CN106943595A - Src/Abl inhibitor is used as the application for preventing or treating radiation injury medicine - Google Patents

Abstract

The invention discloses the application of Src/Abl inhibitors as medicines for preventing or treating radiation damage, aiming at the damage to skin, hair and mucous membrane caused by ionizing radiation in the process of tumor radiotherapy, and adopting anti-intracellular non-receptor tyrosine kinases Src and Abl A class of drugs that have an inhibitory effect on vitality for treatment and protection, including some drugs that have been used clinically, such as: imatinib, dasatinib, nilotinib, bosutinib, bosutinib , KX2‑391, etc., or some natural compound molecules with similar functions, such as quercetin, soybean isoflavones, etc., and their derivatives with the same function and combined use, and the drug administration methods of the technical solution of the present invention are various, Including oral, subcutaneous injection, intramuscular injection, intravenous injection, transdermal, intranasal or rectal administration, it can play a good protective and therapeutic role before receiving radiation, receiving radiation or receiving radiation damage.

Description

Application of Src/Abl Inhibitors as Drugs for Preventing or Treating Radiation Damage

technical field

The invention relates to the field of biomedicine, in particular to the application of a class of drug molecules capable of inhibiting the activity of intracellular non-receptor tyrosine kinase Src-Abl in the prevention or treatment of skin, hair or mucous membrane damage caused by radiation.

Background technique

Tumor radiotherapy is often accompanied by damage to normal tissues, including skin damage, mucosal damage, and hair damage, due to high-energy particles or rays (including high-energy electrons, protons, neutrons, gamma rays, X-rays, etc.) These injuries are more common in the treatment of head and neck tumors, breast cancer, lung cancer, colorectal cancer, etc., where the patient's skin, hair, and mucous membranes are damaged due to long-term exposure to large doses of radiation Shedding, causing acute damage such as redness and swelling, or chronic damage such as tissue fibrosis.

The current treatment methods for radiation damage include superoxide dismutase (SOD) and its adjusted form of antioxidant treatment (relevant technical solutions are disclosed in patent documents CN93111220, CN201510278883 and CN201410172664), using growth factors such as EGF and FGF The growth-promoting effect of triethanolamine, hydration of triethanolamine to relieve symptoms (Biafine), glucocorticoids for anti-inflammatory relief, etc.; there are also some natural products and their extracts are also used to relieve and protect radiation dermatitis, including the use of Glycyrrhizic acid and glycyrrhetinic acid (relevant technical solutions are disclosed in patent document CN201210042289); use borneol, talc, oyster and borax (relevant technical solutions are disclosed in patent document CN201410327405); (Patent document CN201410257420 discloses related technical solutions); use pine leaves, sodium alginate, rosehip oil, spirulina, raw Burnet, chrysanthemum, castor bean, wood turtle, angelica, myrrh, Wulingzhi (patent Document CN201510053368 discloses related technical solutions); using Codonopsis pilosula, Astragalus root, rose, Radix radix Radix, Ophiopogon japonicus, Schisandra chinensis, cicada slough, Cnidium chinensis, seabuckthorn, Sophora flavescens, Kochia chinensis, comfrey, rehmannia glutinosa, white fresh skin, Tribulus terrestris, Angelica dahurica, Polygonum multiflorum, Alisma, Poria, Radix Paeoniae Rubra, Cortex Moutan, Dandelion, Desmodium, Capillary, Fangfeng, Black Snake, Radix Paeoniae Alba, Imperata Rhizome, Polygonatum, Safflower and Zhilicorice (in patent document CN201510335667 There are related technical solutions disclosed); using white leaves, Tribulus terrestris, mandarin core, yellow eggplant flower, Eupatorium, Atractylodes macrocephala, Amomum and Eclipta chinensis (there are related technical solutions disclosed in patent document CN201510415877).

Contents of the invention

The object of the present invention is to provide the application of a class of drug molecules capable of inhibiting the activity of intracellular non-receptor tyrosine kinase Src-Abl in the prevention or treatment of skin, hair or mucous membrane damage caused by radiation.

Src and Abl are intracellular non-receptor tyrosine kinases, which play an important role in cell life activities. The inventors of the present invention found that Src and Abl kinase activities play an important role in tissue damage caused by ionizing radiation. Play a key role, by inhibiting their activity, it can effectively protect normal tissue from radiation damage.

