CN111249298B

CN111249298B - Anticancer pharmaceutical composition containing maduramicin and cisplatin

Info

Publication number: CN111249298B
Application number: CN202010267845.2A
Authority: CN
Inventors: 赵云峰; 戚志敏; 赵翌含; 孙宇
Original assignee: Qufu Normal University
Current assignee: Qufu Normal University
Priority date: 2020-04-08
Filing date: 2020-04-08
Publication date: 2021-03-12
Anticipated expiration: 2040-04-08
Also published as: CN111249298A

Abstract

The invention discloses an anticancer pharmaceutical composition containing maduramicin and cisplatin, which comprises the components of maduramicin and cisplatin; the ratio of maduramicin to cisplatin is 1:0.625-1: 5. The invention has the advantages that a novel anticancer pharmaceutical composition is provided, and the maduramicin and the cisplatin are combined, so that the composition improves the anticancer effect and reduces the toxic and side effects.

Description

Anticancer pharmaceutical composition containing maduramicin and cisplatin

Technical Field

The invention relates to the field of medicines, and in particular relates to an anticancer pharmaceutical composition containing maduramicin and cisplatin.

Background

The incidence of cancer is increasing year by year and the trend toward younger cancers is due to the increased pollution of living environment and the increased pressure of life. Relevant statistics shows that the number of people who die due to cancer in China is up to 281 thousands of people, and the number of people who die due to cardiovascular and cerebrovascular diseases is already higher, so that the cancer poses a serious threat to the life safety of people in China. Meanwhile, lung cancer is the malignant tumor with the highest incidence in China, about 39.9 ten thousand cases of lung cancer are newly increased every year, and about 59.1 ten thousand cases of lung cancer death are caused every year. Lung cancer is classified into non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC), wherein the incidence rate of non-small cell lung cancer is the highest, accounting for more than 85% of all lung cancer incidence rates. The prevalence of lung cancer has increased over the past twenty years. Scientists expect that the number of patients will reach about 100 million people every year in 2025, and the number of patients with lung cancer in China will jump the world first at that time, so research on lung cancer treatment means becomes a problem to be solved urgently at present.

To date, there are three main treatments for lung cancer, surgical resection, radiotherapy and chemotherapy. Surgical treatment is the most effective method, but is limited to the early stage of lung cancer, and in recent years, the development of new nano-drug carriers and immunotherapy provide a new approach for treating lung cancer. Non-small cell lung cancer (NSCLC) has no obvious symptoms in the early stage of the disease and has certain concealment, so when the patient finds the disease, the cancer often reaches uncontrollable stage or even reaches the advanced stage of the cancer, and only the method of radiotherapy and chemotherapy can be used for treating the cancer. Radiotherapy and chemotherapy have many disadvantages, such as: the side effect of the medicine is great; has great negative effect on the physical health of the patient; the postoperative life of the patient faces the problems of low immunity, weak constitution and the like. Despite the recent further development of personalized lung cancer treatment regimens, the prognosis of lung cancer patients remains poor, with a 5-year survival rate of only 16% after surgery. With the progress of treatment, serious side effects are generated on normal cells. Therefore, a new anti-cancer drug with low toxicity and high efficiency needs to be found.

Maduramicin (Maduramicin) is a polyether ionophore antibiotic developed by cyanamide company in America, is widely applied to feed additives before, and has good killing activity on coccidiosis suffered by poultry. The anti-coccidiosis drug has the advantages of wide anti-coccidiosis spectrum, high efficiency, small drug resistance, relatively low price and the like, and is very wide in application. However, maduramicin has obvious toxicity to animals such as rabbits and horses, and the dosage of maduramicin needs to be paid attention to when the maduramicin is used. The maduramicin has a molecular weight of 934.163 and a molecular formula of C₄₇H₈₃NO₁₇The chemical structure is shown in the figure1; structurally, maduramicin can be selectively combined with metal ions, so that the concentration of Na +/K + ions in cells is influenced, the charge balance on cell membranes is broken, and the apoptosis of the cells is further triggered.

