CN109528718B - Medicine for treating cervical cancer and application thereof - Google Patents
Medicine for treating cervical cancer and application thereof Download PDFInfo
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- CN109528718B CN109528718B CN201811520071.9A CN201811520071A CN109528718B CN 109528718 B CN109528718 B CN 109528718B CN 201811520071 A CN201811520071 A CN 201811520071A CN 109528718 B CN109528718 B CN 109528718B
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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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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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Abstract
The invention belongs to the field of medicines, and relates to a medicine for treating cervical cancer and application thereof. The medicine is prepared from aspirin, 1-substituted beta-carboline and medicinal preparation auxiliary materials. Wherein the 1-substituted beta-carboline is selected from 1-acetyl-beta-carboline or 1-methoxycarbonyl-beta-carboline, and is preferably 1-acetyl-beta-carboline. The mass ratio of aspirin to 1-acetyl-beta-carboline in the medicine is 10:1 to 17: 1. The dosage form of the medicament is preferably an oral solid preparation. In experimental research, the combination of the 1-acetyl-beta-carboline and the aspirin has an inhibiting effect on a cervical cancer transplantation model, and has the potential of being applied to the treatment of cervical cancer.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicine for treating cervical cancer and application thereof.
Background
Cervical cancer is one of the common malignancies in women, of which the incidence is second only to ovarian and breast cancer. Human papillomavirus infection is a main cause of cervical cancer, so vaccination of human papillomavirus vaccine is a main means for preventing cervical cancer at present, but is influenced by economic factors, the vaccination rate of developing countries is low, and the incidence rate and death rate of cervical cancer are higher than those of developed countries. According to statistics, the number of new cervical cancer patients is up to 47.1 ten thousand and 21.5 ten thousand death patients are newly generated in the world every year. And the number of new cervical cancer patients in China reaches 12.96 every year, and the patients are young and strong women, so that serious economic and mental burdens are caused to families of the patients and the patients.
Surgery and radiation therapy are the primary means of cervical cancer, with surgery often requiring the resection of the uterus and extensive lymphocleaning. It is a fundamental desire of patients to clean tumor lesions while preserving fertility. Current surgical methods have been able to achieve this goal. However, operative complications such as bladder and urethral dysfunction, anorectal dysfunction and sexual dysfunction can still occur at a higher rate.
Traditionally, cervical cancer has been considered insensitive to cytotoxic chemotherapeutic drugs. However, in recent years, a great deal of clinical practice proves that surgery and radiotherapy can not control and eliminate subclinical and micrometastatic lesions. The treatment effect can be further improved by performing adjuvant chemotherapy before and after operation. However, the current clinical practice also proves that the single chemotherapeutic drug has no effect on the cervical cancer, and the chemotherapeutic drugs which are more effective on the cervical cancer comprise cyclophosphamide, fluorouracil, bleomycin, mitomycin, adriamycin, methotrexate, cisplatin and the like, wherein the cisplatin is widely applied in combined treatment.
As early as 2008, Aspirin Has been shown to have an inhibitory effect on Cervical Cancer cells (Lee SK, Park MS, Nam MJ. Aspirin Has efficacy of tissue Expression of calcium Gene in Cervical Cancer cells. J Oncol, 2008;2008: 285374.). Epidemiological studies have also demonstrated a Low prevalence of Cervical cancer in people taking Aspirin for a long period of time (Friel G, Liu CS, Kolomeyvskaya NV, Hampras SS, Kruszka B, Schmitt K, Cannioto RA, Lele SB, Odunsi KO, Moysich KB. Aspirin and Acetaminophen Use and the Risk of clinical cancer. J.Low Genit Tract Dis, 2015,19(3): 189-193.). Further studies have shown that the mechanism of action of Aspirin against cervical cancer is associated with up-regulation of caspase-3 and down-regulation of bcl-2 (Li L, Mao X, Qin X, Zhou M, Xing H, Dong F, Jiang X, Zhuang W. Aspirin inhibition growth of ovarian cancer by up-regulating caspase-3 and down-regulating bcl-2. Oncol Lett, 2016, 12(1): 93-96.). Drugs with similar mechanisms against cervical cancer also include letrozole.
