CN117597124A - Siro-lonib and application of Siro-lonib in combined drug treatment of breast cancer - Google Patents
Siro-lonib and application of Siro-lonib in combined drug treatment of breast cancer Download PDFInfo
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- CN117597124A CN117597124A CN202280047251.8A CN202280047251A CN117597124A CN 117597124 A CN117597124 A CN 117597124A CN 202280047251 A CN202280047251 A CN 202280047251A CN 117597124 A CN117597124 A CN 117597124A
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Classifications
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
- Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Relates to the field of biological medicine, in particular to the application of the Siro-Ni and the combined drug for treating breast cancer. There is provided the use of sirolimus or a derivative thereof, or a pharmaceutical composition comprising the same and cetadamine or a derivative thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of breast cancer. Animal efficacy tests prove that the single drugs of the Siro-Nib and the Sidamide have tumor inhibiting activity, and the combined application can produce better synergistic treatment effect.
Description
The invention relates to the field of biological medicine, in particular to Siro-lonib and application of the Siro-lonib in combination therapy of breast cancer.
Breast cancer is the female malignant tumor with highest morbidity in the world and China, accounts for 30% of the total number of female malignant tumor patients, and has the second mortality rate in female malignant tumor. The world health organization counts 210 ten thousand new breast cancers in 2018, accounting for 1/4 of all cancers in females. According to the american cancer society statistics, 31.7 thousands of new cases, 4.2 thousands of women die from the disease in 2019. According to the Hormone Receptor (HR) and human epidermal growth factor receptor (HER 2) typing, the highest incidence is about 66% of HR+/HER 2-breast cancers, and the highest invasive triple negative breast cancers are about 10%. The survival rate of breast cancer is greatly different due to different diagnosis stages, and the survival rate is lower when the clinical stage is higher for 5 years, the survival rate is 98% in stage I, 92% in stage II, 75% in stage III and 27% in stage IV. In 2018, the latest breast cancer data report in China indicates that the number of female breast cancer morbidity and mortality accounts for 11.2% and 9.2% of global morbidity and mortality respectively, and the worldwide position is the first, and the 1 st and 5 th female malignant tumor morbidity and mortality in China are located. The national tumor registration 2015 report data shows that the number of new cases of breast cancer reaches 26.9 ten thousand, accounting for 15% of all new malignant tumors of females, and 6.95 ten thousand females die due to breast cancer and present a younger trend. Breast cancer has become an important factor threatening the health of women in china.
There are two main types of methods for typing breast cancer, one is pathological typing and the second is molecular typing.
Breast cancer is pathologically typed by observing the characteristics of tumor cells under a microscope, thereby judging the properties of the breast cancer. According to this system, breast cancer can be generally classified into non-invasive cancer, early invasive cancer, and the like. Non-invasive cancers are early stages, including common ductal carcinoma in situ, and generally have a good prognosis, whereas invasive cancers generally have a poor prognosis, and more comprehensive treatment is often required to achieve good results. Invasive carcinoma is the most common, accounting for more than 80%, and it can be subdivided into invasive catheter carcinoma, invasive lobular carcinoma, etc.
Molecular typing refers to the detection of gene and protein levels for breast cancer, grouping according to the characteristics of gene mutation and protein expression. Molecular typing of breast cancer is more than one system, most classically classified by whether cancer cells express three proteins, ER (estrogen receptor), PR (progesterone receptor) and HER 2. Depending on their positivity and negativity, different combinations are formed, also bringing about different breast cancer subtypes. Such as: if a breast cancer is ER-positive or PR-positive, HER 2-negative (ER+PR+HER2-), we call it hormone receptor positive breast cancer. If one breast cancer is ER-negative, PR-negative, but HER 2-positive (ER-PR-HER2+), we call it HER 2-positive breast cancer. If one breast cancer is ER-negative, PR-negative, HER 2-negative (ER-PR-HER 2-), we call it a triple negative breast cancer.
Distant metastasis has occurred in 5-10% of breast cancer patients at diagnosis, while recurrent metastasis still occurs in 20-50% of early-stage patients receiving treatment. Studies show that the median survival time of patients with advanced metastatic breast cancer is 2-3 years, the five-year survival rate is only 25%, and especially HER2 negative advanced breast cancer is more important due to the lack of effective targeted therapeutic drugs, and the establishment of a scientific therapeutic scheme is more important.