The maduramicin can inhibit the proliferation of chicken myocardial cell lines and induce the cell lines to block in the G1 phase, so that the phenomena of myocardial cell apoptosis, autophagy and the like are promoted, which proves that the maduramicin can inhibit the proliferation capacity of myocardial cells.

Cisplatin, named Cisplatin in English, has the molecular formula C_l2H₆N₂Pt, molecular weight 300.05. Cisplatin cross-links to DNA strands and exhibits cytotoxic effects. After dissolution, the cell membrane can pass through the charged cell membrane without carrier transportation in vivo. Because the concentration of intracellular chloride ions is low (4mmol/L), the chloride ions are replaced by water, the charge is positive, the double-function group has the function similar to an alkylating agent, the double-function group can be combined with the basic group of DNA in a cell nucleus to form three forms of cross-linking, DNA damage is caused, DNA replication and transcription are damaged, and the synthesis of RNA and protein is inhibited at high concentration. Cisplatin has the advantages of wide anticancer spectrum, effectiveness of hypoxic cells, strong action and the like, is widely used for treating testicular cancer, ovarian cancer, uterine cancer, bladder cancer, neck cancer, prostatic cancer, brain cancer and the like, and has obvious curative effect. However, cisplatin has toxicity and side effects when used for treating cancer.

Therefore, the combined use of maduramicin and cisplatin can be tried to improve the treatment effect and reduce the toxic and side effects.

Disclosure of Invention

In order to solve the technical defects, the invention provides the application of maduramicin and cisplatin in preparing anti-cancer drugs.

The invention is realized by the following technical scheme:

the invention provides an anticancer pharmaceutical composition, which comprises maduramicin and cisplatin.

Preferably, the ratio of maduramicin to cisplatin is 1:0.625-1: 5.

More preferably, the ratio of maduramicin to cisplatin is 1:0.625 or 1:1.25, 1:2.5, 1: 5.

More preferably, the dose of maduramicin and cisplatin is 6mg/kg maduramicin +3mg/kg cisplatin.

The invention provides application of the anticancer medicine composition in preparing anticancer medicines.

The invention provides an application of an anticancer medicine composition in preparing an anti-lung cancer medicine.

The invention has the beneficial effects that: the invention has the advantages that a novel anticancer pharmaceutical composition is provided, and the maduramicin and the cisplatin are combined, so that the composition improves the anticancer effect and reduces the toxic and side effects.

Drawings

FIG. 1 shows the molecular structure of maduramicin.

Detailed Description

Example 1 synergistic inhibition of A549 cells and H460 cells by the combination of Madurycin and cisplatin

A549 cells (human lung adenocarcinoma cells), H460 cells (human large cell lung carcinoma cells) and Wi-38 cells (human embryonic lung cells) in logarithmic growth phase and good morphology were washed with PBS, digested with 0.25% pancreatin and blown into single cell suspensions. After conventional counting, the cell concentration was adjusted to 4X 10⁴The cells/mL were inoculated in a 96-well plate at 100 μ L/well. At 37 ℃ with 5% CO₂After culturing for 24h in a saturation humidity incubator, adding a drug to be detected, continuing culturing for a period of time, adding 20 mu L MTT, incubating for 4h, and detecting a light absorption value at 570nm in an enzyme labeling instrument.

Inhibition = 1- (experimental OD-blank OD)/(solvent control OD-blank OD) × 100%.

The interaction coefficient of the two medicines Q = E (A + B)/(EA + EB-EA x EB), E (A + B) means the inhibition rate of A, B on cells by the combination of the two medicines, and EA and EB mean the inhibition rate of A, B on cells respectively. When Q is more than 1.15, the two medicines have synergistic effect; when Q = 0.85-1.15, the two medicines have addition effect; when Q is less than 0.85, the two medicines show antagonism.

The results show that the inhibition effect of maduramicin and cisplatin on the proliferation of A549 cells and H460 cells is remarkably stronger than that of maduramicin or cisplatin alone on the proliferation of the two cells, and the maduramicin and cisplatin show obvious synergistic effect on the A549 cells and the H460 cells (Table 1 and Table 2). Whereas the inhibition of Wi-38 cell proliferation by maduramicin in combination with cisplatin was shown to be additive (Table 3).

