CN115350169A - Application of thiram in preparation of medicine for treating gastric cancer - Google Patents
Application of thiram in preparation of medicine for treating gastric cancer Download PDFInfo
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- CN115350169A CN115350169A CN202110534762.XA CN202110534762A CN115350169A CN 115350169 A CN115350169 A CN 115350169A CN 202110534762 A CN202110534762 A CN 202110534762A CN 115350169 A CN115350169 A CN 115350169A
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- thiram
- gastric cancer
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- 206010017758 gastric cancer Diseases 0.000 title claims abstract description 87
- 208000005718 Stomach Neoplasms Diseases 0.000 title claims abstract description 86
- 201000011549 stomach cancer Diseases 0.000 title claims abstract description 85
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 239000005843 Thiram Substances 0.000 title claims abstract description 83
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Images
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
-
- 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 invention relates to application of thiram in preparation of a medicine for treating gastric cancer, and compared with the prior art, the thiram is found to be capable of obviously inhibiting growth and proliferation of gastric cancer cells, and meanwhile, the gastric cancer resistance effect of the thiram can be obviously enhanced under the assistance of metal ions. The thiram can be used as an active ingredient alone or in combination (simultaneously or sequentially) with other gastric cancer treatment medicaments, and can be used for treating gastric cancer by administering therapeutically effective amount of thiram or pharmaceutical compositions thereof to patients with gastric cancer.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to application of thiram in preparation of a medicine for treating gastric cancer.
Background
Gastric cancer is a common tumor of the digestive system, belongs to malignant tumors with high fatality rate in China worldwide, and has hidden course of disease and extremely difficult early diagnosis. Gastric cancer has a large regional difference, and more than 70% of new gastric cancer cases worldwide are in developing countries, while east asia is mainly china, japan and korea. At present, the diagnosis and treatment means aiming at the gastric cancer is lacked in the world, and the situation is very severe.
Thiram (thiram), CAS number is 137-26-8, molecular formula is C 6 H 12 N 2 S 4 The compound is used as an accelerant, a bactericide, a pesticide and the like of natural rubber, synthetic rubber and latex, and the structural formula is as follows:
fumeishuang is known to function as a seed locusSoil conditioning, soil treatment or spraying. It is toxic to fish, non-toxic to bees, and irritating to human skin and mucous membranes. Acute oral LD 50 : male rats 820 mg/kg, female rats 817.9 mg/kg, male mice 392 mg/kg, female mice 564 mg/kg. Rat acute percutaneous LD 50 3200 mg/kg, no significant accumulation. The teratogenic effect is not seen in the test of rats and mice.
The application of thiram in the treatment of cancer, particularly gastric cancer, is not seen in the prior art.
Disclosure of Invention
The invention aims to provide application of thiram in preparing a medicine for treating gastric cancer.
The purpose of the invention can be realized by the following technical scheme:
application of thiram in preparing medicine for treating gastric cancer.
Furthermore, the thiram is used as an active ingredient of the medicine for treating the gastric cancer, and the medicine for treating the gastric cancer also contains pharmaceutically acceptable auxiliary materials.
Furthermore, the medicine for treating gastric cancer also contains other medicines for treating gastric cancer, and the other medicines for treating gastric cancer comprise one or more of tegafur, eufordine, flutolterone, fluorouracil, mitomycin, cisplatin, adriamycin, etoposide, leucovorin calcium, paclitaxel, platinum oxalate, topoisomerase inhibitor, hirodar, epidermal growth factor receptor inhibitor, angiogenesis inhibitor, cell cycle inhibitor, apoptosis promoter, matrix metalloproteinase inhibitor, BCG (bacillus calmette Guerin), lentinan, interleukin, interferon or tumor necrosis factor.
Furthermore, in the medicine for treating gastric cancer, thiram is combined with metal ions to form thiram-metal ion complexes. The metal ion is preferably a copper ion or a zinc ion, preferably added in the form of a sulfate or a hydrochloride.
