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Application of CDK7 inhibitor THZ1 in nasopharynx cancer radiotherapy resistance treatment

An inhibitor and nasopharyngeal carcinoma technology, which is applied in the application field of CDK7 inhibitor THZ1 in the radiotherapy resistance of nasopharyngeal carcinoma, can solve the problems of transcriptional changes, unclear effectiveness of radiotherapy, etc., and achieve the goal of increasing radiotherapy sensitivity Effect

Pending Publication Date: 2022-04-15
XIANGYA HOSPITAL CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for the various lesions of genomic DNA caused by radiation therapy, how the transcriptional changes caused by these lesions affect the effectiveness of radiation therapy is still unclear.

Method used

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  • Application of CDK7 inhibitor THZ1 in nasopharynx cancer radiotherapy resistance treatment
  • Application of CDK7 inhibitor THZ1 in nasopharynx cancer radiotherapy resistance treatment
  • Application of CDK7 inhibitor THZ1 in nasopharynx cancer radiotherapy resistance treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The phosphorylation level of RNAPII CTD is different in nasopharyngeal carcinoma radiosensitive and resistant cells.

[0041] According to this example, it can be known that there is a difference in the phosphorylation of RNA polymerase II Ser5 in nasopharyngeal carcinoma radiotherapy-sensitive cells and radiotherapy-resistant cells.

[0042] (1) Materials and reagents:

[0043] Purchase the basal medium and serum as shown in the table below, and prepare according to the ratio of 10% FBS for culturing CNE2 and CNE2-IR cells. Cell lysates were used to collect proteins for Western blotting.

[0044]

[0045] (2) Experimental steps

[0046] 1) Collect protein

[0047] Will 4×10 5 Plate cells into 6-well plates at 37 °C and 5% CO 2 Incubate in the environment for 24 hours. Remove the medium, rinse the cells with buffer DPBS 3 times, add 200μl cell lysate (2% SDS, 10% glycerol, 62.5mM Tris-HCl pH6.8; add 1× protease inhibitor cocktail, 10mM sodium fluoride, 1mM Sod...

Embodiment 2

[0072] CNE2 and CNE2-IR differ in sensitivity to the CDK7 inhibitor THZ1.

[0073] (1) Materials and reagents:

[0074] Purchase the following reagents.

[0075]

[0076] (2) Experimental steps

[0077] 1) Drug treatment

[0078] Step 1: Take a 10cm culture dish as an example, digest logarithmic cells with 1ml trypsin, centrifuge to collect after termination of digestion, resuspend into a cell suspension with phenol red-free DMEM medium, count, and count according to 1000 CNE2 per well Cells and 1200 CNE2-IR cells per well, after calculation, take an appropriate amount of cells and plate them in a 96-well plate (the edge wells are filled with sterile PBS), and set more than three replicate wells for each drug concentration. Reserve three duplicate wells and only add the same amount of culture medium as the background, and culture in an environment of 37°C and 5% CO2 until the cell monolayer covers the bottom of the well.

[0079] Step 2: Dissolve the drug in 10% DMSO DP...

Embodiment 3

[0088] The combined effect of radiotherapy exposure and THZ1 on growth proliferation of CNE2 and CNE2-IR.

[0089] (1) Reagents and materials:

[0090] Refer to Example 2.

[0091] (2) Experimental steps:

[0092] 1) Drug treatment

[0093] Taking CNE2 as an example, spread 4×105 cells per well into 2 wells of a 6-well plate, spread 2 pieces, and culture them in an environment of 37°C and 5% CO2 until the cells adhere to the wall. Dissolve the drug in 10% DMSO in DPBS buffer, add THZ1 with a final concentration of 150nM to each plate, and 0μM solvent without THZ1, the final concentration of DMSO in each well is less than 0.2%, put it at 37°C and 5% CO2 environment for 12 hours.

[0094] 2) Ionizing radiation

[0095] Take one of the 6-well plates, and use a linear accelerator (X-Rad 225, Precision) to irradiate with a dose of 2Gy at room temperature and 200cGy / min. The CNE2 cells of the control group (solvent, 0Gy) and the experimental group (drug, 0Gy; solvent, 2Gy; dru...

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Abstract

The invention relates to the technical field of biology, in particular to application of a CDK7 inhibitor THZ1 in nasopharyngeal carcinoma radiotherapy resistance treatment. According to the invention, the difference of phosphorylation levels of RNA polymerase II C-terminal repetitive domain S5 in nasopharyngeal carcinoma radiotherapy resistance and radiotherapy sensitive cells and after radiotherapy irradiation is carried out on the nasopharyngeal carcinoma radiotherapy resistance and radiotherapy sensitive cells is firstly explored. An inhibitor THZ1 of a CDK7 target spot is adopted to detect nasopharyngeal carcinoma radiotherapy resistance and drug sensitivity of sensitive cells. THZ1 and radiotherapy are combined to act on radiotherapy-resistant cells, and whether THZ1 can increase radiotherapy sensitivity or not is explored. THZ1 is applied to a radiotherapy-resistant mouse model, and the treatment effect of THZ1 on radiotherapy-resistant tumors is explored. The CDK7 inhibitor THZ1 provided by the invention can effectively inhibit the growth of nasopharyngeal carcinoma radiotherapy resistant tumors in an in-vitro level cell experiment and an in-vivo level nude mouse subcutaneous tumor formation experiment. From the cellular level and the animal level, when the THZ1 is combined with the radiotherapy, the radiotherapy sensitivity can be increased, which indicates that the THZ1 is feasible to treat the nasopharyngeal carcinoma radiotherapy resistance.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to the application of CDK7 inhibitor THZ1 in the treatment of nasopharyngeal carcinoma radiotherapy resistance. Background technique [0002] Tumor is the main cause of death in my country. In the past half century, the incidence and mortality of tumors in my country have maintained an upward trend. In 2018, there were about 4.3 million new cases of cancer and about 2.9 million deaths. How to effectively treat tumors is an urgent public health problem. [0003] Thanks to the research on the treatment strategy of nasopharyngeal carcinoma, the treatment effect of nasopharyngeal carcinoma has been greatly improved, but 20-30% of nasopharyngeal carcinoma patients still have recurrence and metastasis due to radiotherapy resistance, radiotherapy resistance is considered to be A major obstacle to clinical cancer treatment. Platinum-based dual chemotherapy regimens are currently used as firs...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61P35/00
CPCA61K31/506A61P35/00
Inventor 袁凯刘虹璐俞春红张娜孟阳黄璨华陈芳
Owner XIANGYA HOSPITAL CENT SOUTH UNIV
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