TABLE 1 proliferation inhibition of A549 cells by Madurycin in combination with cisplatin

TABLE 2 proliferation inhibition of H460 cells by the combination of maduramicin and cisplatin

TABLE 3 inhibition of Wi-38 cell proliferation by maduramicin in combination with cisplatin

Example 2 inhibition of Madurycin and cisplatin combination in mouse transplanted Lung cancer A549

Establishing a nude mouse lung cancer transplantation tumor model: dilution of A549 cells with physiological saline to 1.2X 10⁷and/mL, inoculating 0.2mL of the tumor-bearing male nude mice to the armpits of the upper limbs of male nude mice for experiments respectively, establishing a transplantation tumor model of the nude mice, and then randomly dividing the tumor-bearing male nude mice into a control group, a cisplatin group, a maduramicin group and a combined treatment group, wherein each group comprises 10 mice.

And (3) drug treatment: when the tumor grows to about 1.0cm, the medicine is administered by tail vein injection. The control group is injected with 0.2mL of physiological saline, the concentration of the antitumor drug taxol added to the armpit of the upper limb of the nude mouse in the cis-platinum group is 3mg/kg, the concentration of the maduramicin added to the armpit of the upper limb of the nude mouse in the maduramicin group is 6mg/kg, and the combined treatment group is 3mg/kg of cis-platinum and 6mg/kg of maduramicin. Tumor diameter (A) and tumor transverse diameter (B) were measured every three days with a vernier caliper, and tumor volume was calculated according to the formula V = π/6 × (A/2+ B/2)3, and tumor size was counted.

24h after the last administration, the nude mice were weighed and the tumor volume was counted.

The results show that the inhibition rates of the maduramicin or the cisplatin on the A549 cells are respectively 16.75% and 33.6%, the combined action of the maduramicin and the cisplatin enhances the tumor inhibition effect, the tumor inhibition rate reaches 69.8%, the growth of the tumor is obviously inhibited, the CDI value is 1.56, and the two drugs show obvious synergistic action (Table 4). The weight of the control group, the cisplatin-treated group and the maduramicin-treated group was significantly reduced, and the weight of the combination-treated group was not significantly changed (table 4).

TABLE 4 inhibition of the combination of maduramicin and cisplatin in mouse transplanted Lung carcinoma A549

Example 3 Effect of Madurycin in combination with cisplatin on the blood routine in tumor-bearing mice

The experimental animal modeling and grouping administration method are the same as above. 24h after the last administration, the nude mice are weighed, 0.5 mL of 0.5% heparin is injected into each abdominal cavity, the eyeballs are removed after heparinization, blood is taken, and the concentration of white blood cells, red blood cells and platelets in the blood routine is detected by whole blood.

The results show that the numbers of white blood cells, red blood cells and platelets in the control group and the combination treatment group are close to each other and are obviously higher than those in the cisplatin treatment group and the maduramicin treatment group (Table 5). The combination of maduramicin and cisplatin is shown to reduce toxic and side effects.

TABLE 5 Effect of Madurycin in combination with cisplatin on blood conventions in tumor-bearing mice

The foregoing is only a preferred embodiment of this patent, and it should be noted that, for those skilled in the art, various modifications and substitutions can be made without departing from the technical principle of this patent, and these modifications and substitutions should also be regarded as the protection scope of this patent.

Claims

1. An anticancer pharmaceutical composition, which is characterized in that: the components of the composition are maduramicin and cisplatin.

2. The anticancer pharmaceutical composition according to claim 1, wherein: the ratio of the maduramicin to the cisplatin is 1:0.625-1: 5.

3. The pharmaceutical composition of claim 2, wherein: the ratio of the maduramicin to the cisplatin is 1:0.625 or 1:1.25, 1:2.5 and 1: 5.

4. The pharmaceutical composition of claim 2, wherein: the dose of the maduramicin and the cisplatin is 6mg/kg of maduramicin and 3mg/kg of cisplatin.

5. The use of an anticancer pharmaceutical composition according to any one of claims 1-4 in the preparation of an anticancer drug.

6. The use of the anticancer pharmaceutical composition according to any one of claims 1 to 4 for the preparation of an anti-lung cancer medicament.