CN114028394A

CN114028394A - Application of low-dose ranvatinib in preparation of medicines for treating liver cancer

Info

Publication number: CN114028394A
Application number: CN202110558816.6A
Authority: CN
Inventors: 夏建川; 向橦; 杨洁莹; 翁德胜
Original assignee: Sun Yat Sen University; Sun Yat Sen University Cancer Center
Current assignee: Sun Yat Sen University; Sun Yat Sen University Cancer Center
Priority date: 2021-05-21
Filing date: 2021-05-21
Publication date: 2022-02-11

Abstract

The invention provides application of low-dose ranvatinib in preparation of a medicine for treating liver cancer. The research of the invention finds that the low-dose Lunvatinib can inhibit the growth of the liver cancer cell transplantation tumor and promote the normalization of liver cancer blood vessels, has obvious curative effect on liver cancer, can be applied to the prevention and treatment of liver cancer, provides a new treatment medication scheme for the treatment of liver cancer, and has good application prospect in the prevention and treatment of liver cancer.

Description

Application of low-dose ranvatinib in preparation of medicines for treating liver cancer

Technical Field

The invention relates to application of low-dose ranvatinib in preparation of a medicine for treating liver cancer.

Background

Many liver cancer patients lose the opportunity of radical treatment (such as operation, liver transplantation or radio frequency ablation) and local treatment such as chemoembolization when in treatment, and the prognosis of the liver cancer patients is poor due to the low sensitivity of the liver cancer to systemic chemotherapy. Therefore, there is an urgent need to find new effective methods for treating advanced liver cancer.

The new blood vessel is one of ten characteristics of the tumor, and plays an important role in multiple links of occurrence, development, relapse, metastasis and the like of the liver cancer. From the aspect of tumor angiogenesis, anti-angiogenesis targeted drugs are used for resisting the growth, recurrence and metastasis of tumors in clinic, and a better curative effect is achieved. The anti-angiogenesis targeted drug approved by FDA and used in the late unresectable liver cancer does not achieve ideal treatment effect in the treatment process of the liver cancer, and has more remarkable disease progression in the later stage. Many studies at present show that, compared with a high-dose anti-angiogenesis targeted drug, a low-dose anti-angiogenesis drug can reconstruct the internal vascular structure of a tumor by promoting the normalization of blood vessels, recruit perivascular cells while inhibiting the abnormal proliferation of new blood vessels, enhance the tight connection between endothelial cells so as to promote the maturation of the vascular structure, improve the blood perfusion and the hypoxia, reduce the vascular leakage, promote the infiltration of circulating immune cells into the tumor tissue and enhance the killing activity of the circulating immune cells. The high dose application of the angiogenesis inhibitor excessively blocks the blood supply of the tumor, cuts off the bridge of the anti-tumor drug and immune cells to reach the tumor tissue, and can aggravate hypoxia. Therefore, anti-tumor vascular therapy should seek a reasonable dose of the angiogenesis inhibitor to induce the tumor vessels to undergo vascular transformation towards normal tissues.

Lovatinib is a multi-target receptor tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, FGFR1-4, PDGFR α, RET and KIT. Preclinical studies have shown that lenvatinib effectively blocks VEGF and FGF driven angiogenesis, KIT dependent angiogenesis, RET fusion/RET mutation related tumorigenesis and VEGFR3 related lymphangiogenesis. Clinical studies show that the objective remission rate of ranvatinib is nearly 3 times that of sorafenib, the disease-free progression period is improved by 1 time compared with sorafenib, but the total survival period has no statistical difference. The subgroup analysis results of Chinese patients show that the total survival period of the Ranuncutinib is prolonged by 4.8 months compared with the sorafenib, and the non-inferiority statistical standard is achieved. In 2018, lenvatinib was approved for marketing in china for first-line treatment of unresectable hepatocellular carcinoma.

Disclosure of Invention

The invention aims to overcome the defects of the existing targeting drugs for treating liver cancer and provides the application of low-dose Lunvatinib in preparing drugs for treating liver cancer. The invention discovers that the low-dose Lunvatinib can normalize the blood vessels of the liver cancer, has no obvious difference in the inhibition effect on the growth of the liver cancer compared with the high-dose Lunvatinib, has higher treatment value on the liver cancer after long-term use, and can be applied to the prevention and treatment of the liver cancer.

In order to realize the purpose, the technical scheme is as follows: use of low dose of ranvatinib in the preparation of a medicament for the treatment of liver cancer.

Preferably, the medicament for treating liver cancer is a medicament for inhibiting the growth of liver cancer.

Preferably, said inhibition of liver cancer growth is inhibition of growth of liver cancer cells or vascular endothelial cells within liver cancer tissue.

Preferably, the liver cancer is primary hepatocellular carcinoma.

Preferably, the low dose is 5mg/kg body weight/day.

Preferably, the medicament is an oral medicament.

The invention provides a medicine for treating liver cancer, which contains low-dose Lunvatinib.

Preferably, the medicament further comprises a medically acceptable adjuvant or carrier.

