阅读说明：本技术 氯沙坦钾与达卡巴嗪联合用药在制备治疗肠癌药物中的应用 (Application of losartan potassium and dacarbazine combined medicine in preparation of medicine for treating intestinal cancer ) 是由 李斌 于 2019-09-04 设计创作，主要内容包括：本发明属于医药领域,特别涉及氯沙坦钾和达卡巴嗪联合用药在制备治疗肠癌药物中的应用。本发明首次提出氯沙坦钾和达卡巴嗪联合用药在制备治疗肠癌药物中的应用,两者具有明显的协同作用,有效提高疗效,相对于单一组分疗效更为显著,提高了对肿瘤细胞的杀伤性；有效降低用药量,从而减少毒副作用。两者联合使用也可节约成本,减轻病人的经济负担,为肠癌的防治提供了一条新途径,在医药学领域有广阔的应用前景。(The invention belongs to the field of medicines, and particularly relates to application of a losartan potassium and dacarbazine combined medicine in preparation of a medicine for treating intestinal cancer. The invention provides the application of the losartan potassium and dacarbazine combined medicine in preparing the medicine for treating intestinal cancer for the first time, the losartan potassium and dacarbazine combined medicine have obvious synergistic effect, the curative effect is effectively improved, the curative effect is more obvious compared with that of a single component, and the killing property to tumor cells is improved; effectively reduces the dosage, thereby reducing the toxic and side effects. The combined use of the two can also save the cost, reduce the economic burden of patients, provide a new way for preventing and treating intestinal cancer, and have wide application prospect in the field of medicine and pharmacology.)

1. The losartan potassium and dacarbazine are combined to be applied to the preparation of the medicine for treating intestinal cancer.

2. Use according to claim 1, characterized in that: the dosage proportion of the losartan potassium to the dacarbazine is 100-6400 ng/ml: 12 μ g/ml.

3. Use according to claim 1, characterized in that: the dosage proportion of the losartan potassium to the dacarbazine is 100-6400 ng/ml: 24 μ g/ml.

4. Use according to claim 1, characterized in that: the dosage proportion of the losartan potassium to the dacarbazine is 100-6400 ng/ml: 48. mu.g/ml.

5. Use according to claim 1, characterized in that: the dosage proportion of the losartan potassium and the dacarbazine is 6400 ng/ml: 48. mu.g/ml.

6. A preparation for treating intestinal cancer is characterized in that: the composition consists of the composition as claimed in claims 1 to 5 and pharmaceutically acceptable auxiliary materials.

7. The formulation of claim 6, wherein: the preparation is in the form of injection, tablet, granule or capsule.

Technical Field

The invention belongs to the field of medicines, and particularly relates to application of losartan potassium and dacarbazine in preparation of a medicine for treating intestinal cancer.

Background

Intestinal cancer refers to cancer occurring in the intestinal tract, mainly colon cancer and rectal cancer, and is one of the most common malignant tumors worldwide. Due to changes of living environment and living habits of people, the incidence of intestinal cancer in China tends to rise year by year in recent years. Intestinal cancer can spread to other tissues and organs through lymph, blood circulation, direct spreading and other ways, has no obvious symptoms in the early stage, and patients often miss the opportunity of surgical treatment when discovering the intestinal cancer, only can adopt radiotherapy and chemotherapy for treatment, most chemotherapy drugs have great side effects, and the death rate of the intestinal cancer is very high due to frequent postoperative transfer, multiple drug resistance to the chemotherapy drugs and the like.

Dacarbazine is a novel anti-tumor drug, has spectral anti-tumor activity and is a first-line drug for treating intestinal cancer. Dacarbazine is a triazabenzene derivative, and is alkaline brownish red solid powder, unstable in acid and light, odorless and slightly astringent in taste after being decomposed by heat. The dacarbazine has the action mechanism that methyl positive ions are released in vivo to play the role of alkylation, and the dacarbazine also serves as an analogue of a purine nucleotide precursor to inhibit the synthesis of purine nucleotide, and has better anti-tumor metastasis activity.