Carbolines are a typical class of nitrogen-containing multi-heterocyclic organic compounds, and a large number of natural carbolines exist in the biological world. Some carboline structure-containing drugs, such as tadalafil, are also present in synthetic chemical drugs. Such compounds have been shown to possess a wide range of biological activities, including antimicrobial, hypotensive, antitumor, neuroprotective, and the like. However, the structure-activity relationship is rarely studied, and the range of application of different compounds is different. For example, tadalafil has an effect of dilating blood vessels and slightly lowering blood pressure as a drug for treating erectile dysfunction. In addition, Tadalafil has been shown to have clinical effects on head and neck cancers (Califano JA, Khan Z, Noonan KA, Rudracaju L, Zhang Z, Wang H, Goodman S, Gourin CG, Ha PK, Fakhry C, Saunders J, Levine M, Tang M, Neuner G, Richmon JD, Blanco R, Agrawal N, Koch WM, Marur S, Weed DT, Serafii P, Borrello I. Tadalafil augments tufting project tumor in patients with head and necqqualus cell L Cancer. Clin Cancer Res. 2015;21(1): 30-38.) and clinical trial for Tadalafil in combination with PD-1 inhibitors has been carried out on clinical trial No. 032T 38365 (NCT). With respect to another drug containing a carboline structure, arbekalanil (abecannil) is mainly used as an anxiolytic drug, and no report on the blood pressure reduction or antitumor activity of arbekalanil is found.
Similarly, although natural carboline compounds all have carboline structures, the change of the position and the type of the substituent group can cause different activities, and even if the natural carboline compounds also have antitumor activities, the change of the position and the type of the substituent group can cause different antitumor spectrums and different antitumor activities. For example, some of the 1-substituted β -carbolines showed cytotoxic effects on leukemia P388 cells, while some of the 3-substituted β -carbolines showed cytotoxic effects on leukemia HL-60 cells, oral epidermoid carcinoma KB cells, gastric cancer BGC cells, and cervical cancer Hela cells. Kwon et al isolated Two carboline alkaloids and some other carboline alkaloids that have been discovered in the past in 2018, and found that 3 of them have cytotoxic effects on ovarian cancer A2780 and SKOV3 cell lines (Kwon HS, Lee H, Lee JS, Lee K, Choi JH, Jang DS. Two new beta-carboline analogs from the systems of Picrasma squassioides, Arch Pharm Res. 2018, 41(5): 513-518.). In the same year, Ibrahim et Al discovered a New tetrahydrocarboline compound, Ingene F, and examined its effects on cell lines of breast cancer, lung cancer, colon cancer, cervical cancer, etc., and found that it was Cytotoxic to breast cancer MCF7 cells, colon cancer HCT116, and lung cancer A549 cells, but not to sympathetic nervous system tumor cells PC12 and cervical cancer Hela cells (Ibrahim S, Mohamed G, Al Haideri R, El-K A, Zayed M. Ingene F: A New Cytoxic tumor cell line sodium acrylate responsive of the insulin Maron porous antibiotic conjugates. Pharmacogn Mag, 2018,14(54): 231-234).
In 2007, Cao et al reviewed the activity of β -carbolines (Cao R, Peng W, Wang Z, Xu A. beta-Carboline analogs: biochemical and pharmacological functions. Curr Med chem. 2007;14(4): 479-500.). The study of carboline modifications has been a focus, and the study of higher antimicrobial and antitumor drugs by adding different substituents at different positions has been continued so far, for example, in 2018, foreign Venkataraman et al (Venkataraman Red PO, Hridheay M, Nikhil K, Khan S, Jha PN, Shah K, Kumar D, Synthesis and innovation in the antibacterial and antibacterial activity students of beta-carbonate crystals and bacteria salts, Bioorg Med Chem Lett.2018, 28(8): 1278-1282), i.e., the antimicrobial and antitumor effects of a series of carboline compounds alkylated at N-atom position have been studied.