The progress of treatment for HR negative/HER 2 negative breast cancers lags behind other molecular subtypes, limited to chemotherapy for non-metastatic disease to date, but this pathological type presents high aggressiveness, with susceptibility to distant metastasis. The first-line, second-line and later-line chemotherapy of recurrent metastatic advanced breast cancer has not yet determined the optimal scheme, including anthracyclines, taxanes, capecitabine and the like, and the treatment adopts a single-drug chemotherapy or combined chemotherapy mode. There is a great deal of evidence that the jersey and anthracyclines are preferred as first line therapies. The choice of the post-line treatment regimen should integrate prior treatments, drug toxicity, co-existence of the disease, patient willingness, etc. Through multi-line chemotherapy, the curative effect benefit of patients shows a gradually decreasing trend, for example, continuous 3 chemotherapy schemes are invalid or ECOG score is more than or equal to 3, and cytotoxic drugs are not considered any more, and palliative treatment is adopted instead. Immunotherapy is an emerging area of breast cancer treatment, particularly for triple negative breast cancers without specific targeted therapies. Studies have shown that the use of the PD-L1 checkpoint inhibitor atezolizumab in combination with nanoalbumin-conjugated paclitaxel in-line can extend patient survival. Targeted therapies include the use of anti-angiogenic drugs, PARP inhibitors, etc., but are still in the clinical exploration phase, there is a need to find new methods for the treatment of such breast cancers after chemotherapy failure.
HR positive/HER 2 negative breast cancer is currently the most common subtype in various ethnic/ethnic groups. Clinical oncology society of America (ASCO) recommends clinical practice guidelines for HER2 negative breast cancer chemotherapy and targeted therapy that endocrine therapy be the first-line standard regimen for hormone receptor positive advanced breast cancer females, in addition to immediate life-threatening lesions (such as symptomatic visceral metastasis) or resistance to endocrine therapy. Endocrine therapy is susceptible to primary or secondary resistance, resulting in limited use. The NCCN guidelines in the united states indicate that no benefit or symptomatic visceral metastasis occurs in 3 consecutive endocrine treatment regimens, and that systemic chemotherapy is a consideration. However, most of antitumor drugs can induce adverse reactions at the same time, so that the life quality of patients is affected, and the research on molecular mechanisms and related targeted drugs of endocrine treatment drug resistance is a current urgent problem to be solved. At present, the study of endocrine combination dosing schemes in endocrine resistant subjects comprises that CDK4/6 inhibitor, PI3K alpha inhibitor, AKT inhibitor and HDAC inhibitor can effectively prolong the progression-free survival period, improve the survival rate of metastatic diseases in the past 30 years, and is a new opportunity for hormone receptor positive endocrine treatment resistant subjects. Whether other combination regimens are effective in endocrine resistant patients or whether a new therapeutic option can be provided for that part of the population is a subject of considerable research in the field.
The Siro is a brand new molecular body with global patent protection, which is independently developed by Shenzhen micro-core biotechnology, inc., has no indication and is marketed in batches at home and abroad, is a small-molecule antitumor targeting drug taking polyprotein kinase as a target point, and has three-way antitumor synergistic action mechanisms of antitumor angiogenesis, tumor cell mitosis inhibition, tumor inflammatory microenvironment regulation and the like through high selective inhibition activity on VEGFR/PDGFR/c-Kit, aurora B and CSF-1R targets; and simultaneously, the high target selectivity of the method also reduces the side effect risk caused by off-target effect.
CN200910223861.5 discloses a sierozen compound, which specifically discloses a derivative of naphthalene amide, a preparation method and application thereof. The compounds have protein kinase inhibitory activity and histone deacetylase inhibitory activity at the same time, and can be used for treating diseases related to abnormal protein kinase activity or abnormal histone deacetylase activity, including inflammation, autoimmune diseases, cancers, nervous system diseases and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergy, asthma and diseases related to hormone. CN201610856945.2 discloses a non-solvated crystal A, B, C of sirolimus and a preparation method thereof, and also relates to a pharmaceutical composition containing the crystal, and application of the crystal in preparing a medicament for treating diseases related to abnormal protein kinase activity or abnormal histone deacetylase activity.
