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Combination drug composition for treating liver cancer

A technology for the treatment of liver cancer and its composition, which is applied in the field of biomedicine, can solve the problem that the proliferation of cancer cells cannot be inhibited from the root cause, and achieve the effect of inhibiting proliferation

Inactive Publication Date: 2019-03-26
TONGJI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Patent CN107929712A discloses a method of treating liver cancer by combining two anticancer drugs, carfilzomib and kosorafenib, but it can only prolong the survival of patients by 2-3 years, and cannot fundamentally inhibit the proliferation of cancer cells

Method used

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  • Combination drug composition for treating liver cancer
  • Combination drug composition for treating liver cancer
  • Combination drug composition for treating liver cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Establish a reporter mouse model for detecting the efficiency of homologous recombination repair (HR) and non-homologous end joining repair (NHEJ) in vivo and detect the repair efficiency in mouse liver cancer.

[0024] 1. Establishment of reporter mouse model

[0025] Both HR or NHEJ reporter vectors are constructed based on the green fluorescent protein (GFP) gene and are integrated behind the first exon of the mouse Rosa26 gene. In the HR report vector ( figure 1 ), the GFP gene is split into two exons by the intron Pem1. In the first exon, the 22bp sequence was deleted and two reversed I-SceI sequences were inserted, so that the I-SceI endonuclease can recognize and cut DNA double-strand breaks, and at the same time ensure that even if it is repaired by NHEJ Does not generate complete GFP sequences. Following the second exon is the cognate template GFP-Pem1 lacking the promoter and ATG. The entire HR reporter vector was electrotransfected into mouse e...

Embodiment 2

[0029] Example 2: Mechanism of up-regulation of DNA double-strand break repair pathway in liver cancer tissue

[0030] 1. Detection of expression levels of repair-related genes in mouse liver cancer tissues and paracancerous tissues

[0031] Firstly, the proteins of 8 pairs of mouse liver cancer tissues and corresponding paracancerous tissues were extracted and subjected to Western blot experiments and semi-quantitative analysis. The results showed that the expression levels of DNA-PKcs and Parp1 were significantly increased in liver cancer tissues ( Figure 4 ), indicating that DNA-PKcs and Parp1 proteins play a key role in the abnormal up-regulation of DNA double-strand break repair pathway in mouse liver cancer.

[0032] 2. Detection of expression levels of repair-related genes in human liver cancer tissues and paracancerous tissues

[0033] In order to detect whether this change is also conserved in human liver cancer, 108 pairs of human liver cancer and corresponding pa...

Embodiment 3

[0034] Example 3: Inhibition of PARP1 and DNA-PKcs can inhibit HR and NHEJ repair efficiency in liver cancer tissue respectively

[0035]Olaparib is an inhibitor of PARP1, and NU7441 is an inhibitor of DNA-PKcs. In order to study whether olaparib and NU7441 can block the DNA double-strand break repair pathway, + / Rosa26HR or + / Rosa26NHEJ reporter mice were induced to form orthotopic liver cancer, and then Continuous intraperitoneal injection of 15 days of olaparib or / and NU7441 (olaparib: 50mg / kg / day; NU7441: 4mg / kg / day). On the fifth day of inhibitor injection, 50 μg pCMV-I-SceI and 15 μg pDsRed2-N1 plasmid were injected through the tail vein, and the mice were sacrificed 10 days later to remove liver cancer tissues and paracancerous tissues and digest them into single cells for flow analysis. The results showed that in the liver cancer tissues of + / Rosa26HR mice, both the olaparib and olaparib+NU7441 experimental groups could significantly inhibit the repair efficiency of HR ...

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Abstract

The invention relates to a combination drug composition for treating liver cancer. The combination drug composition is prepared from a PARP1 protein inhibitor Olaparib and a DNA-PKcs protein inhibitorNU7441. A DNA double strand breakage repair passage in a liver cancer cell is highly activated by protein inhibited by the combination drug composition, and accordingly an effective target spot is provided for treating liver cancer. Compared with the prior art, the micromolecular drug Olaparib can interdict homologous recombination repairing and selective non-homologous end joining repairing in liver cancer tissue, while NU7441 can interdict the non-homologous end jointing repairing, so that a combination of the two drugs can completely interdict the DNA double strand breakage repairing passage and thereby effectively inhibit proliferation of liver cancer, and the tumor increasing inhibition rate is as lowest as 62.3%, and as highest as 83.9%.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a combined pharmaceutical composition for treating liver cancer. Background technique [0002] At present, the incidence rate of liver cancer ranks sixth in the world, but the fatality rate ranks second, of which China accounts for more than half. In China, one person is diagnosed with liver cancer every 67 seconds, and at the same time, one person dies of liver cancer every 74 seconds. [0003] Although there are many traditional treatment methods for liver cancer, such as surgery, intervention, chemotherapy, radiotherapy, liver transplantation and so on. However, because early diagnosis is very difficult, few patients can receive curative treatments such as effective surgery or liver transplantation, and the postoperative recurrence and metastasis rates are very high, and there is a lack of effective targeted drugs. Most of the rest of the patients are mostly advanced patients, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/502A61K31/5355A61P35/00
CPCA61K31/502A61K31/5355A61P35/00A61K2300/00
Inventor 毛志勇王晨唐欢胤耿安珂蒋颖孙方霖
Owner TONGJI UNIV
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