Disclosure of Invention
In view of the above prior art, one of the objects of the present invention is to provide a new use of 1-acetyl- β -carboline. The specific scheme of the invention is as follows:
the application of 1-acetyl-beta-carboline or 1-methoxycarbonyl-beta-carboline in preparing the sensitizing medicament for the cervical cancer chemotherapy. The chemosensitization drug conforms to the generally accepted definition at present, namely the chemosensitization drug has no effect of killing tumor cells when used alone, but can improve the treatment effect of the chemosensitization drug when used together with the chemosensitization drug. This concept is not provided by the commonly used concept of synergy, which is the phenomenon that the effect of two or more drugs with the same activity is higher than the additive effect when used in combination.
Furthermore, the sensitization object of the chemotherapy sensitization medicine in the application is aspirin, namely the application of 1-acetyl-beta-carboline or 1-methoxycarbonyl-beta-carboline in preparing the chemotherapy sensitization medicine when the aspirin is used for treating cervical cancer. Namely the application of the 1-acetyl-beta-carboline or the 1-methoxycarbonyl-beta-carboline in preparing the chemotherapy sensitization medicine for improving the anti-cervical cancer effect of the aspirin.
Further, the chemosensitizer in the application is preferably 1-acetyl-beta-carboline.
Based on the basic thought, the invention also provides the application of the combination drug of one of 1-acetyl-beta-carboline or 1-methoxycarbonyl-beta-carboline and aspirin in preparing the drug for treating cervical cancer.
Based on the basic thought, the invention further provides a medicine for treating cervical cancer, which contains aspirin, pharmaceutical preparation auxiliary materials and one of the following components: 1-acetyl-beta-carboline or 1-methoxycarbonyl-beta-carboline.
Preferably, the medicine for treating cervical cancer is prepared from aspirin, pharmaceutical preparation auxiliary materials and 1-acetyl-beta-carboline.
Preferably, the medicament for treating the cervical cancer is an oral solid medicament.
Preferably, the mass ratio of aspirin to 1-acetyl-beta-carboline in the medicine for treating cervical cancer is as follows: (10-17): 1.
Preferably, the mass ratio of aspirin to 1-acetyl-beta-carboline in the medicine for treating cervical cancer is as follows: 15:1.
Preferably, the mass ratio of aspirin to 1-acetyl-beta-carboline in the medicine for treating cervical cancer is as follows: 12:1.
Preferably, the oral solid medicine is a capsule. The medicinal preparation auxiliary materials of the capsule comprise lactose, povidone K30, citric acid and purified water. Wherein the citric acid is preferably anhydrous citric acid.
For the preparation of capsules, the capsule shell can adopt an enteric capsule shell or a common hard capsule shell, but the common hard capsule shell does not have the enteric function, so that the gastric mucosa of aspirin can be damaged, and necessary gastric mucosa protection medicaments such as gastric bismuth magnesium particles and the like need to be used.
For the preparation of the granules contained in the capsules, the following formulation and process can be used:
f1 (10000 capsules): 2400g of aspirin, 200g of 1-acetyl-beta-carboline, 873.5g of lactose, 3078 povidone K3078 g, 69g of anhydrous citric acid and 700g of purified water.
Adding povidone K30 and citric acid into purified water, and mixing to obtain adhesive; uniformly mixing aspirin, 1-acetyl-beta-carboline and lactose according to the prescription amount, adding an adhesive to prepare a soft material, sieving the soft material by using a 18-mesh sieve, drying wet granules at 50 ℃, and subpackaging. Or drying wet granules until the water content is 0.5-1.5%, mixing with 390g of corn starch and 19.5g of magnesium stearate, drying, and packaging.
F2 (10000 capsules): 3000g of aspirin, 200g of 1-acetyl-beta-carboline, 1100g of lactose, 3097 povidone K3097 g, 86g of anhydrous citric acid and 875g of purified water.
Adding povidone K30 and citric acid into purified water, and mixing to obtain adhesive; uniformly mixing aspirin, 1-acetyl-beta-carboline and lactose according to the prescription amount, adding an adhesive to prepare a soft material, sieving the soft material by using a 18-mesh sieve, drying wet granules at 50 ℃, and subpackaging.
In the scheme, the aspirin, the 1-acetyl-beta-carboline, the lactose, the povidone K30 and the anhydrous citric acid are all marketed varieties and can be purchased from the market.
