CN111012775A - Application of lobaplatin in preparation of medicines for treating bladder cancer - Google Patents
Application of lobaplatin in preparation of medicines for treating bladder cancer Download PDFInfo
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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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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 relates to an application of lobaplatin in preparing a medicament for treating bladder cancer, belongs to the technical field of new application of chemical medicaments, and particularly relates to an application of a platinum medicament in bladder cancer; the lobaplatin dosage form is lyophilized powder for injection, small-volume injection or large-volume injection, and the effective treatment amount is 45-55mg/m2Body surface area. The lobaplatin and the preparation thereof have strong bladder cell tumor resisting effect, obvious treatment effect, low toxicity and safety, provide a new treatment medicament for bladder cancer and expand the clinical application of the lobaplatin and the preparation thereof.
Description
Technical Field
The invention belongs to the technical field of new application of chemical drugs, and particularly relates to application of a platinum drug in bladder cancer.
Background
Bladder cancer, the tenth most common cancer worldwide, is one of the cancers common in the urinary system. The incidence of bladder cancer is higher in men than in women, where bladder cancer is the sixth most common cancer and the ninth most lethal cancer. Over the past 30 years, bladder cancer has progressed little more and there has been no improvement in survival. Chemotherapy is an important step in the treatment of bladder cancer. Studies have shown that adjuvant chemotherapy can delay relapse and improve overall survival, neoadjuvant chemotherapy can increase median survival and can reduce the incidence of residual disease, and among chemotherapy for bladder cancer, cisplatin-based chemotherapeutic drug combination regimens are the most common chemotherapy regimens, with neoadjuvant chemotherapy also being a class i recommendation in the NCCN guideline, however, cisplatin has strong side effects, mainly manifested in: 1) gastrointestinal reactions such as nausea and vomiting; 2) nephrotoxic effects mainly of the renal tubule; 3) neurotoxic effects with acoustic nerve damage predominating; 4) bone marrow suppression such as leukocyte and/or platelet lowering.
The prior art shows that lobaplatin has definite cytotoxic effect on various animal and human tumor cell lines, is equivalent to or better than the tumor inhibition effect of cisplatin, overcomes the kidney toxicity and the digestive tract toxicity of the cisplatin, has lighter bone marrow inhibition than carboplatin, and has cross drug resistance with the cisplatin. Lobaplatin has lower side effects than cisplatin and carboplatin, strong antitumor activity, lower toxicity, safety, good solubility and stability in water, and is mainly used for treating breast cancer, small cell lung cancer and chronic myelocytic leukemia.
Based on the current situation of the prior art, the inventor of the application intends to further evaluate the potential value of lobaplatin in the treatment of bladder cancer through experimental study on the role of lobaplatin in bladder cancer, and provides a new method and a new idea for clinical treatment of bladder cancer.
Disclosure of Invention
The invention aims to provide application of lobaplatin in preparation of a medicament for treating bladder cancer, so as to solve the technical problems mentioned in the background technology.
In order to achieve the purpose, the specific technical scheme of the application of the lobaplatin in the preparation of the medicine for treating bladder cancer is as follows:
application of lobaplatin in preparation of medicines for treating bladder cancer.
Further, the effective therapeutic amount of lobaplatin is 45-55mg/m2Body surface area.
Further, the effective therapeutic amount of lobaplatin is 40-50mg/m2Body surface area.
Further, the application is that lobaplatin is prepared into an injection preparation.
Furthermore, the injection preparation is a freeze-dried powder injection, a small-volume injection or a large-volume injection.
Furthermore, the injection preparation is a freeze-dried powder injection.
Further, the injection preparation is prepared by a conventional method by adding or not adding pharmaceutically conventional carriers, wherein the carriers are selected from excipients, stabilizers, surfactants and regulators.
Further, the administration route of the lobaplatin preparation is intravenous injection.
Lobaplatin, a third-generation platinum chemotherapeutic drug, has been approved for the treatment of inoperable metastatic breast cancer, chronic myeloid leukemia and small cell lung cancer. In addition, research shows that lobaplatin has an anti-tumor effect in cancers such as gastric cancer, nasopharyngeal carcinoma, esophageal squamous cell carcinoma, colorectal cancer, endometrial cancer and the like. The mechanism of the antitumor effect of lobaplatin is similar to that of cisplatin, and both lobaplatin and cisplatin inhibit proliferation of cells and induce apoptosis by causing DNA damage through the formation of DNA adducts. Lobaplatin has lower nephrotoxic, neurotoxic or ototoxic side effects than cisplatin, and in some preclinical tumor models, lobaplatin can overcome cisplatin resistance produced by cancer cells. The third-generation platinum drug lobaplatin with good curative effect and little side effect is not used for chemotherapy of bladder cancer, and the effect of lobaplatin in bladder cancer is not researched.
