CN1491643A - Medicine for treating and preventing tumor metastasis and its application method - Google Patents

Abstract

The present invention relates to a kind of medicine for preventing and treating tumor metastasis and its usage. It features that the medicine nitroglycerin is a kind of commonly used medicine for treating cardiac vascular diseases and likely to produce 'resistance' after continuous taking for over three days, and the 'resistance' is utilized in sustained low-dosage administration to reach the effect of treating tumor and preventing tumor from metastasis. When used for treatment, the medicine is orally taken, or is guided via duct to local tumor part; and when used for prevention, the medicine is orally taken in low dosage or transdermal applied.

Description

Medicine for treating and preventing tumor metastasis and its application method

The present invention relates to a new application of traditional medicine, specifically nitroglycerin. So far, the drug has been used to treat cardiovascular diseases, and the present invention shows that nitroglycerin has new effects of treating tumors and preventing tumor metastasis.

Nitroglycerin (glyceryl trinitrate, GTN; C ₃ H ₅ (ONO ₂ ) ₃ , 227.1) has been used to treat angina pectoris for more than 100 years, and it is still one of the first-aid drugs for treating angina pectoris. However, its mechanism of action was not very clear at first , only known to dilate coronary arteries, until 1998 to unravel this mystery. It turns out that GTN treats angina pectoris because it can be degraded in the body to generate NO, which activates guanylate cyclase, increases the content of cGMP in smooth muscle cells, and activates protein kinases that depend on cGMP, which promotes the dephosphorylation of myosin light chain. Relaxation of smooth muscle, its main advantage is that the diastolic blood pressure drops less than the systolic blood pressure, can increase coronary blood flow, reduce ventricular volume and wall tension, relax larger epicardial vessels and collateral vessels, but have a weak relaxing effect on resistance vessels .

The effect of GTN intravenous infusion takes 1 to 3 minutes, and subsides in 5 to 10 minutes after stopping the drug. In addition to intravenous injection, the sublingual drug is easily absorbed through the oral mucosa, and its bioavailability is 80%, while it is only 8% when it is taken orally. Oral administration of small doses of GTN is rapidly metabolized in the liver, and it is difficult to achieve curative effect. Only when large doses are taken orally, liver enzymes are saturated, and some drugs escape liver metabolism and enter the systemic circulation as the original drug to play a role. Therefore, oral administration of GTN has a vasodilation effect on cardiovascular patients Poor, mostly adopt the way of sublingual oral administration. GTN can also be absorbed through the skin to achieve therapeutic effects.

GTN is reduced to a large amount of dinitrate metabolites by glutathione reductase in cells, and a small amount is mononitrate metabolites and inorganic nitrite. The speed of denitrification of nitrates mainly depends on the content of endogenous glutathione, because glutathione must provide reducing sulfhydryl groups in the process of drug metabolism and release of NO.

It has been clinically proven that GTN can quickly develop tolerance, which can be reversed after a certain period of time after drug withdrawal. At present, the mechanism of tolerance is believed to be: GTN generates NO through complex biological reactions in vascular smooth muscle cells or through extracellular pathways, and the reaction process requires the participation of thiol (-SH), and -SH mainly comes from cysteine [Munzel T et al.Circulation 1989,79:188], No interacts with -SH to form nitrosothiol (nitrosothiol), which can activate guanylate cyclase in smooth muscle cells to generate c GMP, and resistance occurs due to the lack of -SH Receptivity.

Tumor cell metabolism has three important characteristics: 1) High division and high metabolism, therefore, a large number of free radicals are produced during the metabolic process; 2) Energy supply is mainly based on anaerobic glycolysis, so it is in a relatively acidic environment compared with normal cells Environment, acidic environment is conducive to the generation of NO; 3) highly active expression of glutathione S-transferase (GST), especially the GST isoenzyme --- GSTπ, GSTπ is the most obvious increase in malignant tumors; it can Remove peroxides to protect cells from peroxidation damage; combine with lipids such as 4-hydroalkene, propylene, hydrogen peroxide or peroxidative metabolites of DNA to remove the toxicity of these substances to cells. In short, rapidly growing tumor cells had significantly higher levels of reduced glutathione than normal cells.