A pharmaceutical composition for treating gastric cancer comprises thiram and pharmaceutically acceptable adjuvants.
Preferably, in the pharmaceutical composition, the thiram accounts for 0.1-99% by mass.
Furthermore, the medicine composition also contains other medicines for treating gastric cancer.
Further, in the pharmaceutical composition, the thiram exists in the form of thiram-metal ion complex.
A medicine box contains thiram and pharmaceutically acceptable auxiliary materials.
Further, in the kit, the thiram and the pharmaceutically acceptable auxiliary materials are respectively and independently packaged, or the thiram and the pharmaceutically acceptable auxiliary materials are prepared into a thiram preparation in advance.
Furthermore, the medicine box also contains other gastric cancer treatment medicines, the thiram, the pharmaceutically acceptable auxiliary materials and the other gastric cancer treatment medicines are respectively and independently packaged, or the thiram preparation and the other gastric cancer treatment medicines are respectively and independently packaged.
Compared with the prior art, the invention discovers that thiram can obviously inhibit the growth and proliferation of gastric cancer cells, and meanwhile, the gastric cancer resistance effect of thiram can be obviously enhanced under the assistance of metal ions. The thiram can be used as an active ingredient alone or in combination (simultaneously or sequentially) with other gastric cancer treatment medicaments, and can be used for treating gastric cancer by administering therapeutically effective amount of thiram or pharmaceutical compositions thereof to gastric cancer patients.
Drawings
FIG. 1 is a graph showing the effect of thiram on the growth and proliferation of a gastric cancer cell line in example 1. Wherein, A shows the influence of thiram with different concentrations of 0 muM, 0.01 muM, 0.1 muM and 1 muM on cell proliferation after the treatment of the gastric cancer cell line, B shows the influence of thiram on cell proliferation detected by a soft agarose clone formation experiment, and C shows the difference of thiram on proliferation inhibition of the gastric cancer cell line and a normal cell line.
FIG. 2 is a graph showing the effect of thiram and thiram-copper ion complex on the proliferation of the gastric cancer cell line HGC-27 in example 2. Wherein, A shows the effect of thiram or thiram-copper ion complex treatment on cell proliferation of different concentrations of 0 muM, 0.01 muM, 0.1 muM and 1 muM, and B shows the effect of copper ion concentration gradually rising on the proliferation of thiram treatment gastric cancer cell lines.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
It is to be understood that each of the technical features of the present invention and each of the technical features described in detail below (e.g., the examples) may be combined with each other to constitute a preferred embodiment.
The invention discovers that thiram which is only used as an antibacterial agent at present can obviously inhibit the growth and proliferation of gastric cancer cells. The present invention thus proposes the use of thiram as active ingredient of a medicament for the treatment of gastric cancer.
Accordingly, the present invention provides a method of treating gastric cancer comprising administering to a gastric cancer patient a therapeutically effective amount of thiram. In the present invention, the gastric cancer may be any of various types of gastric cancer known in the art, such as early-stage gastric cancer and advanced-stage gastric cancer; classified according to histopathology, the cancer can be adenocarcinoma, adenosquamous carcinoma, squamous carcinoma, carcinoid and the like, and most of the cancers are gastric adenocarcinoma; classified according to the location of the disease, it can be classified into gastric fundus and cardia cancer, corpus gastri cancer and antral carcinoma; typing by molecule, including EBV infection, microsatellite instability, genome stability and chromosome instability; according to the pathogenic cause, the cancer of stomach caused by helicobacter pylori infection can be included.