At present, some inhibitor molecules targeting Src and Abl kinase activity have been discovered and synthesized, some of which have been clinically used in tumor targeting therapy, and some similar compounds have been or are undergoing clinical trials, such as: imatinib Imatinib, Dasatinib, Nilotinib, Bosutinib, KX2-391, etc.

In addition, there is a class of molecules with similar functions of inhibiting Src and Abl kinase activity from the isolation and purification of natural compounds and their improved molecules, such as: Quercetin, soybean isoflavones (Genistein) and their derivatives with the same function , can also effectively inhibit the activity of Src and Abl kinases, in addition, it can also be used according to the combination of drugs to provide another method for effectively inhibiting the activities of Src and Abl kinases.

Based on the research of the inventors of the present application, the present invention provides the following technical solutions:

The technical scheme of the present invention is: the application of Src/Abl inhibitor as a drug for preventing or treating radiation damage.

Further, the radiation mentioned is radiation during X-ray diagnosis, radiotherapy radiation in cancer treatment links, CAT scanning radiation, radionuclide scanning radiation, radiation of interventional radiotherapy under the guidance of CT or fluorescence microscope, intake pollution Radiation from incorporation of tissues with radionuclides from food or water, exposure to radiation in the vicinity of uncontrolled nuclear weapons, radiation from leakage of radioactive material, or ionizing radiation from cosmic radiation.

Further, the radiation damage includes skin radiation damage, radiation-induced hair loss, or oral cavity and digestive tract mucosal damage caused by radiation.

Further, the Src/Abl inhibitor is imatinib, dasatinib, nilotinib, bosutinib, KX2-391, quercetin or soybean isoflavones.

Further, the administration method of the drug is oral administration, subcutaneous injection, intramuscular injection, intravenous injection, transdermal administration, intranasal administration or rectal administration.

Further, the dosage form of the medicine is capsule, tablet, inhalant, buccal tablet, spray, medicine drink or food and medicine additive.

Further, the administration time of the drug is before receiving radiation, while receiving radiation or after receiving radiation.

Using the above-mentioned technical scheme, the inventors of the present application have found through a large number of experiments that the above-mentioned medicines not only have a protective effect on the skin, hair and mucous membranes of the test sample before and when the test sample is irradiated, but also have a protective effect after receiving the radiation. When the skin, hair and mucous membrane are damaged, the drug of the present invention can also have a good auxiliary repairing effect, and the drug administration method of the technical solution of the present invention is various, not limited to oral or subcutaneous injection. , the use of intramuscular injection, intravenous injection, transdermal administration and other methods can achieve certain effects, so that patients can use it simply and conveniently and achieve a good recovery effect. Adjustment or combination under the guidance to achieve the purpose of radiation protection or treatment should also be within the essence of the technical solution of the invention.

detailed description

The technical solution of the present invention will be further elaborated below in conjunction with specific embodiments for the technical solution of the present invention:

Application of Src/Abl inhibitor as medicine for preventing or treating radiation damage.

Further, the radiation mentioned is radiation during X-ray diagnosis, radiotherapy radiation in cancer treatment links, CAT scanning radiation, radionuclide scanning radiation, radiation of interventional radiotherapy under the guidance of CT or fluorescence microscope, intake pollution Radiation from incorporation of tissues with radionuclides from food or water, exposure to radiation in the vicinity of uncontrolled nuclear weapons, radiation from leakage of radioactive material, or ionizing radiation from cosmic radiation.

Further, the radiation damage includes skin radiation damage, radiation-induced hair loss, or oral cavity and digestive tract mucosal damage caused by radiation.

Further, the Src/Abl inhibitor is imatinib, dasatinib, nilotinib, bosutinib, KX2-391, quercetin or soybean isoflavones.

Further, the administration method of the drug is oral administration, subcutaneous injection, intramuscular injection, intravenous injection, transdermal administration, intranasal administration or rectal administration.

Further, the dosage form of the medicine is capsule, tablet, inhalant, buccal tablet, spray, medicine drink or food and medicine additive.

Further, the administration time of the drug is before receiving radiation, while receiving radiation or after receiving radiation.