Losartan potassium is the first angiotensin II receptor antagonist worldwide to treat hypertension and was officially marketed in china in 1998. Results from a number of large clinical studies show: the losartan can lower blood pressure, reduce cardiovascular risks and delay end-stage nephropathy strongly. The losartan potassium is proved to have 24-hour strong blood pressure reduction, long-term stable blood pressure reduction, blood pressure circadian rhythm improvement and cardiovascular and renal protection effects in a plurality of classical medical researches, and has high safety. Reports on the effect of losartan potassium on the combined action of dacarbazine have not yet been made. The invention researches the effect of losartan potassium in sensitizing dacarbazine to treat intestinal cancer in a human intestinal cancer model.

Disclosure of Invention

Object of the Invention

The application of losartan potassium sensitization dacarbazine in preparing the medicine for treating intestinal cancer is provided, the curative effect of the compound is enhanced, and a basis is provided for new application of old medicines.

Technical scheme

The invention provides application of losartan potassium and dacarbazine combined medicine in preparation of medicines for treating intestinal cancer

Therefore, the application of the losartan potassium and dacarbazine combined medicine in preparing the medicine for treating intestinal cancer and the anti-intestinal cancer medicine containing both the losartan potassium and the dacarbazine are both within the protection scope of the invention.

Preferably, the intestinal cancer is human intestinal cancer cells HCT116 cells and HT29 cells.

Preferably, the intestinal cancer is human intestinal cancer tissue organoid.

In addition, preferably, the dosage ratio of the losartan potassium to the dacarbazine is 100-6400 ng/ml: 12 μ g/ml.

Preferably, the dosage ratio of the losartan potassium to the dacarbazine is 100-6400 ng/ml: 24 μ g/ml.

Preferably, the dosage ratio of the losartan potassium to the dacarbazine is 100-6400 ng/ml: 48. mu.g/ml.

Particularly preferably, the dosage ratio of the losartan potassium to the dacarbazine is 6400 ng/ml: 48. mu.g/ml.

Advantageous effects

The invention discloses the discovery of losartan potassium in the aspect of improving the sensitivity of intestinal cancer cells to dacarbazine for the first time, can realize the synergistic effect and obviously improve the anti-tumor effect, and reduces the dosage of dacarbazine through combined medication so as to reduce toxic and side effects, thereby having obvious significance for the anti-intestinal cancer application of the combined medication of losartan potassium and dacarbazine.

Drawings

FIG. 1 is a graph showing the results of the inhibition rate analysis of individual treatment of intestinal cancer cells with losartan potassium by MTT method.

FIG. 2 is a graph showing the results of MTT method for detecting the inhibition rate of dacarbazine alone or combination of losartan potassium and dacarbazine after intestinal cancer cells are treated; wherein, A: HCT116 cell outcome analysis; HT29 cell result analysis.

FIG. 3 is a graph showing the results of analysis of inhibition rates of dacarbazine alone or in combination with losartan potassium and dacarbazine after treatment of human intestinal cancer tissue organoids.

Detailed Description

The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.

The kit materials used in the following examples are all commercially available unless otherwise specified.

Example 1MTT method for detecting sensitivity of different intestinal cancer cells to losartan potassium

1. Experimental Material

(1) Medicine preparation: the losartan potassium has the following chemical structural formula:

(2) intestinal cancer cells: human intestinal cancer cells HCT116 cells and HT29 cells.

(3) Commercial MTT kit.

2. Experiment grouping

(1) Control group: the blank control, i.e. intestinal cancer cells, was not subjected to any drug treatment.

(2) Experimental groups: intestinal cancer cells were treated with different concentrations of losartan potassium.

3. Sensitivity of different tumor cells to losartan potassium by MTT method

(1) The method comprises the steps of inoculating human intestinal cancer cells HCT116 cells and HT29 cells to a 96-well plate according to the number of 5000-9000 cells per well, and respectively adding PBS solutions of losartan potassium with different concentrations after the cells adhere to the wall. After 24 hours of incubation, 10. mu.l of 5mg/ml MTT was added to each well for another 4 hours, and then 100. mu.l of DMSO was added to each well after discarding the culture solution, and the absorbance of each well was read at 490nm using a microplate reader. Statistical analysis was performed on the data.

