Pharmaceutical composition for treating digestive tract cancers

A digestive tract and drug technology, applied in the field of medicine, can solve problems such as failure of cancer chemotherapy

Active Publication Date: 2020-05-08
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, like other anticancer drugs, tumor resistance to it is one of the main reasons for the failure of chemotherapy, and there is no effective drug resistance reversal agent available, which has become the biggest pain point in the failure of clinical gastrointestinal cancer chemotherapy

Method used

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  • Pharmaceutical composition for treating digestive tract cancers
  • Pharmaceutical composition for treating digestive tract cancers
  • Pharmaceutical composition for treating digestive tract cancers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Overexpression of SphK2 triggers 5-FU resistance

[0049] Using SphK2 overexpression and knockout mouse models to administer 5-FU after AOM / DSS colorectal cancer modeling, the specific method is as follows: SphK2 gene overexpression and knockout mice were delivered to Beijing Saiye Company for Crisper / Cas9 Gene-edited, lineage background of C57BL / 6J, reared in a specific pathogen-free (SPF) environment. First, wild-type mice and SphK2 gene overexpression mice were selected, 6 to 8 weeks old, with 6 mice in each group. The mice in each group were intraperitoneally injected with 10 mg / kg AOM on the first day, and the mice received 7 days of AOM after one week. Drinking water with 1.0% DSS. Then the mice were given regular normal drinking water for 14 days, and the above-mentioned 21 days were taken as one cycle and repeated for two more cycles. The mice were weighed once a week and observed daily for blood in the stool and other signs of disease. After the 70-day model...

Embodiment 2

[0052] Overexpression of SphK2 increases 5-FU degradation in colorectal cancer cells and leads to 5-FU resistance

[0053] The colorectal cancer cell HCT116 overexpressing SphK2 and the vector control group were stimulated with 30 μM 5-FU. After 24 hours, the cells were taken out and washed 5 times with PBS, and the cells were completely detached from the bottle wall with a cell scraper. Centrifuge at 1000r / min at 4°C for 5min, discard the supernatant, add 0.5mL of PBS, pipette evenly, pipette into EP tubes, place them in a cell ultrasonic grinder for 10min, and then centrifuge in a centrifuge at 12000r / min at 4°C After 30 minutes, draw the supernatant into another clean EP tube, perform HPLC-UV detection after separation by solid phase extraction. The solid-phase extraction process is as follows: the solid-phase extraction column Styre ScreenHP is sequentially activated with 1 mL of ethanol and 1 mL of deionized water containing 0.1% trifluoroacetic acid. Draw 0.5mL of cell ...

Embodiment 3

[0056] Immunohistochemical section detection of FTY720 combined with chemotherapy drug 5-fluorouracil

[0057] After treatment with SphK2 inhibitor FTY720 combined with chemotherapy drug 5-fluorouracil, the immunohistochemical section detection of H&E and DPD was performed.

[0058] The wild-type mice and SphK2 gene overexpression mice in the feeding environment in Example 1 were respectively selected, 6-8 weeks old, and the number was 6, and daily intraperitoneal injection of 5-fluorouracil was performed after the aforementioned AOM / DSS modeling , the injection dose was 30 mg / kg, and at the same time, intraperitoneal injection of FTY720 was carried out every day, and the injection dose was 1 mg / kg. After 2 months, the samples were collected and fixed, and other sample analysis processes were the same as in Example 1. Paraffin sections were made after 4% paraformaldehyde fixation, and H&E and DPD immunohistochemical staining were performed on each section.

[0059] The result...

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Abstract

The present invention provides a pharmaceutical composition for treating digestive tract cancers, belongs to the technical field of drugs and an application of FTY720 or a combination of the FTY720 with JTE-013 in preparation of 5-fluorouracil (5-FU) drug resistance reversal agents. The provided pharmaceutical composition for treating the digestive tract cancers comprises 5-fluorouracil and at least one of the following 5-fluorouracil drug resistance reversal agents: FTY720 and JTE-013. The present invention also provides use of SphK2 and S1PR2 in screening drugs for reversing drug resistanceof fluorouracil compounds for the digestive tract cancers. The SphK2 up-regulates DPD expression-induced fluorouracil primary drug resistance and S1PR2 translocation-induced fluorouracil acquired drugresistance, and besides, the SphK2 and S1PR2 can be used as new molecular targets by designing targeted drugs to solve a drug resistance problem of the fluorouracil and derivatives thereof in cancertreatment processes.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a pharmaceutical composition for treating digestive tract cancer. Background technique [0002] Gastrointestinal cancer is a common malignant tumor, and the progressive application of immunotherapy in recent years shows that the prognosis is poor. In addition to surgery, chemotherapy plays an extremely important role in the comprehensive treatment of gastrointestinal cancer. Since the synthesis of 5-fluorouracil (5-FU) by Duschinsky et al. in 1957, 5-FU and its derivatives have been the basic drugs for chemotherapy of gastrointestinal tumors. 5-FU belongs to the class of thymidylate synthase inhibitor drugs, and is widely used as a first-line chemotherapy drug in various gastrointestinal cancers such as gastric cancer, colorectal cancer, head and neck squamous cell carcinoma, and liver cancer. The current FOLFOX treatment plan mainly includes the basic drug 5-FU co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/137A61K31/444A61K45/06A61P35/00
CPCA61K31/137A61K31/444A61K45/06A61P35/00A61K2300/00
Inventor 曲显俊张宇航崔淑香
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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