Compound serving as anti-tumor medicine synergist and reversal agent

Abstract

The invention discloses a compound serving as an anti-tumor medicine synergist and a reversal agent and belongs to the technical field of medicines. The invention provides application of an avermectinmedicine to preparation of an anti-tumor medicine and application of the avermectin medicine to preparation of the anti-tumor medicine synergist or the reversal agent. The invention also provides ananti-tumor medicine composition which comprises one or more anti-tumor medicines and one or more avermectin medicines as effective components. The avermectin medicine is avermectin, ivermectin, epiomycin, doramectin or eprinomectin, and the anti-tumor medicine is vincristine and salt thereof, daunorubicin, taxol and salt thereof or doxorubicin. The avermectin medicine can improve the sensibility of tumors to chemotherapeutic medicines and thus can be used as the anti-tumor medicine synergist; and the avermectin medicine has an excellent effect on reversing the medicine resistance of tumor cells to the anti-tumor medicine.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a compound used as a synergist and a reversal agent for antitumor drugs. Background technique [0002] Cancer is one of the important diseases that endanger public health, and its morbidity and mortality are increasing year by year. Although there are many ways to treat cancer, chemotherapy is still a common method of treatment, but long-term chemotherapy can easily lead to multidrug resistance in patients, resulting in reduced curative effect or even failure of chemotherapy. [0003] The mechanism of multidrug resistance in tumor cells is quite complex, and there are many influencing factors. Among them, multidrug resistance gene 1 (MDR1) plays a major role in multidrug resistance of tumor cells and is the most deeply studied. It is P-glycoprotein (P-gp), which acts as an efflux pump for macromolecular drugs or poisons that rely on ATP energy, and can expel drugs o...

AI Technical Summary

Problems solved by technology

The first-generation reversal agents mainly include calcium ion channel blockers, calmodulin inhibitors, lipophilic compounds, protein kinase C inhibitors, immunosuppressive drugs, anti-biotin compounds, and surfactants. Can effectively reverse the drug resistance of tumor cells and increase the death rate of tumor cells; but when used in vivo, the effective concentration of reversal cannot be achieved at a safe blood concentration, such as the cardiotoxicity of verapamil, cyclosporine A nephrotoxicity and immunosuppressive effects

The toxicity and side effects associated with the activity of the first generation of reversal agents are too large. In clinical use, at a tolerable dose, the reversal activity of reversal agents for tumor drug resistance is not high. On the contrary, the toxicity caused by unnecessary pharmacological activities The side effects are more pronounced, which makes it difficult to design safe and effective therapeutic doses of chemotherapy drugs

The second-generation reversal agent that appeared subsequently mainly includes: dexverapamil (dexverapamil), dexnigudipine (dexnigudipine), PSC833 and VX-710, etc. Compared with the first generation, the second-generation reversal agent has relatively Low cytotoxicity, and in vivo experiments can achieve the concentration required to effectively reverse the drug resistance of tumor cells; but when the second-generation reversal agent is used in combination with anti-tumor drugs, it is found that the second-generation reversal agent is the base of cytochrome P4503A4 Drugs that can inhibit the metabolism and elimination of antineoplastic drugs, and increase the side effects of antineoplastic drugs (Lei Yan, Zhang Jianhua, Zhang Ming, Chen Geng, Sun Baoying. Research progress on P-glycoprotein inhibitors. Guangzhou Chemical Industry. 2016,44:27 -30), this feature also limits the clinical application of second-generation reversal agents

When chemotherapy drugs are used in combination with second-generation reversal agents, there is an interaction between the reversal agent and the drug metabolism target, which affects the metabolism of chemotherapy drugs and increases the side effects of chemotherapy drugs, and the selectivity is low

The third-generation reversal agents include S9788, GF120918, Zosuquidar (LY335979), Lanquidar (R101933), tetrandrine, ONT-093 (OC144-093), XR9576, and FG020326, etc., although to some extent overcome the second-generation reversal agents defects, but there is still a certain distance from clinical application

At present, studies have shown that ivermectin can inhibit the growth of various tumor cells in vitro, and can also directly inhibit the growth of tumor cells in tumor models formed in immunodeficient mice, but its high dosage may cause toxic effects on animals (Liu Y, Fang S, Sun Q, Liu B. Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2016, 480:415-421; Dou QH, Kchen HN, Wang , Yuan KF, Lei YL, Li K, Lan J, Chen Y, Huang Z, Xie N, Zhang L, Xiang R, Edouard CN, Wei YQ, Huang CH. Ivermectin induces cytostatic autophagy by blocking the PAK1 / Akt axis inbreast cancer. CancerRes. 2016,76:4457-4469)

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