Medicine for resisting cancer cell spread and application

Abstract

The invention provides a medicine and a method for inhibiting histamine from increasing the permeability of blood capillaries or directly reducing the permeability of the blood capillaries, so that metastasis of tumor cells is inhibited. Specifically, the anti-histamine drug exists in the human body by taking the anti-histamine drug, so that the anti-histamine drug can immediately act with histamine secreted during cancer tumor resection operation to prevent the histamine from increasing capillary permeability, and the effect of preventing cancer cell diffusion is achieved.

Description

TECHNICAL FIELD

[0001] The present invention relates to a substance and method for inhibiting the spread of cancer cells, particularly by hindering the increase of capillary permeability, and preventing the spread of cancer cells. BACKGROUND

[0002] The number of cancer patients is increasing year by year, and has become the second largest factor endangering human health in the world next to cardiovascular disease. Although primary tumors are very dangerous, they will eventually cause the death of only about 10% of tumor patients, and about 90% of tumor patients eventually die of the growth of metastatic tumors at sites other than the primary site. Generally, the metastasis rate of early malignant tumors is low after surgery, and the cure rate is relatively high. The cure rate of medium or late malignant tumors will decrease significantly because of easy postoperative metastasis and recurrence. In particular, most patients with advanced metastatic malignant tumors cannot be cured and can only prolong survival.

[0003] The formation of tumor metastatic foci is the result of tumor cells leaving the primary site, searching for new sites in the body along blood vessels, and regrowing to form cell clones. The entire process of the invasion-metastasis cascade includes the following links. In the initial stage, local invasion causes destruction of carcinoma in situ cells and breaks through the basement membrane, invades capillaries, and then these tumor cells circulate with the blood to anatomically distant sites, where the tumor cells reside and penetrate the capillary wall, thereby forming occult micrometastatic foci. Histamine can increase capillary permeability, promote tumor cells from tumor sites into the blood circulation, and facilitate tumor cells to penetrate the capillary wall to reach and colonize normal tissues, thereby forming metastatic foci. SUMMARY

[0004] The purpose of the present invention is to develop a drug and method for inhibiting histamine from increasing capillary permeability or directly reducing capillary permeability, thereby inhibiting tumor cell metastasis.

[0005] Histamine is a signal transduction molecule in the human body with multiple physiological functions. Histamine binds to receptor H1 to participate in allergic reactions. During allergic reactions, histamine released by mast cells activates histamine receptor H1, causing smooth muscle contraction and increasing capillary permeability, leading to typical allergic symptoms.

[0006] The cause of the large amount of histamine production in the human body may be an allergic reaction or an inflammatory response caused by other diseases. Histamine is a biological amine that can participate in many physiological processes, including inflammatory responses in the immune system, nervous system, cardiovascular system, and gut. When the human body is stimulated by allergens such as pollen, strawberries, shrimp, truffles, and alcohol, the immune system responds by releasing a large amount of histamine. In addition, many diseases and inflammatory responses can also cause a large amount of histamine production, such as certain tumors, arthritis, pancreatitis, and asthma. Therefore, the production of a large amount of histamine in the body may be due to an inflammatory response, an allergic reaction, or other physiological responses caused by diseases.

[0007] Another cause of the large amount of histamine production in the human body is when the body's tissue cells are damaged, the tissue cells will immediately produce a large amount of histamine.

[0008] Histamine has many effects on human cells and tissues, and the following are its main actions:

[0009] 1. Immune response effect: Histamine is an important immune mediator that participates in regulating and producing immune responses in the immune system, including leukocyte movement, nerve ending activation, and other responses.

[0010] 2. Inflammatory response effect: Histamine is a major inflammatory mediator that can induce and exacerbate inflammatory responses, such as causing redness, swelling, pain, and other symptoms. Inflammatory responses can also cause other health problems.

[0011] 3. Vasodilation effect: Histamine can promote vasodilation and increase vascular (including capillary) permeability, allowing blood and cellular components to enter tissues and cause symptoms such as itching, swelling, and local numbness.

[0012] 4. Neural response effect: Histamine can also act as a neural mediator by binding to neurons, triggering various physiological responses in the human body, such as inducing headaches, facial flushing, chills, vomiting, and other symptoms.

[0013] Mechanism of cancer cell spread:

[0014] Process of cancer cell spread:

[0015] a) The first condition for cancer cell spread is that the cancer cells should be able to move freely. We call this type of cancer cell a free cancer cell.

[0016] b) The free cancer cell first passes through the capillary wall into the human blood circulation system.

[0017] c) The permeability of the capillary wall determines the ability of the cancer cell to pass through the capillary wall

[0018] . The higher the permeability of the capillary wall, the stronger the ability of the cancer cell to pass through the capillary wall.

[0019] d) Cancer cells reach the vicinity of the organ to which the cancer cells spread in the human body with the blood flow.