In the present invention, a therapeutically effective amount is an amount sufficient to ameliorate or in some way reduce the symptoms associated with the disease. Such amounts may be administered as a single dose or may be administered according to an effective treatment regimen. The amount administered may be a cure for the disease, but is generally administered to ameliorate the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
Thiram may be formulated in pharmaceutical compositions as the therapeutically active ingredient in pharmaceutical compositions. In addition, the pharmaceutical composition can also optionally contain other drugs for treating gastric cancer and optional pharmaceutically acceptable carriers. Oral chemotherapeutic drugs commonly used to treat gastric cancer include, but are not limited to, tegafur, idoxuridine, and fluocinolone; intravenous chemotherapy drugs commonly used in the treatment of gastric cancer include, but are not limited to, fluorouracil, mitomycin, cisplatin, adriamycin, etoposide, and calcium formyltetrahydrofolate, and the like; other drugs commonly used in the treatment of gastric cancer include paclitaxel, platinum oxalate, topoisomerase inhibitors, and Hirodada, among others. Gastric cancer targeted therapeutic agents may also be used, including but not limited to epidermal growth factor receptor inhibitors, angiogenesis inhibitors, cell cycle inhibitors, apoptosis promoters, matrix metalloproteinase inhibitors, and the like. The metal ions include, but are not limited to, those provided in the form of copper sulfate, copper chloride, zinc sulfate, zinc chloride, and the like. In other embodiments, thiram or a pharmaceutical composition thereof may be co-administered with immunotherapy for gastric cancer. Suitable immunotherapies include non-specific biological response modifiers such as bcg, lentinan, etc.; cytokines such as interleukins, interferons, tumor necrosis factors, etc.; and adoptive immunotherapy such as killing cells after Lymphocyte Activation (LAK), tumor Infiltrating Lymphocytes (TIL) and the like.
Thiram or a pharmaceutical composition thereof may be administered to a patient by means conventional in the art. Common therapeutic drug routes for gastric cancer include, but are not limited to, oral, intravenous, peritoneal, perfusion, etc.
In certain embodiments, the present invention also provides a pharmaceutical composition, in particular for the treatment of gastric cancer, comprising thiram as an active ingredient together with pharmaceutically acceptable excipients. In the invention, thiram in the pharmaceutical composition is an active ingredient of the pharmaceutical composition and has a treatment purpose. In certain embodiments, the pharmaceutical composition may further comprise other gastric cancer therapeutic agents, such as those described above. In certain embodiments, the active ingredient in the pharmaceutical composition of the present invention may be thiram only.
In certain embodiments, the present invention also provides a kit comprising thiram as a therapeutically active ingredient. The kit can also contain other pharmaceutically acceptable auxiliary materials and optional other gastric cancer treatment medicines. For example, the kit may contain thiram, pharmaceutically acceptable excipients and optionally other drugs for treating gastric cancer, which are packaged separately. When the medicine box is required to be used for administration, the thiram can be prepared into a corresponding preparation, such as an injection or a perfusion solution, by using the pharmaceutically acceptable auxiliary materials, and can be simultaneously or sequentially administered with other optional gastric cancer treatment medicines. Alternatively, the kit may contain thiram (i.e. containing thiram and pharmaceutically acceptable excipients) formulated as a pharmaceutical preparation and optionally other therapeutic agents for gastric cancer.
In certain embodiments, the invention also includes the use of thiram for the manufacture of a medicament for the treatment of gastric cancer. In certain embodiments, the present invention also includes thiram or a pharmaceutical composition thereof for use in the treatment of gastric cancer. The gastric cancer may be any gastric cancer known in the art, including those described above.
The present invention will be illustrated below by way of specific examples. It should be understood that these examples are illustrative only and are not intended to limit the scope of the present invention. The methods and reagents used in the examples are, unless otherwise indicated, those conventional in the art and conventional commercial reagents.
Basic experimental methods:
1. cell culture: GES-1 and HGC-27 cells were obtained from a commercial source and cultured in RPMI1640 (Invitrogen) medium supplemented with 10% serum, 100. Mu.g/ml penicillin and 100. Mu.g/ml streptomycin, respectively. The cells were cultured at 37 ℃ with a carbon dioxide concentration of 5%.