The Sidamascamine is also a brand-new molecular body with global patent protection, which is independently developed by Shenzhen micro-core biotechnology Co-Ltd, has two indications in China, is a new generation subtype selective histone deacetylase inhibitor, mainly aims at the I large class HDAC subtype (HDAC 1, 2 and 3) closely related to tumorigenesis and development, and has been proved by researches that the Sidamascamine obviously inhibits lymph and blood tumor cells in the G0/G1 period and induces tumor cell apoptosis through inhibiting specific HDAC subtype and causing chromatin reconstruction and gene transcription regulation (namely epigenetic regulation); inducing and enhancing Natural Killer (NK) and antigen-specific cytotoxic T Cell (CTL) -mediated tumor killing and inhibiting inflammatory response of tumor pathological tissues, not only can directly contribute to the curative effect on circulating tumor cells and local lesions in T lymphoma, but also can be applied to inducing and enhancing the overall regulatory activity of anti-tumor cell immunity against other types of tumors; in addition, the sitagliptin has the functions of inducing the differentiation of tumor stem cells, reversing the epithelial mesenchymal phenotype transformation (EMT) of the tumor cells and the like through an epigenetic regulation mechanism, thereby playing a potential role in restoring the sensitivity of drug-resistant tumors to drugs, inhibiting tumor metastasis, relapse and the like.
CN03139760.3 discloses a cidamine compound, in particular a benzamide histone deacetylase inhibitor with differentiation and antiproliferative activity, and a preparation method and application of a pharmaceutical preparation thereof, which discloses a structural general formula and defines substituents. The compounds are useful as inhibitors of histone deacetylase and in the treatment of diseases associated with differentiation and proliferation such as cancer and psoriasis. CN201210489178.8 discloses two crystalline forms of cetosteanamine, namely cetosteanamine form a and cetosteanamine form B, and a process for preparing new crystalline forms of cetosteanamine. The crystalline form A and the crystalline form B of the Sidamide have excellent performance in oral absorbability and inhibition of cell differentiation and proliferation, have weak toxicity, have good storage and treatment stability, and can be used for preparing medicaments for treating diseases related to cell differentiation and proliferation. CN201410136761.X discloses an E-configuration benzamide compound, a medicinal preparation and application thereof, wherein the E-configuration benzamide compound is sitagliptin, the chemical name of the E-configuration benzamide compound is N- (2-amino-4-fluorophenyl) -4- [ N- [ (E) -3- (3-pyridine) acryloyl ] aminomethyl ] benzamide, and in the structural formula, the configuration of the 3-pyridine acryloyl is E-type. The E-configuration cidamine has subtype selective histone deacetylase inhibiting activity and mainly inhibits HDAC1, HDAC2, HDAC3 in class I HDAC and HDAC10 in class IIb HDAC. The E-configuration ciladalimine can be used for treating diseases related to abnormal histone deacetylase activity, such as cancers, including lymphomas, solid tumors, blood system tumors and the like.
Advanced breast cancer patients first line treatment have a well-defined systemic endocrine treatment or chemotherapy regimen that would benefit based on HR receptor and HER2 tumor marker expression. However, after first-line, particularly multi-line, treatment, the patient's rate of benefit gradually decreases, toxic response increases, tolerability decreases, alternative treatment regimens are limited, and palliative treatment is often selected to improve patient quality of life. Thus, there is an unmet clinical need for advanced breast cancer treatment.
Disclosure of Invention
The invention aims to provide a drug and a drug combination composition which can effectively prevent and/or treat breast cancer after first-line treatment, particularly multi-line treatment.
To achieve this object, the present invention proposes the use of sirolimus or a derivative thereof or a pharmaceutical composition comprising the same with cetadalimamine or a derivative thereof for the manufacture of a medicament for the treatment and/or prevention of breast cancer. Preferably, wherein the breast cancer is a triple negative breast cancer.
Wherein the Siro-lonitrile derivative comprises pharmaceutically acceptable salts thereof and unsolvated crystals A, B and C, and the Siro-lonitrile derivative comprises pharmaceutically acceptable salts, enantiomers and crystal forms A and B thereof.
The content of the Siro-Raney or its derivative is 10-80mg, preferably 20-50mg, more preferably 10mg,15mg,20mg,25mg,30mg,35mg,40mg,45mg,50mg,55mg,60mg,65mg,70mg,75mg,80mg, and the content of the Siro-present amine or its derivative is 5-60mg, preferably 10-30mg, more preferably 5mg,10mg,15mg,20mg,25mg,30mg,35mg,40mg,45mg,50mg,55mg,60mg.
Wherein the medicine is one-line, two-line, three-line, four-line, five-line or six-line medicine.
The pharmaceutical composition provided by the invention comprises a compound preparation or a medicine box.
The kit refers to a kit comprising a therapeutic agent. The correct proportions of the various drugs are typically provided in a kit and packaged in a form that enables those drugs, which are expensive and difficult to obtain, to be best and economical, with the individual drugs being in precise doses and ready for use in a kit for the treatment of a disease.