[0020] e) Cells penetrate the capillary wall into the organ to which the cancer cells spread, where they develop into new cancers.

[0021] f) Due to the barrier function of the capillary wall, cancer cells cannot normally penetrate the capillary wall into the blood circulation system, even if they are free cancer cells, and cancer cell spread does not occur.

[0022] The relationship between histamine and cancer cell spread

[0023] a) In 1910, when Henry Dale was studying the toxicity of rye, he discovered a substance which he called "histamine". Histamine is a substance secreted by human tissue cells.

[0024] b) Histamine activates the H1 receptors in the histamine receptors of the tissue cells, causing smooth muscle contraction and increasing capillary permeability. Histamine thus has the function of increasing capillary permeability, i.e. the ability of substances, including cancer cells, to pass through the capillary.

[0025] c) The more histamine there is, the stronger the ability of histamine to increase capillary permeability, the higher the permeability of the capillary, and as a result, the stronger the ability of cancer cells to pass through the capillary. The more histamine there is, the easier cancer cell spread occurs. Cancer cell spread thus occurs more easily in situations in which more histamine is produced.

[0026] d) When human tissue cells are damaged, the tissue cells immediately produce a large amount of histamine. When a cancerous tumour tissue is surgically removed, the normal tissue cells are generally damaged first, and a large amount of histamine is immediately produced. If free cancer cells are present at this time, cancer cell spread will occur in this case.

[0027] e) Controlling the increase in capillary permeability by histamine prevents cancer cell spread.

[0028] Preventing cancer cell spread by reducing capillary wall permeability:

[0029] 1. Use of antihistamine drugs to reduce the increase in capillary permeability by histamine

[0030] a) In order to treat allergic diseases such as urticaria, skin rash and itching, antihistamine drugs have been developed which are effective in treating such diseases. The principle of treatment is that the antihistamine drugs block the interaction between histamine and the histamine receptors to reduce the interaction between histamine and the histamine receptors to treat the above-mentioned allergic diseases. At the same time, they also reduce the increase in capillary permeability by histamine.

[0031] b) The anti-histamine drugs that can be used to block the interaction between histamine and H1 receptor are as follows (three generations of such drugs have been developed):

[0032] The first generation drugs include diphenhydramine, promethazine (phenargan), chlorpheniramine (chlorphenamine), and cyproheptadine.

[0033] The second generation drugs include loratadine (claritin), cetirizine (Zyrtec), terfenadine (Seldane), astemizole, ebastine (Hispran), Mizolastine (Bekitab), and azelastine. Terfenadine and astemizole have been reduced in use due to their serious cardiac toxicity.

[0034] The third generation drugs include fexofenadine, desloratadine, levocetirizine, and the like.

[0035] The second generation drugs are currently used as the common drugs for treating allergic diseases. They can also be used as the alternative drugs for preventing the anti-histamine from increasing the permeability of capillary vessels, i.e., the alternative drugs for preventing the spread of cancer cells.

[0036] 2. Use of other drugs to reduce the permeability of capillary vessels, such as indole alkaloids

[0037] The results of animal studies on the effect of indole alkaloids on the permeability of skin blood vessels of sensitized guinea pigs show that indole alkaloids can quickly reduce the permeability of capillary vessels of sensitized rats.

[0038] Application of surgical resection of cancer tumors to inhibit the spread of cancer cells:

[0039] a) Selecting appropriate anti-histamine drugs from the alternative anti-histamine drugs or using other drugs or developing new drugs and determining their use methods. The anti-histamine drugs can be selected from the above-mentioned alternative anti-histamine drugs, or a combination of two or more of the above-mentioned anti-histamine drugs can be used.

[0040] b) Before the cancer tumor resection surgery, anti-histamine drugs are taken to make the human body have anti-histamine drugs, which can immediately interact with the histamine secreted during the cancer tumor resection surgery to prevent the histamine from increasing the permeability of capillary vessels and achieve the effect of preventing the spread of cancer cells. In order to achieve the effect of having a sufficient concentration of anti-histamine drugs in the human body before the cancer tumor resection surgery, long-acting anti-histamine drugs need to be taken several days before the surgery and on the day of the surgery, and the dosage of the anti-histamine drugs needs to be increased within the range of side effects of the anti-histamine drugs that the human body can tolerate to increase the effect of preventing the spread of cancer cells.

[0041] c) Before the cancer tumor resection surgery, other drugs that can reduce the permeability of capillary vessels can also be taken.

[0042] d) performing a cancer tumor resection surgery.

[0043] e) continuing to take the antihistamine drug and observing the cancer patient for cancer cell spread after the cancer tumor resection surgery new method of preventing cancer cell spread is approved for a period of time. DETAILED DESCRIPTION

[0044] The results of the animal study of the effect of the indole alkaloid on the vascular permeability of sensitized guinea pigs showed that the indole alkaloid can quickly reduce the capillary permeability of sensitized rats.