The research of the inventor shows that the 1-acetyl-beta-carboline has no inhibiting effect on Hela-229 cervical cancer, but can enhance the anti-Hela-229 cervical cancer effect of aspirin, and is in line with the characteristics of a chemotherapy sensitizer. And 1-acetyl-beta-carboline does not increase the bleeding risk of aspirin.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the following examples are only intended to illustrate the present invention, but not to limit the scope of the present invention, especially with regard to the selection of pharmaceutical formulation excipients and the amounts thereof in the formulation.
EXAMPLE 1 anti-tumor oral capsules
2400g of aspirin
200g of 1-acetyl-beta-carboline
Lactose 873.5g
Povidone K3078 g
69g of anhydrous citric acid
700g of purified water.
Adding povidone K30 and citric acid into purified water, and mixing to obtain adhesive; the aspirin, the 1-acetyl-beta-carboline and the lactose in the prescription amount are taken and evenly mixed, the adhesive is added to prepare soft materials, the soft materials are sieved by a 18-mesh sieve, and the wet granules are subpackaged into 10000 capsules after being dried at 50 ℃.
Example 2 anti-tumor oral capsules
Aspirin 3000g
200g of 1-acetyl-beta-carboline
Lactose 1100g
Povidone K3097 g
86g of anhydrous citric acid
875g of purified water.
Adding povidone K30 and citric acid into purified water, and mixing to obtain adhesive; the aspirin, the 1-acetyl-beta-carboline and the lactose in the prescription amount are taken and evenly mixed, the adhesive is added to prepare soft materials, the soft materials are sieved by a 18-mesh sieve, and the wet granules are subpackaged into 10000 capsules after being dried at 50 ℃.
Example 3 anti-tumor oral capsules
Aspirin 3400g
200g of 1-acetyl-beta-carboline
Lactose 1100g
Povidone K3097 g
86g of anhydrous citric acid
875g of purified water.
Adding povidone K30 and citric acid into purified water, and mixing to obtain adhesive; the aspirin, the 1-acetyl-beta-carboline and the lactose in the prescription amount are taken and evenly mixed, the adhesive is added to prepare soft materials, the soft materials are sieved by a 18-mesh sieve, and the wet granules are subpackaged into 10000 capsules after being dried at 50 ℃.
Example 41-acetyl-beta-carboline, Aspirin and animal Experimental study for anti-cervical cancer with Combined oral administration
BALB/c female nude mice, the weight of which is 18-20 g, are injected with Hela-229 cervical cancer cell strains subcutaneously to establish a nude mouse cervical cancer transplantation tumor model. During the experiment animals were housed in a laboratory under 12 hour light/12 hour dark cycle and pathogen-free conditions, and were given free access to water and ration feed.
Hela-229 cervical cancer cell line is diluted by normal saline after conventional recovery, and tumor cell fluid is injected subcutaneously into the right back of a nude mouse, wherein the injection volume is 200 microliters (the cell number is about 2x 10)6One). After inoculation, nude mice were randomized into 4 groups of 8 mice each day and gavage was started.
The blank control group was perfused with normal saline for 1 time a day for 4 weeks.
The 1-acetyl-beta-carboline group is prepared by suspending the 1-acetyl-beta-carboline group in normal saline for intragastric administration, wherein the intragastric administration is carried out for 4 weeks continuously, and the content of 1-acetyl-beta-carboline per day is 1.2 mg.
In the aspirin group, aspirin is suspended in normal saline for intragastric administration, 1.2mg of aspirin is administered per day for continuous intragastric administration for 4 weeks.
The combined administration group comprises 1-acetyl-beta-carboline and aspirin which are suspended in normal saline for intragastric administration, wherein 1.2mg of aspirin and 0.1 mg of 1-acetyl-beta-carboline are administered per day for continuous intragastric administration for 4 weeks.
On the 2 nd day after the administration, the nude mice exposed the tail after fixation, disinfected with alcohol at the position of the tail close to the pelvis, punctured at the position of the tail close to the pelvis to bleed with the puncturing depth of 2mm, then wiped the punctured part with filter paper once every 15 seconds until no fresh blood appears, and the time from the completion of puncturing to the occurrence of no fresh blood is recorded as the bleeding time of each animal.