Wherein the compound preparation comprises a solid preparation and a liquid preparation. The solid preparation comprises tablets, capsules, granules, pills, powder and suppositories, and the liquid preparation comprises oral liquid and injection. The kit is a unit preparation of the Siro-lonib or the derivative thereof and the Sidamide or the derivative thereof with the same or different specifications, wherein the unit preparations are respectively placed in separate containers or placed in the same container.
The present invention also provides a method for treating and/or preventing breast cancer, comprising the step of administering the Siro-lonil or a derivative thereof or simultaneously or sequentially administering the Siro-lonil or a derivative thereof and the Sidamide or a derivative thereof.
Preferably, wherein the breast cancer is a triple negative breast cancer.
Wherein the Siro-lonitrile derivative comprises pharmaceutically acceptable salts thereof and unsolvated crystals A, B and C, and the Siro-lonitrile derivative comprises pharmaceutically acceptable salts, enantiomers and crystal forms A and B thereof.
The content of the Siro-Raney or its derivative is 10-80mg, preferably 20-50mg, more preferably 10mg,15mg,20mg,25mg,30mg,35mg,40mg,45mg,50mg,55mg,60mg,65mg,70mg,75mg,80mg, and the content of the Siro-present amine or its derivative is 5-60mg, preferably 10-30mg, more preferably 5mg,10mg,15mg,20mg,25mg,30mg,35mg,40mg,45mg,50mg,55mg,60mg.
The invention has the beneficial effects that:
the invention is proved by animal efficacy tests: the different doses of the Siro Luo Nishan medicine have remarkable tumor growth inhibition activity, and the drug effect models of different tumor donor sources have slightly different therapeutic effects on the Siro, so that the drug effect models show more or less dose dependence. Compared with the single-drug use of the Siro-Hilde and the Sidamine, the Siro-Hilde and the Sidamine have stronger inhibition effect on tumor growth, i.e. the combination of the two drugs can produce better treatment effect.
FIG. 1 represents the TNBC @ of Siro-Raney at different dosesTriple negative breast cancer) -tumor-inhibiting activity of PDX (humanized tumor graft) model 1. Wherein the abscissa represents the number of days after completion of treatment and the ordinate represents the tumor volume (mm 3 )。
Figure 2 represents the tumor-inhibiting activity of sironi on TNBC (triple negative breast cancer) -PDX (human tumor graft) model 2 at different doses. Wherein the abscissa represents the number of days after completion of treatment and the ordinate represents the tumor volume (mm 3 )。
FIG. 3 represents the tumor-inhibiting activity of Siro-Hi-Nib in combination with Sida-amine in a 4T1 (mouse triple negative breast cancer cell line) model. Wherein the abscissa represents the number of days after completion of treatment and the ordinate represents the tumor volume (mm 3 )。
The invention is further illustrated by the following non-limiting examples, which are not intended to limit the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Example one drug efficacy test of Siro on tumor graft model (PDX) derived from triple negative breast cancer patients
Establishing a human PDX model: selecting two different donor sourcesBreast cancer (purchased from the company of the midribs coronal biotechnology (beijing)) was designated BR1458 and BR1282, respectively, and both donors were from tumors of asian Triple Negative Breast Cancer (TNBC) patients. BR1458 was inoculated into BALB/c nude mice (purchased from Beijing Vitre Lihua Biotechnology Co., ltd.) until they grew to 100mm 3 Left and right, denoted model 1; BR1282 was inoculated into BALB/c nude mice until they grew to 100mm 3 On the left and right, denoted model 2.
Model 1 mice were divided into 4 groups: the solvent control group, the low-dose group of Siro (5 mg/kg), the Siro Luo Nizhong dose group (10 mg/kg), the Siro Luo Nigao dose group (20 mg/kg) were administered once daily (QD) for 3 weeks, and the tumor volume change was monitored, and the results are shown in FIG. 1.
Model 2 mice were dosed in groups in the same manner as model 1 mice, and tumor volume changes were monitored, as shown in figure 2.
As can be seen from fig. 1: in model 1, the tumor volume was significantly reduced in the low-dose group of the seolony compared to the solvent control group, i.e., the seolony had significant tumor-inhibiting activity at the lowest dose (5 mg/kg); moreover, the difference between the 3 different doses of Siro-lonib (5 mg/kg, 10mg/kg and 20 mg/kg) is not obvious, and it is presumed that it may be related to the sensitivity of the tumor of this origin to Siro-lonib.