Apoptosis is a form of programmed cell death, and apoptotic changes are responsible not only for the development and progression of tumors, but also for the resistance of tumors to treatment. Most anticancer drugs currently used in clinical oncology utilize an intact apoptotic signaling pathway (e.g., PI3K/AKT signaling pathway) to trigger cancer cell death. Thus, defects in the death pathway may lead to drug resistance, thereby limiting the effectiveness of the treatment. The apoptosis promoting effect of the anticancer drug on cancer cells is evaluated by detecting the change of apoptosis factors (for example, Bax, Cleaveccaspase-3 is a pro-apoptosis factor, Bcl-2 is an anti-apoptosis factor) in the cancer cells, thereby indicating the treatment capability of the drug on cancer.
The lobaplatin used in the invention is a drug on the market.
The application of the lobaplatin in preparing the medicine for treating bladder cancer has the following advantages: the lobaplatin and the preparation thereof have strong bladder cell tumor resisting effect, obvious treatment effect, low toxicity and safety, provide a new treatment medicament for bladder cancer and expand the clinical application of the lobaplatin and the preparation thereof.
Drawings
FIG. 1 is a graph showing the effect of different concentrations of lobaplatin on the cell viability of T24 human bladder cell line after 24h, 48h and 72h in example 1.
FIG. 2 is a graph showing the effect of different concentrations of lobaplatin on the cell viability of ScaBER human bladder cell lines after 24h, 48h and 72h in example 1.
FIG. 3 is a graph showing the effect of varying concentrations of lobaplatin on cell migration of T24 human bladder cell line after 24h in example 1.
FIG. 4 is a graph showing the effect of varying concentrations of lobaplatin on cell migration of ScaBER human bladder cell line after 24h in example 1.
FIG. 5 shows the crossing of cells of T24 human bladder cancer between the lobaplatin-administered group and the control group after 24 hours in example 1 through a Transwell chamber.
FIG. 6 shows the crossing of ScaBER human bladder cancer cells through a Transwell chamber after 24 hours in example 1 between the lobaplatin-administered group and the control group.
FIG. 7 is a graph showing the change in tumor size between the control group and the lobaplatin-administered group in example 2.
FIG. 8 is a statistical graph showing body weight change data of nude mice of the control group and the lobaplatin-administered group in example 2.
FIG. 9 is a statistical graph showing the tumor volume change data of the control group and the lobaplatin-administered group in example 2.
FIG. 10 shows apoptosis of T24 human bladder cells in the control group and the lobaplatin-administered group in example 3.
FIG. 11 shows the apoptosis of ScaBER human bladder cells in the control group and the lobaplatin-administered group in example 3.
FIG. 12 shows the expression of the apoptosis proteins and signaling pathway proteins in T24 human bladder cells in the control and administration groups in example 3.
FIG. 13 shows the expression of the corresponding apoptotic proteins and signaling pathway proteins in ScaBER human bladder cells of control and administered groups in example 3.
The notation in the figure is: 1. a control group; 2. lobaplatin administration group.
Detailed Description
In order to better understand the purpose, structure and function of the present invention, the application of lobaplatin in the preparation of drugs for treating bladder cancer is described in further detail below with reference to the accompanying drawings.
In order to make the present invention better understood by those skilled in the art, the applicant conducted a series of experimental studies to prove the effects of the present invention:
the technical scheme adopted is as follows:
test example 1: lobaplatin activity against bladder cancer cells in vitro, inhibition of bladder cancer cell migration and invasion studies.
1.1 materials and reagents:
1.1.1 drug name, manufacturer and lot number: lobaplatin for injection, international pharmaceutical limited, changan, hainan, batch No.: 20180320
The configuration method comprises the following steps: lobaplatin was formulated at the corresponding concentration in serum-free medium.
1.1.2 cell lines
T24, ScaBER: human bladder cancer cell lines, purchased from cell banks of the Chinese academy of sciences, were cultured in the manner provided in the specification.
1.1.3 reagents
Fetal bovine serum, purchased from Biological Industries; RPMI-1640 medium, purchased from GE Healthcare; CCK-8 reagent, available from Selleck & Bimake; transwell cells and Matrigel gel, available from Corning.