Day 3 at the end of dosing, each group of nude mice was sacrificed, tumors were dissected off, and weighed as tumor weight per animal.
The results of the experiments are shown in the following table.
T-test comparison among the tumor weights shows that the tumor weight of the 1-acetyl-beta-carboline group is not significantly different from that of a blank control group; the tumor weights of the aspirin group and the combined administration group are significantly lower than that of the blank control group (P < 0.01); the tumor significance of the combination group is significantly lower than that of the aspirin group (P < 0.01). In the experimental process, the medicine is administered immediately after tumor cell inoculation, so the anti-tumor result of the experiment is closer to the situation of residual after cervical cancer operation, namely, aspirin or aspirin and 1-acetyl-beta-carboline are administered together to inhibit the growth of residual tumor tissues, thus being possibly suitable for combined chemotherapy after or during cervical cancer operation.
T-test comparison among groups of bleeding time shows that the bleeding time of the 1-acetyl-beta-carboline group is not significantly different from that of a blank control group; the bleeding time of the aspirin group and the combined administration group is significantly longer than that of a blank control group (P < 0.01); however, the bleeding time of the aspirin group and the combination group is not obviously different. It is suggested that the administration of 1-acetyl-beta-carboline in combination with aspirin does not increase the bleeding risk of aspirin.
Claims (8)
1. The medicine for treating the cervical cancer is characterized by being prepared from aspirin, pharmaceutical preparation auxiliary materials and 1-acetyl-beta-carboline; the medicine for treating cervical cancer comprises aspirin and 1-acetyl-beta-carboline in a mass ratio of: (10-17): 1.
2. The drug for treating cervical cancer according to claim 1, wherein the drug for treating cervical cancer is an oral solid drug.
3. The medicine for treating the cervical cancer according to claim 2, wherein the medicine for treating the cervical cancer comprises aspirin and 1-acetyl-beta-carboline in a mass ratio of: 15:1.
4. The medicine for treating the cervical cancer according to claim 2, wherein the medicine for treating the cervical cancer comprises aspirin and 1-acetyl-beta-carboline in a mass ratio of: 12:1.
5. The medicament for treating the cervical cancer according to any one of claims 2 to 4, wherein the oral solid medicament is a capsule.
6. The medicine for treating cervical cancer according to claim 5, wherein the pharmaceutical preparation auxiliary materials of the capsule comprise lactose, povidone K30, citric acid and purified water.
7. Use of the medicament for the treatment of cervical cancer according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of cervical cancer.
8.1-acetyl-beta-carboline in preparing aspirin sensitivity enhancing medicine for treating cervical cancer.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811520071.9A CN109528718B (en) | 2018-12-12 | 2018-12-12 | Medicine for treating cervical cancer and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811520071.9A CN109528718B (en) | 2018-12-12 | 2018-12-12 | Medicine for treating cervical cancer and application thereof |
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| CN109528718A CN109528718A (en) | 2019-03-29 |
| CN109528718B true CN109528718B (en) | 2020-11-24 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1055203A (en) * | 1964-09-16 | 1967-01-18 | Ici Ltd | -ß-carboline derivatives, a process for their manufacture, and compositions containing them |
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2018
- 2018-12-12 CN CN201811520071.9A patent/CN109528718B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1055203A (en) * | 1964-09-16 | 1967-01-18 | Ici Ltd | -ß-carboline derivatives, a process for their manufacture, and compositions containing them |
Non-Patent Citations (3)
| Title |
|---|
| The Beta-Carboline Alkaloid Harmine inhibits BCRP and Can Reverse Resistance to the Anticancer Drugs Mitoxantrone and Camptothecin in Breast Cancer Cells;Yonggang Ma等;《Phytother. Res.》;20090622;第24卷;第146-149页 * |
| 子宫颈癌中乳腺癌耐药蛋白mRNA的表达及其临床意义;杨丰美等;《肿瘤研究与临床》;20131130;第25卷(第11期);第754-762页 * |
| 阿司匹林对宫颈癌裸鼠移植瘤生长的影响及Bax与 VEGF的表达变化;李龙等;《西安交通大学学报（医 学 版）》;20130918;第34卷(第6期);第808-812页 * |
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