2. Cell proliferation assay: detection of cell proliferation Using ATP cell viability assay kit (CellTiter-
Luminescent Cell visual Assay). Cells with medium were prepared in a 96-well plate with opaque walls, 100. Mu.l/well, cell count 3000/well, adding thiram (0. Mu.M, 0.01. Mu.M, 0.1. Mu.M, N) with different concentrations after the next day of adherence,1 μ M, 10 μ M) while preparing control wells containing medium only and no cells to obtain background luminescence. Cell viability was determined after 48h using Promega CellTiter reagent. Equilibrate the plate and its contents to room temperature, taking approximately 30 minutes. CellTiter-
Reagent 100. Mu.l. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis, and the plate was incubated at room temperature for 10 minutes to stabilize the fluorescence signal value and the luminescence signal was recorded.
3. Soft agarose cell clone formation experiments: after the number of cells reached 104, the cells were seeded on soft agarose in 6-well plates, and clones with a diameter of more than 0.05 mm were counted after 14 days.
4. Cell IC 50 : processing the data cell proliferation experiment result by Graphpad Prism software to obtain IC 50 Numerical values.
5. And (3) data analysis: data were analyzed using the SAS data software analysis package (9.1.3) and the mean ± standard deviation of the data was counted. One-way variational analysis (ANOVA) and Student's t-test were used to analyze continuous variables. The confidence interval was P <0.05.
Example 1:
thiram has inhibiting effect on the growth of gastric cancer cells
1. The purpose of the experiment is as follows: determination of the Effect of thiram on gastric cancer cell growth
2. The experimental method comprises the following steps: the cell culture and cell proliferation assay methods were as described in basic assay methods 1 and 2. Cell clone formation experiments were as described in basic experimental method 3.
3. Experimental results and analysis:
using thiram-treated cells at different concentrations (0.01. Mu.M, 0.1. Mu.M, 1. Mu.M, 10. Mu.M), and cells treated without thiram were used as a control group (i.e., 0. Mu.M), and after 48 hours, cellTiter-
Reagent assayAnd (5) determining the cell activity. The results are shown in FIG. 1, A. The result shows that thiram has an inhibiting effect on the proliferation of the gastric cancer cell HGC-27, and the inhibition rate of thiram is increased along with the increase of the concentration, which indicates that thiram can obviously inhibit the proliferation of the gastric cancer cell.
Cancer cell lines were treated with thiram by a soft agarose cell clone formation experiment, with DMSO as solvent for the compound as blank control. The result is shown as B in FIG. 1. The result shows that thiram has obvious inhibition effect on the proliferation of the cancer cell HGC-27.
Using thiram-treated cells at different concentrations (0.01. Mu.M, 0.1. Mu.M, 1. Mu.M), and cells treated without thiram as a control group (i.e., 0. Mu.M), 48h later were treated with CellTiter-
Reagents measure cell viability. The result is shown as C in FIG. 1. The result shows that thiram has an inhibition effect on the proliferation of gastric cancer cell HGC-27, but has no obvious inhibition effect on the proliferation of normal human gastric mucosal cell GES-1.
Example 2:
the thiram-copper ion complex has the effect of inhibiting the growth of gastric cancer cells
1. Purpose of the experiment: determining the effect of thiram and thiram-copper ion complex on the growth of gastric cancer cell HGC-27
2. The experimental method comprises the following steps: cell culture and cell proliferation experiments were as described in basic experimental methods 1 and 2.
3. Experimental results and analysis:
cells were treated with thiram and thiram-copper ion complex at various concentrations (0.01. Mu.M, 0.1. Mu.M, 1. Mu.M), copper ion-treated cells served as a control group, and 48h later, cellTiter-
Reagents measure cell viability.
