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Application of parp1 inhibitor in the preparation of drugs for reversing drug resistance of tumor cells to methotrexate

A technology of tumor cells and methotrexate, which is applied in the direction of anti-tumor drugs, drug combinations, and pharmaceutical formulations, and can solve problems such as poor fidelity and abnormal chromosome structure

Active Publication Date: 2018-12-28
HARBIN MEDICAL UNIVERSITY
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Problems solved by technology

In addition, the A-NHEJ repair process often produces large genomic deletions, microhomologies, and large insertions of DNA fragments of unknown origin, which is a less fidelity, more prone to genome rearrangement, and abnormal chromosome structure.

Method used

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  • Application of parp1 inhibitor in the preparation of drugs for reversing drug resistance of tumor cells to methotrexate
  • Application of parp1 inhibitor in the preparation of drugs for reversing drug resistance of tumor cells to methotrexate
  • Application of parp1 inhibitor in the preparation of drugs for reversing drug resistance of tumor cells to methotrexate

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Embodiment 1

[0060] 1. Cell culture

[0061] Human colon cancer cell line HT29 and HT29 MTX drug-resistant cells containing DMs (HT29 10 -4 mol / L MTX), cultured in DMEM high-glucose medium containing 15% fetal bovine serum, and corresponding concentrations of MTX were added to the culture medium of drug-resistant cell lines. All cells were in 5% CO 2 , Cultured in a 37°C cell culture incubator.

[0062] 2. Expression analysis of A-NHEJ pathway-related proteins

[0063] The total cell protein was extracted, and the expression changes of PARP1, LIG3 and XRCC1 in HT29 and HT29 MTX-resistant cells containing DMs were detected by Western Blot method.

[0064] a. Extraction of total cell protein

[0065] The cells were washed 3 times with pre-cooled PBS to remove the protein components attached to the cell surface. Place the cell culture flask on ice and aspirate the residual PBS. Add an appropriate amount of cell lysate (the volume ratio of protease inhibitor: phosphatase inhibitor: RIPAb...

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Abstract

The invention discloses application of a PARP1 inhibitor in the preparation of a medicine for reversing drug resistance of tumor cells to amethopterin and belongs to the technical field of tumour biotherapy. It is found by the inventor through researches that as for malignant cells with MTX resistance and DHFR gene high-amplification, by specifically inhibiting the key protein RARP1 of A-NHEJ pathway, DHFR gene copy number can be reduce and DMs in cells can be decreased so as to reverse drug resistance of tumors and enhance efficiency of tumor therapy. Therefore, on the basis of the above researches, the invention brings forward the application of the PARP1 inhibitor in the preparation of a medicine for reversing the drug resistance of tumor cells to MTX by reducing DHFR gene copy number. The invention provides a new targeting therapeutic scheme for the MTX as the main therapeutic drug and for the biotherapy of malignant tumors which are easy to resist drugs and also provides a scientific basis for effectively fighting against MTX drug resistance. In addition, the invention is also of great positive significance for deeply understanding the nature of chemotherapy resistance and finding resistance target for individualized treatment.

Description

technical field [0001] The invention relates to a method for PARP1 inhibitors to reverse the drug resistance of tumor cells to MTX by reducing the copy number of DHFR gene in tumor cells, providing a scientific basis for revealing new therapeutic targets and more effectively combating MTX drug resistance, belonging to tumor biology Therapeutic technology field. Background technique [0002] Methotrexate (Methotrexate, MTX) is an antifolate antineoplastic drug that can competitively bind to dihydrofolate reductase (Dihydrofolatereductase, DHFR) to inhibit nucleotide metabolism, thereby blocking DNA synthesis and specifically killing proliferating cells. However, in the process of tumor treatment, long-term continuous administration will cause tumor cells to acquire drug resistance, making the treatment effect poor. DHFR gene amplification and increased enzyme levels are important mechanisms leading to MTX resistance. Gene amplification refers to the phenomenon of a large i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K48/00A61K31/4184A61K31/519A61P35/00
CPCA61K31/4184A61K31/519A61K45/00A61K48/005
Inventor 孟祥宁侯丽青高巍关荣伟刘鹏冀国华马金法宋盈
Owner HARBIN MEDICAL UNIVERSITY
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