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Application of mercaptopurine and derivatives thereof in preparation of drugs for removing malignant tumor immunosuppression

A technology for malignant tumors and immunosuppression, applied in the direction of antineoplastic drugs, drug combinations, active ingredients of heterocyclic compounds, etc., to achieve the effect of releasing tumor immunosuppression, inhibiting the occurrence and development, and reducing protein levels

Pending Publication Date: 2021-04-16
KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Whether the protein glycosylation of PD-L1 is regulated by GLT8D1 has not been reported
At present, there are no relevant reports on the use of thioguanine in the treatment of other malignant tumors except for the treatment of hematological malignancies

Method used

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  • Application of mercaptopurine and derivatives thereof in preparation of drugs for removing malignant tumor immunosuppression
  • Application of mercaptopurine and derivatives thereof in preparation of drugs for removing malignant tumor immunosuppression
  • Application of mercaptopurine and derivatives thereof in preparation of drugs for removing malignant tumor immunosuppression

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Western Blotting Experiment

[0045] First, add different concentrations of 6-MP or 6-TG to A549, H1299, HCT116, LoVo, MDA-MB-231, SUM149, Huh-7, A375, SK-MEL-5 cells for 12 hours, and then add IFN-γ (10ng / mL) treatment, IFN-γ treatment for 24 hours, add RIPA lysate to lyse the cells, extract protein samples, after BCA protein quantification, add the protein samples to the gel plate through the pipette gun, electrophoresis at 150V until bromophenol blue about to run out. Transfer membrane: put the transfer membrane rack in the pre-cooled membrane transfer solution, with the black plastic plate facing down and the white plate on top, put a sponge pad on top of the black surface, and a piece of filter paper on the sponge pad; gently remove the gel from the Remove the electrophoresis glass plate and put it on the filter paper, put the PVDF membrane on the top of the gel, put another piece of filter paper, put a sponge pad on the top of the filter paper, fix the...

Embodiment 2

[0047] Embodiment 2: PBMC tumor killing experiment

[0048] For the extraction of PBMC cells, take the blood of healthy people, add the Fico separation solution at room temperature to the centrifuge tube, slowly add the blood (do not break the boundary between the separation solution and the blood), centrifuge at 1590 rpm for half an hour at room temperature, and the centrifugation ends Finally, the cells in the middle layer are taken as PBMC cells, suck out the PBMC cells and add them to PBS, centrifuge at 1590 for 10 minutes, repeat twice, then resuspend the cell pellet with 1640 full medium, add it to the cell culture dish for 2 hours, and take it out after 2 hours Put the non-adherent cells into a new culture dish, add CD3 (100ng / mL) and IL-2 (10ng / mL) to activate for 48h;

[0049] After the tumor cells were counted, they were inoculated in a 24-well plate. After the cells adhered to the wall, different concentrations of 6-MP or 6-TG were added for pretreatment for 12 hour...

Embodiment 3

[0051] Example 3: Detection of PD-L1 on the membrane surface

[0052] First add 6-MP (10µM) or 6-TG (4µM) to A549, H1299, HCT116, MDA-MB-231, MDA-MB-453, A375, SK-MEL-5 and Huh-7 cells for 12h pretreatment , then add IFN-γ (10ng / mL) for treatment, after IFN-γ treatment for 24 hours, digest the cells into single cells with trypsin, centrifuge the cells at 790 rpm, then resuspend the cells with 5mL of PBS, centrifuge again and discard Add 500µL of cell staining buffer to each tube of cells to resuspend the cells, then add 5µL of PD-L1APC antibody, incubate at 37°C for 30min, centrifuge the cells coated with the antibody at 790 rpm, discard the supernatant, and use 3mL of cell staining Wash the cells twice with the buffer, and finally resuspend the cell pellet with 500 µL of cell staining buffer, filter the cells with a filter membrane, detect the fluorescence intensity with a flow cytometer, and finally analyze the flow cytometry results with Flow Jo software;

[0053] The resu...

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Abstract

The invention discloses new application of mercaptopurine and derivatives thereof, namely application of mercaptopurine and derivatives thereof in preparation of drugs for removing malignant tumor immunosuppression, mercaptopurine and thioguanine act on tumor cells of human lung cancer, colorectal cancer, liver cancer, melanoma, breast cancer and the like. The expression of glycosyltransferase GLT8D1 can be remarkably reduced. Further, the protein level and glycosylation level of PDL1 are inhibited, so that the killing effect of peripheral blood mononuclear cells on tumor cells is improved, and the purpose of inhibiting tumors is achieved; the invention finds that mercaptopurine / thioguanine which interferes with nucleic acid biosynthesis and is widely applied to anti-leukemia drugs can inhibit glycosyltransferase GLT8D1 and a programmed cell death ligand 1 (PDL1) in a targeting manner to enhance tumor killing of T cells so as to achieve the purpose of drugs for treating various tumors; The invention provides a new therapeutic drug for treating various tumors.

Description

technical field [0001] The invention belongs to the field of tumor treatment, specifically relates to the application of mercaptopurine and its derivatives in the preparation of drugs for releasing immunosuppression of malignant tumors, and belongs to the technical field of biomedicine. Background technique [0002] According to the calculation of the proportion of all cancers, including non-melanoma skin cancers, in all age groups and genders, it is estimated that there will be 18.1 million new cancer cases and 9.6 million cancer deaths worldwide in 2018. Asia accounted for nearly 50% of the 18.1 million new cancer patients and nearly 70% of the 9.6 million cancer deaths. The highest incidence of new cancers in the world are: lung cancer (11.6%), breast cancer (11.6%), colorectal cancer (10.2%), prostate cancer (7.1%), gastric cancer (5.7%); the highest mortality rate in the world Cancers are: lung cancer (18.4%), colorectal cancer (9.2%), gastric cancer (8.2%), liver canc...

Claims

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Application Information

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IPC IPC(8): A61K31/52A61P35/00
Inventor 陈勇彬杨翠萍石玉林
Owner KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI
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