海市第六人民医院 | Application of aucubin in prevention or treatment of cisplatin ototoxicity |
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