(2) The analysis results are shown in fig. 1, which shows that losartan potassium has a certain effect of inhibiting the proliferation of intestinal cancer cells, but the inhibition effect is weak.

Example 2 Effect of dacarbazine alone or combination of losartan Potassium and dacarbazine on the inhibition of intestinal cancer cells

1. Experimental Material

(1) Medicine preparation: losartan potassium and dacarbazine.

(2) Intestinal cancer cells: human intestinal cancer cells HCT116 cells and HT29 cells.

(3) Commercial MTT kit.

2. Experiment grouping

(1) Control group: intestinal cancer cells were treated with dacarbazine only.

(2) Experimental groups: various concentrations of losartan potassium and dacarbazine are used in combination to treat intestinal cancer cells.

3. MTT method for detecting sensitivity of intestinal cancer cells to combined administration of losartan potassium and dacarbazine

(1) The method comprises the steps of inoculating human intestinal cancer cells HCT116 cells and HT29 cells to a 96-well plate according to the number of 5000-9000 cells per well, and respectively adding PBS solutions with different proportions of losartan potassium and dacarbazine after the cells are attached to the wall. After 24 hours of incubation, 10. mu.l of 5mg/ml MTT was added to each well for another 4 hours, and then 100. mu.l of DMSO was added to each well after discarding the culture solution, and the absorbance of each well was read at 490nm using a microplate reader. Statistical analysis was performed on the data.

(2) The analysis result is shown in fig. 2, compared with the single use of the losartan potassium, the losartan potassium is added on the basis of the use of the dacarbazine, so that the intestinal cancer cell proliferation can be more remarkably inhibited, the combined use of the losartan potassium and the dacarbazine is shown to remarkably improve the treatment effect of the intestinal cancer, and the synergistic treatment effect is realized.

Example 3 Effect of the combination of Darbazin Potassium losartan and Darbazin on the organoid inhibitory Rate of human intestinal cancer tissues

1. Experimental Material

(1) Medicine preparation: losartan potassium and dacarbazine.

(2) Intestinal cancer cells: human intestinal cancer tissue organoids.

(3) The commercially available CellTiter-Glo 3D kit.

2. Experiment grouping

(1) Control group: only dacarbazine was used for treatment.

(2) Experimental groups: different concentrations of losartan potassium and dacarbazine are used in combination to treat human intestinal cancer tissue organoids.

3. Sensitivity of human intestinal cancer tissue organoids to combinations of losartan potassium and dacarbazine

(1) Mixing the treated human intestinal cancer cells with Matrigel, adding 50 μ l of the mixed Mtrigel Matrigel into each well of 48-well plate, and each well after gellingAdd 250. mu.l of complete medium to well, incubate at 37 ℃ with CO₂Culturing in 5% cell culture box. The culture solution is replaced every 3-4 days, and can be subcultured and frozen every 1-2 weeks. After the organoid modeling is successful, subculturing is carried out for drug treatment, culture solution with different proportions of losartan potassium and dacarbazine is added into each hole, and the mixture is placed in an incubator for culturing for 5 days. Adding CellTiter-Glo 3D detection reagent with the same volume as the culture medium into each hole, shaking and uniformly mixing, incubating at room temperature for 25 minutes, detecting by using an enzyme-linked immunosorbent assay (ELISA) instrument, and performing statistical analysis on data.

(2) The analysis result is shown in figure 2, compared with the single use of the losartan potassium, the losartan potassium and the dacarbazine are added on the basis of the use of the dacarbazine, so that the cell proliferation of human intestinal cancer tissue organoids can be more remarkably inhibited, the combined use of the losartan potassium and the dacarbazine is shown to remarkably improve the treatment effect of intestinal cancer, and the synergistic treatment effect is realized.