As can be seen from fig. 2: in model 2, the tumor volume was significantly reduced in the 3 different dose (5 mg/kg, 10mg/kg and 20 mg/kg) groups of seo-lony compared to the solvent group, i.e. the seo-lony had significant tumor inhibiting activity at all 3 doses; furthermore, the difference between the 3 different doses of Siro-lonib (5 mg/kg, 10mg/kg and 20 mg/kg) groups was evident, showing a clear dose-dependent character, and the sensitivity of the tumor to Siro-lonib was relatively low.
Example Di-Siro-Raney and drug efficacy test of Simultaneous Sida-amine on triple negative breast cancer cell line derived transplantation tumor model
Establishing a TNBC model of mouse origin: mouse triple negative breast cancer cell line 4T1 (purchased from Zhongmeiguanke biotechnology (Beijing) Co., ltd.) was inoculated into normal BALB/c mice (purchased from Beijing Vitre Lihua biotechnology Co., ltd.) until it grew to 100mm 3 Left and right.
The model mice obtained above were divided into 6 groups: the control group, low-dose group of Siro (5 mg/kg), luo Nizhong-dose group of Siro (10 mg/kg), luo Nigao-dose group of Siro (20 mg/kg), single-drug group of Siro-present-amine (25 mg/kg), and combined-drug group of two-drug (Siro-present-amine 10 mg/kg+Siro-present-amine 25 mg/kg) were administered once daily (QD) for 3 weeks, and the tumor volume change was monitored, and the results are shown in FIG. 3.
As can be seen from fig. 3: compared with the solvent control group, the tumor volume of the groups with 3 different dosages (5 mg/kg, 10mg/kg and 20 mg/kg) of the Siro-romide is reduced, namely the Siro-romide has tumor inhibiting activity at 3 dosages; moreover, the low dose (5 mg/kg) of Siro-lonil group is different from the medium and high dose (10 mg/kg and 20 mg/kg) group, and shows a certain dose-dependent characteristic, while the Siro-Luo Nizhong dose (10 mg/kg) group and the high dose (20 mg/kg) group are not different significantly. Compared with the solvent control group, the volume of the tumor in the single-drug group of the Sidamine (25 mg/kg) is reduced, namely the single-drug group of the Sidamine has a certain tumor inhibiting effect. The greatest decrease in tumor volume in the two-drug combination (10 mg/kg of Siro+25 mg/kg of Siro) compared to the other groups, represents a significantly stronger tumor-inhibiting effect of the two-drug combination of Siro and Siro, which is stronger than the 3-dose group of Siro-amine single drug and Siro Luo Nishan, resulting in unexpected synergistic effect.
While the invention has been described in detail and with specific examples, the principles and embodiments of the invention are described herein, the above examples are provided solely to aid in the understanding of the method of the invention and its core concept, including the best mode, and to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims. The scope of the patent protection is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.
Claims (11)
- Use of sirolimus or a derivative thereof or a pharmaceutical composition comprising the same with cetadamine or a derivative thereof for the manufacture of a medicament for the treatment and/or prophylaxis of breast cancer.
- The use of claim 1, wherein the breast cancer is a triple negative breast cancer.
- The use according to claim 1, said seoronic derivative comprising a pharmaceutically acceptable salt thereof and non-solvated crystals A, B and C.
- The use according to claim 1, wherein the cidamine derivative comprises pharmaceutically acceptable salts, enantiomers and forms a and B thereof.
- Use according to claim 1, wherein the content of the cetrorelix or derivative thereof is 10-80mg, preferably 20-50mg, and the content of the cetostelamine or derivative thereof is 5-60mg, preferably 10-30mg.
- The use of claim 1, wherein the medicament is a one-wire, two-wire, three-wire, four-wire, five-wire or six-wire medicament.
- The use of claim 1, wherein the pharmaceutical composition comprises a compound formulation or a kit.
- The use of claim 7, wherein the compound formulation comprises a solid formulation and a liquid formulation.
- The use of claim 8, wherein the solid formulation comprises tablets, capsules, granules, pills, powders, and suppositories, and the liquid formulation comprises oral liquids and injections.
- The use according to claim 7, wherein the kit is a unit preparation of cetroroni or its derivatives and cetadalim or its derivatives, respectively, having the same or different specifications.
- The use according to claim 10, wherein the unit formulations are placed in separate containers or in the same container, respectively.
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