The Lovatinib is an oral multi-target inhibitor, and the action targets comprise 1-3 vascular endothelial growth factor receptors, 1-4 fibroblast growth factor receptors, alpha, RET and KIT of platelet-derived growth factor receptors. Compared with the high-dose Lunvatinib, the low-dose Lunvatinib can promote the normalization of liver cancer tissue blood vessels, inhibit the abnormal proliferation of new blood vessels, and improve blood perfusion and hypoxia under the condition of still maintaining the same effect of inhibiting the growth of liver cancer.

Has the advantages that:

the invention provides application of low-dose ranvatinib in preparation of a medicine for treating liver cancer. The research of the invention discovers that the low-dose Lunvatinib can inhibit the growth of the liver cancer cell transplantation tumor and promote the normalization of the liver cancer blood vessel, has obvious curative effect on the liver cancer, can be applied to the prevention and treatment of the liver cancer, provides a new treatment medication scheme for the treatment of the liver cancer, and has good application prospect in the prevention and treatment of the liver cancer.

Drawings

FIG. 1 is a graph of the effect of low and high dose of Lunvatinib on size of hepatoma cell transplants.

FIG. 2 is a graph of the effect of low and high dose of Lunvatinib on vascular maturation and hypoxia in liver cancer tissues.

Detailed Description

To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples. The reagents, methods and apparatus employed in the present invention are conventional in the art, unless otherwise indicated. Unless otherwise indicated, reagents and materials used in the following examples are commercially available.

Example 1 effect of different doses of lenvatinib on size of hepatoma cell transplants.

1. Experimental Material

(1) Medicine preparation: lunvatinib (lenvatinib) of the formula: C21H19ClN4O4, CAS No.: 417716-92-8

(2) Cancer cell: human hepatoma mountain large cell (PLC/PRF/5)

(3) Commercially available immunodeficient NCG mice.

2. Experiment grouping

(1) Control group: the blank control, i.e., hepatoma bearing mice, was not treated with any drug.

(2) Low dose lenvatinib group: hepatoma tumor-bearing mice were treated with low doses of ranvatinib.

(3) High dose lenvatinib group: hepatoma tumor-bearing mice were treated with high doses of ranvatinib.

3. Immunodeficient NCG mouse subcutaneous tumor formation experiment for detecting influence of N low-dose Lunvatinib on liver cancer cell transplantation tumor

(1)Are respectively 2 × 10⁶Numerical values of human hepatoma-Li mountain large cells (PLC/PRF/5) were implanted subcutaneously in the axilla of 15 NOD/SCID mice of 3-4 weeks of age. Randomized into 3 groups: a blank control group, a low dose group and a high dose group of ranvatinib.

(2) When the size of subcutaneous tumor reaches 100-200 mm³The method comprises the following steps: the low dose of Lunvatinib group was orally gavaged once daily for 1 time with 5mg/kg of Lunvatinib; the high dose of Lunvatinib group was given once daily oral gavage of 30mg/kg 1 time per mouse. According to the prior art, 30mg/kg is reported as the usual dose for animal experimental mice of Ranatinib (from selelck).

(3) Tumor size was measured every 2 days and the difference in tumor size between groups was compared.

(4) After 3 weeks, injecting 5mg of pimonidazole as hypoxia detection reagent into the abdominal cavity of each mouse, killing the mouse by breaking the neck after 30 minutes, cutting off tumor tissues, performing immunohistochemical detection on vascular markers CD31, alpha-SMA and VEGFR2, and simultaneously detecting the hypoxia condition of the tumor tissues by using a hypoxia kit.

4. Results of the experiment

The results are shown in figure 1, the low dose of ranvatinib and the high dose of ranvatinib can inhibit the growth of liver cancer cell transplanted tumor, and the tumor growth of the mice in the low dose group and the mice in the high dose group has no obvious difference.

In addition, as shown in fig. 2, immunohistochemical results showed that low and high doses of ranvatinib significantly reduced microvascular density in liver cancer tissues (CD 31). However, compared with the high-dose lenvatinib group, the low-dose lenvatinib can simultaneously increase the expression of perivascular alpha-SMA (perivascular cell marker), i.e. peripheral cells are recruited to cover vascular endothelium, so that vascular maturation is promoted, blood vessels are normalized, and the hypoxia condition of local tissues is improved.

Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. Use of low dose of ranvatinib in the preparation of a medicament for the treatment of liver cancer.

2. The use of claim 1, wherein the agent for treating liver cancer is an agent that inhibits the growth of liver cancer.

3. The use of claim 2, wherein said inhibition of liver cancer growth is inhibition of growth of vascular endothelial cells within liver cancer cells or liver cancer tissue.

4. The use according to claim 1, wherein the liver cancer is primary hepatocellular carcinoma.

5. Use according to claim 1, wherein the low dose is 5mg/kg body weight/day.

6. Use according to claim 1, wherein the medicament is an oral medicament.

7. A medicament for the treatment of liver cancer, wherein the medicament comprises low dose of ranvatinib.

8. The medicament of claim 7, further comprising a pharmaceutically acceptable adjuvant or carrier.