1.2 research methods: CCK-8 method; cell scratching method; transwell method
1.2.1CCK-8 method: cells were seeded at 1X 104 per well in 96-well plates in complete culture with 10% fetal bovine serum, 1% penicillin-streptomycinIn nutrient medium, 5% of CO at 37 DEG C2Under the condition, the cells are fully attached to the wall by culturing overnight. The medium was discarded and various concentrations of lobaplatin (0.5, 1, 2, 4, 8, 16, 32. mu.g ∙ ml) were added-1) 6 replicate wells per concentration. Culturing for 24h, 48h and 72h respectively, adding CCK-8 reagent, adding an equal volume of culture medium into a control group, and incubating for 2h under the cell culture condition. The microplate reader detects the absorbance (OD value) at a wavelength of 450 nm. The blank group was added with complete medium only.
Cell viability (%) - (OD experiment-OD blank)/(OD control-OD blank) × 100%.
1.2.2 cell scratch method: cells were seeded at 5 × 105 per well in six-well plates and cultured overnight until the cells grew to around 90%. The medium was discarded, scratched and ∙ ml of various concentrations (0, 0.5, 1, 2. mu.g) were added-1) The cells were transferred by a cell transfer area change rate which was calculated by taking a photograph of the same position after 24 hours of incubation in an incubator of a 2% serum-containing culture medium containing lobaplatin after labeling.
Cell migration area (%) (initial scratch area-scratch area after 24 h)/initial scratch area.
1.2.3Transwell method: the Matrigel gel was uniformly spread on the bottom of a Transwell chamber according to the instructions, cells were seeded into the chamber at 2 × 103 wells, divided into two groups, one group was added with a serum-free medium, the other group was added with a serum-free medium containing lobaplatin, the chamber was taken out after 24 hours of culture, the upper layer was wiped clean with a cotton swab, the chamber was then fixed with methanol, stained with 0.5% crystal violet, and the number of cells in the lower layer of the chamber was observed under a microscope.
1.3 test results:
1.3.1 lobaplatin was able to inhibit the growth of bladder cancer cells in vitro, resulting in a decrease in their cell viability, which was more pronounced with increasing lobaplatin concentration, see FIGS. 1-2.
1.3.2 lobaplatin was able to slow the migration of bladder cancer cells and increased with increasing lobaplatin concentration, see FIGS. 3-4.
1.3.3 lobaplatin is able to inhibit bladder cancer cell invasion, see FIGS. 5-6.
1.4 conclusion of the test: lobaplatin can inhibit the proliferation of bladder cancer cells in vitro, and the action intensity is increased along with the increase of the concentration; lobaplatin can inhibit the migration of bladder cancer cells and increase the inhibition with increasing concentration; lobaplatin can inhibit the invasion of bladder cancer cells.
Test example 2: in vivo study of inhibition of proliferation of bladder cancer cells by lobaplatin
2.1 materials and reagents
2.1.1 drug name and Source: lobaplatin for injection, international pharmaceutical limited, changan, hainan, batch No.: 20180320
2.1.2 configuration method: lobaplatin was brought to the desired concentration with water for injection.
2.1.3 Experimental animals
A academy of sciences cell bank; BALA/c male nude mice were purchased from Experimental animals technology, Inc. of Weitongli, Beijing (license number: SCXK (Jing) 2016-. A breeding environment: SPF grade.
2.2 test methods:
collecting cultured T24 cells, and diluting with serum-free medium to 2 × 107Each per milliliter. Injecting 200 μ L cell suspension subcutaneously on the right back side of the back of nude mice until the tumor grows to 200mm volume3On the left and right sides, nude mice were randomly divided into control group and administration group, and the administration group was administered with lobaplatin 25mg ∙ kg via tail vein injection-1. Nude mice body weight and tumor volume measurements were performed every three days.
Tumor volume (L.times.W)2) And/2 (L is the major diameter of the tumor tissue, and W is the minor diameter). 21d, the nude mice were sacrificed and the tumors were removed.
2.3 test results
On the premise of no difference in body weight of nude mice, the tumor growth rate of the lobaplatin injection group was significantly reduced compared to the control group, as shown in fig. 7 to 9.
2.4 conclusion
The lobaplatin can inhibit the growth of bladder cancer cells in vivo, and the test result shows that the lobaplatin can be used for chemotherapy of the bladder cancer.
Test example 3: the lobaplatin has the apoptosis promoting effect on the bladder cancer cells and the influence on related apoptosis proteins and apoptosis signal pathways.