As an important biologically active molecule, nitric oxide (NO) participates in a series of biological processes under physiological and pathological conditions in the body, and regulates a series of physiological activities in the circulatory, nervous, immune and other systems, such as vasodilation, vascular Permeability, platelet adhesion and aggregation, nerve signal transmission, host defense response, etc., are also involved in pathological processes including tumors. Studies have further shown that high concentrations of NO have a killing effect on tumor cells and inhibit the growth and metastasis of tumor cells. The possible mechanisms are:

1) Broad-spectrum killing effect of activated Mφ on tumor cells mediated by NO. The mechanism may go through: T cells recognize antigen → T cells secrete cytokines → cytokines stimulate Mφ to produce NO → NO kills tumor cells. [Kumagai H et al. J Antibiot Tokyo. 1995; 48(4): 321]

2) NO is very easy to react with the protein Fe containing Fe-S center to form Fe-NO, which will cause the degradation of Fe-S prosthetic group in aconitase in the citric acid cycle and complexes I and II on the mitochondrial respiratory chain, Block the energy metabolism of tumor target cells, thereby inhibiting tumor cell growth or causing tumor cell death. [Rao DN et al. Arch Biochem Biophys. 1995; 321(2): 363]

3) NO acts on enzymes in the DNA synthesis process of tumor cells, affects DNA replication or directly nitrates DNA, and inhibits tumor cell proliferation. [Roy B et al. Biochemistry. 1995; 34(16): 5411]

4) NO reacts with superoxide anion (O ₂ ^- ) to form peroxynitrite (ONOO ^- ), and after protonation, ONOO ^- rapidly splits into more toxic hydroxyl radical (OH) and stable NO ₂ ^- . Hydroxyl free radicals are very active, and can induce various damages to tumor cells in vivo, such as lipid peroxidation, protein, amino acid gelation, and covalent binding with DNA and RNA, so that NO has an anti-tumor function. [Ngugen T et al. Pro Natl Acad Sci USA, 1992; 89(7): 3030]

The present invention is achieved in this way: long-term small doses (2.5 mg each time; 3 times a day) are given to GTN orally, or large doses (10-30 mg) are introduced into tumor tissue through an auxiliary device or administered through the skin for sustained release, so that the body Normal tissues such as blood vessels are resistant due to the lack of -SH, and will not cause vasodilation and lower blood pressure, while reduced glutathione in tumor cells is massively oxidized:

1) Reaction with glutathione consumes reduced glutathione, reduces antioxidant activity and indirectly increases the toxic effect of free radicals produced by tumor cells due to high metabolism and improves the sensitivity of radiotherapy and chemotherapy.

2) GTN is reduced to metabolites of dinitrate, metabolites of mononitrate, and inorganic nitrite. Nitrite reacts with reducing sulfhydryl groups under the slightly acidic conditions of tumor cells to generate nitrosothiols, which further react to generate NO. High concentrations of NO can kill tumor cells and inhibit the growth and metastasis of tumor cells.

The advantages of the present invention are:

1) Reuse of old medicines. Utilizing the catabolism of GTN and the metabolic characteristics of tumor cells, the drugs for treating angina pectoris can be used for the treatment and prevention of tumors.

2) Safety. Because the drug has been used for hundreds of years and has accumulated clinical experience, we have a deep understanding of its characteristics.

3) Low cost. Compared with the antineoplastic drugs currently used clinically, the drug has a very obvious price advantage.

4) Multipurpose. The drug can be used to prevent tumors, treat tumors and reduce drug resistance of chemotherapy drugs, etc.

Claims (4)

1. the medicine and the using method that shift of treatment and prophylaxis of tumours is characterized in that this medicine is treatment cardiovascular common drug----nitroglycerin.It had the effect of treatment tumor and prophylaxis of tumours transfer when low dosage long-term (more than three days) used;

2. can make tablet, capsule oral administration gastrointestinals such as (comprising hard capsule, soft capsule and slow releasing capsule) according to described this medicine of claim 1 absorbs and plays a role;

3. can be made into dosage form external transdermal skin such as pad pasting absorbs and plays a role according to described this medicine of claim 1;

4. can directly import in the tumor tissues by various auxiliary device according to described this medicine of claim 1 and play a role.