[0045] The process of the indole alkaloid animal test is as follows:

[0046] The body weight is in the range of 160-200g, and after adaptive feeding for one week, it is used for test. After the start of the test, it is randomly divided into the following five groups, 8 in each group, half male and half female, and given the corresponding excipient or drug. (1) Test A group: indole alkaloid 8mg / kg; (2) Test B group: indole alkaloid 24mg / kg; (3) positive control group: fexofenadine hydrochloride 20mg / kg; (4) normal control group: 2mL normal saline; (5) model control group: 2mL normal saline. Based on the body weight of guinea pigs, each group of animals is given intragastrically (excipient) once a day at 9:00 am, and after 2 days, the sensitized points of guinea pigs are selected, and after shaving, the normal control group is injected intradermally with 0.1mL of sterile normal saline, and the other groups of animals are injected intradermally with 0.1mL of prepared anti-OVA serum, and the animals in each group continue to be given medicine for 1 day. 24 hours after the last administration, antigen challenge is performed, i.e. 1mL of a mixture containing 10g / L OVA and 10g / L Evans blue dye is injected into the tail vein, the degree of blue staining of the skin on the back of each group of guinea pigs is observed, the diameter of the blue spot is measured after 30 minutes, and then the blue spot skin is quickly cut off and placed in a 71:4 volume ratio of acetone-normal saline mixed solution, cut into small pieces, soaked for 48 hours, centrifuged, and the supernatant was taken and the absorbance value was measured at a wavelength of 610nm using a spectrophotometer. The preparation method of the anti-OVA serum is as follows: healthy male Wistar guinea pigs are taken, 0.5mL of normal saline containing 10g / L OVA is injected into the muscles of both hind limbs, and 0.2mL of white B-P vaccine is injected into the abdominal cavity at the same time. 3 days later, it is reinforced once. The IgE production reaches the highest peak after 9 days of the first sensitization. The venous blood of the sensitized guinea pigs is taken, the serum is collected, filtered to remove bacteria, diluted with normal saline at a volume ratio of 1:10, and used.

[0047] The test results are as follows: According to the test statistical results in Table 1, the blue spot diameter and the dye content in the skin of the model control guinea pigs are significantly higher than those of the drug groups, and the difference is statistically significant (P<0.01), especially in the test B group of the high-dose indole alkaloid, the difference compared with the positive drug fexofenadine also has significance (P<0.05). This shows that the indole alkaloid can quickly reduce the capillary permeability of the sensitized rats, thereby blocking the release of histamine, leukotriene and other inflammatory mediators by mast cells to achieve the effect of treating allergic rhinitis.

[0048] Table 1: Sensitized guinea pig skin vascular permeability index

[0049]

[0050] Compared with the model control group, * P<0.01; compared with the positive control group, # P<0.05.

[0051] Test conclusion: indole alkaloid can quickly reduce the capillary permeability of sensitized rats

[0052] The present inventors found that by inhibiting the increase of capillary permeability, or reducing the permeability of capillary, the spread of cancer cells can be prevented, and the survival time of cancer patients can be increased, therefore, any method and drug that can prevent cancer cells from crossing blood vessels by interfering with capillary should be within the protection scope of the present application.

Claims

1. An antihistamine drug, characterized by inhibiting the increase in capillary permeability by using an antihistamine drug, preventing the spread of cancer cells.

2. The antihistamine drug according to claim 1, characterized by one or more of diphenhydramine, promethazine (Phenergan), chlorpheniramine (Chlor-Trimeton), cyproheptadine, loratadine (Claritin), cetirizine (Zyrtec), fexofenadine (Allegra), acrivastine, azelastine, astemizole, ebastine, mizolastine, desloratadine, levocetirizine.

3. A method of preventing the spread of cancer cells, characterized by inhibiting the increase in capillary permeability, preventing the passage of cancer cells through capillaries.

4. The method of claim 3, wherein by inhibiting the effect of histamine on the increase in capillary permeability.

5. The method of claim 4, wherein by using an antihistamine drug, inhibiting the effect of histamine on the increase in capillary permeability.

6. The method of claim 5, wherein the antihistamine drug includes one or more of diphenhydramine, promethazine (Phenergan), chlorpheniramine (Chlor-Trimeton), cyproheptadine, loratadine (Claritin), cetirizine (Zyrtec), fexofenadine (Allegra), acrivastine, azelastine, astemizole, ebastine, mizolastine, desloratadine, levocetirizine.

7. A medicament for preventing the spread of cancer cells, characterized by reducing the increase in capillary permeability.

8. The pharmaceutical preparation according to claim 7, characterized in that inhibiting the increase in capillary permeability by using an antihistamine drug, preventing the spread of cancer cells.

9. The pharmaceutical preparation according to claim 7, characterized in that the drug is an indole alkaloid.

Images