3.1 materials and reagents
3.1.1 drug name and Source: lobaplatin for injection, international pharmaceutical limited, changan, hainan, batch No.: 20180320, respectively; the FITC Annexin v apoptosis kit was purchased from BD Biosciences; SDS-PAGE gel preparation kits were purchased from Solarbio; primary anti-Bcl-2, Bax, Caspase-3, cleared Caspase-3, GAPDH, Pi3k, Akt, P-AKT, fluorescent secondary antibodies were purchased from Cell Signaling Technology.
3.2 test methods: apoptosis detection, western blot assay
3.2.1 apoptosis assay: the cells were cultured at 5X 105The cells were completely attached to each well overnight in 6-well plates and divided into control (lobaplatin concentration 0) and experimental groups (0.5, 1, 2, 4, 8, 16, 32. mu.g ∙ ml) with lobaplatin concentrations-1) And (4) lobaplatin treatment. After 24h, cells were harvested according to the instructions of the apoptosis test kit and tested by flow cytometry.
3.2.2 Western blot assay: the cells are divided into a control group and an administration group, the cells are collected after 48 hours, the extraction of cell holoprotein is carried out according to the instruction of a protein extraction kit, and the protein concentration is measured by a BCA method. Proteins were loaded in equal amounts for electrophoretic separation, and the separated proteins were transferred to NC membranes and blocked and incubated overnight at 4 ℃. And (4) washing off redundant primary antibodies, incubating fluorescent secondary antibodies at room temperature, and finally performing detection analysis by using an Odyssey two-color infrared laser imager.
3.3 test results:
3.3.1 the cells in the first and third quadrants are apoptotic cells, compared with the control group, the ratio of apoptosis of the lobaplatin administration group is higher, as shown in fig. 10-11.
3.3.2 cells from the group administered with lobaplatin exhibited increased Bax expression, decreased Bcl-2 expression, increased clear-Caspase-3/Caspase-3, decreased Pi3k expression in the PI3K/AKT signaling pathway, and decreased P-Akt/Akt, as shown in FIGS. 12-13.
3.4 conclusion of the test: lobaplatin was able to promote apoptosis of bladder cancer cells compared to the control group; lobaplatin promotes the expression of a pro-apoptotic protein Bax, inhibits the expression of an anti-apoptotic protein Bcl-2, and simultaneously inhibits the expression of a proto-oncogene PI3K/AKT signal pathway protein to promote the apoptosis of bladder cancer cells, so that the bladder cancer is treated.
It is to be understood that the present invention has been described with reference to certain embodiments, and that various changes in the features and embodiments, or equivalent substitutions may be made therein by those skilled in the art without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.
Claims (8)
1. Application of lobaplatin in preparation of medicines for treating bladder cancer.
2. The use of lobaplatin of claim 1 for the preparation of a medicament for the treatment of bladder cancer, wherein the therapeutically effective amount of lobaplatin is from 45-55mg/m2Body surface area.
3. The use of lobaplatin of claim 2 for the manufacture of a medicament for the treatment of bladder cancer, wherein the therapeutically effective amount of lobaplatin is from 40 to 50mg/m2Body surface area.
4. The use of lobaplatin as defined in claim 1 for the preparation of a medicament for the treatment of bladder cancer, wherein the lobaplatin is formulated as an injectable formulation.
5. The application of lobaplatin in preparation of drugs for treating bladder cancer as claimed in claim 4, wherein the injection preparation is a lyophilized powder injection, a small-volume injection or a large-volume injection.
6. The use of lobaplatin as defined in claim 5 in the preparation of a medicament for the treatment of bladder cancer, wherein the injectable formulation is a lyophilized powder for injection.
7. The use of lobaplatin as defined in claim 4 in the preparation of a medicament for the treatment of bladder cancer, wherein the injectable formulation is prepared by a conventional method with or without pharmaceutically conventional carriers selected from the group consisting of excipients, stabilizers, surfactants, and modulators.
8. The use of lobaplatin as defined in claim 5 for the preparation of a medicament for the treatment of bladder cancer, wherein the lobaplatin preparation is administered intravenously.
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| CN114164176A (en) * | 2021-12-13 | 2022-03-11 | 深圳市第二人民医院(深圳市转化医学研究院) | Human bladder cancer cis-platinum drug-resistant cell strain and application thereof |
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| CN114164176A (en) * | 2021-12-13 | 2022-03-11 | 深圳市第二人民医院(深圳市转化医学研究院) | Human bladder cancer cis-platinum drug-resistant cell strain and application thereof |
| CN114164176B (en) * | 2021-12-13 | 2023-10-13 | 深圳市第二人民医院(深圳市转化医学研究院) | Cisplatin-resistant cell strain for human bladder cancer and application thereof |
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