The results are shown in FIG. 2. Thiram and thiram-copper ion complex have an inhibitory effect on proliferation of gastric cancer cell HGC-27, and the inhibition effect of the thiram-copper ion complex is far higher than that of the thiram group (shown as A in figure 2). Meanwhile, the inhibition rate of thiram on gastric cancer cell HGC-27 was increased with the increase of the copper ion concentration (shown as B in FIG. 2). The results show that the copper ions can effectively enhance the sensitivity of the gastric cancer cells to thiram and inhibit the growth of the gastric cancer cells.
The embodiments described above are intended to facilitate a person of ordinary skill in the art in understanding and using the invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make modifications and alterations without departing from the scope of the present invention.
Claims (10)
1. Application of thiram in preparing medicine for treating gastric cancer.
2. The use of thiram according to claim 1 for preparing a medicament for treating gastric cancer, wherein thiram is used as an active ingredient of a medicament for treating gastric cancer, and the medicament for treating gastric cancer further comprises pharmaceutically acceptable excipients.
3. The use of thiram in the preparation of a medicament for the treatment of gastric cancer according to claim 2, wherein the medicament for the treatment of gastric cancer further comprises other medicaments for the treatment of gastric cancer, and the other medicaments for the treatment of gastric cancer comprise one or more of tegafur, eufordine, flutolterone, fluorouracil, mitomycin, cisplatin, adriamycin, etoposide, leucovorin calcium, paclitaxel, platinum oxalate, topoisomerase inhibitors, hiloda, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, cell cycle inhibitors, apoptosis promoters, matrix metalloproteinase inhibitors, bcg, lentinan, interleukins, interferons, or tumor necrosis factors.
4. The use of thiram according to claim 1 for the preparation of a medicament for the treatment of gastric cancer, wherein thiram is bound to a metal ion to form a thiram-metal ion complex.
5. The pharmaceutical composition for treating gastric cancer is characterized by comprising thiram and pharmaceutically acceptable auxiliary materials.
6. The pharmaceutical composition for treating gastric cancer according to claim 5, wherein the pharmaceutical composition further comprises other gastric cancer therapeutic drugs.
7. The pharmaceutical composition of claim 5, wherein the thiram is present as a thiram-metal ion complex.
8. A medicine box is characterized in that the medicine box contains thiram and pharmaceutically acceptable auxiliary materials.
9. The kit of claim 8, wherein the thiram and the pharmaceutically acceptable excipient are packaged separately, or the thiram and the pharmaceutically acceptable excipient are pre-formulated into a thiram preparation.
10. The kit of claim 9, wherein the kit further comprises other gastric cancer treatment drugs, wherein the thiram, the pharmaceutically acceptable excipients and the other gastric cancer treatment drugs are packaged separately, or the thiram preparation and the other gastric cancer treatment drugs are packaged separately.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6740681B1 (en) * | 1998-01-11 | 2004-05-25 | Yeda Research And Development Co. Ltd. | Pharmaceutical compositions comprising thiram |
| WO2019094053A1 (en) * | 2017-11-13 | 2019-05-16 | Duke University | Disulfiram and copper salt dosing regimen |
| CN110833546A (en) * | 2018-08-17 | 2020-02-25 | 中国科学院上海生命科学研究院 | Use of dorzolomide in treating gastric cancer |
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2021
- 2021-05-17 CN CN202110534762.XA patent/CN115350169A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6740681B1 (en) * | 1998-01-11 | 2004-05-25 | Yeda Research And Development Co. Ltd. | Pharmaceutical compositions comprising thiram |
| WO2019094053A1 (en) * | 2017-11-13 | 2019-05-16 | Duke University | Disulfiram and copper salt dosing regimen |
| CN110833546A (en) * | 2018-08-17 | 2020-02-25 | 中国科学院上海生命科学研究院 | Use of dorzolomide in treating gastric cancer |
Non-Patent Citations (1)
| Title |
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| I. HAJDÚ ET AL.: "Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 28, no. 18, 1 October 2018 (2018-10-01), pages 3113 - 3118, XP085456358, DOI: 10.1016/j.bmcl.2018.07.001 * |
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