Embodiment one

(1) 20 2-month-old healthy male mice of the C57BL/6 strain were divided into groups, including 10 in the experimental group and 10 in the control group;

(2) The mice in the experimental group and the control group were irradiated with a single dose of 40Gy on the skin of the feet at the same site. The dose of mg/kg was subcutaneously injected with Dasatinib once, and the mice in the control group were subcutaneously injected with PBS phosphate buffer solution with a pH of 7.4 according to the subcutaneous injection time of the mice in the experimental group, and then the mice in the experimental group and the control group were injected respectively Group mice were placed in the same culture environment for culture observation;

(3) After 20 days of continuous observation, it was found that the skin of the feet of the mice in the control group had obvious peeling, swelling and ulceration in varying degrees, while the skin of the feet of the mice in the experimental group received radiation was in relatively good condition. 50% of the mice suffered from the first-grade injury, which manifested as dry peeling of the skin on the feet, and the other 50% suffered from the second-grade injury, which manifested as swelling and wet peeling; 30% of the mice in the experimental group had no obvious damage to the skin of the feet. Fifty percent of the lesions were primary lesions with dry desquamation and only 20% were secondary lesions with swelling and wet desquamation.

Embodiment two

(1) 20 2-month-old healthy male mice of the C57BL/6 strain were divided into groups, including 10 in the experimental group and 10 in the control group;

(2) The mice in the experimental group and the control group were irradiated with a single dose of 40Gy on the foot skin at the same site. The mice in the experimental group received 4 mg of radiation on the day of radiation and two consecutive days after radiation. Subcutaneous injection of soy isoflavones at a dosage of 100 mg/kg, the mice in the control group were subcutaneously injected with PBS phosphate buffer solution with a pH of 7.4 according to the subcutaneous injection time of the mice in the experimental group, and then the mice in the experimental group and the control group were injected with PBS phosphate buffer solution respectively. Rats were placed in the same culture environment for culture observation;

(3) After 20 days of continuous observation, it was found that the skin of the feet of the mice in the control group had obvious peeling, swelling and ulceration in varying degrees, while the skin of the feet of the mice in the experimental group received radiation was in relatively good condition. 50% of the mice suffered from the first-grade injury, which manifested as dry peeling of the skin on the feet, and the other 50% suffered from the second-grade injury, which manifested as swelling and wet peeling; 30% of the mice in the experimental group had no obvious damage to the skin of the feet. 30% were primary lesions with dry desquamation and 40% were secondary lesions with swelling and wet desquamation.

Embodiment three

(1) 20 2-month-old healthy male mice of the C57BL/6 strain were divided into groups, including 10 in the experimental group and 10 in the control group;

(2) The mice in the experimental group and the control group were irradiated with a single dose of 40Gy on the foot skin at the same site. The mice in the experimental group received 1 mg of radiation on the day of radiation and two consecutive days after radiation Quercetin was added to drinking water for dissolving and then taken orally at the dose of 1 kg/kg. The mice in the control group took the same amount of drinking water as the mice in the experimental group at the corresponding oral time of the mice in the experimental group, and then the mice in the experimental group and the mice in the experimental group were given The mice in the control group were placed in the same culture environment for culture observation;

(3) After continuous observation for 20 days, it was found that the skin of the feet of the mice in the control group had obvious peeling, swelling and ulceration in different degrees, while the skin of the feet of some mice in the experimental group received radiation did not appear obvious peeling. Oral administration of quercetin can also play a certain role in radiation prevention and treatment.

Embodiment Four

(1) 10 2-month-old healthy male rats of the Sprague Dawley strain were divided into groups, including 5 in the experimental group and 5 in the control group;

(2) The rats in the experimental group and the control group were irradiated with a single dose of 10Gy on the oral skin at the same site, among which, the rats in the experimental group received a dose of 5uM on the day of radiation and two consecutive days after radiation. The dasatinib aqueous solution was used for oral spraying, and the rats in the control group were sprayed with drinking water according to the oral spraying time of the experimental group, and then the experimental group and the control group were placed in the same culture environment for culture observation;

(3) After continuous observation for 20 days, it was found that the oral cavity of the rats in the control group had redness, swelling and ulceration in varying degrees, while the oral skin of the rats in the experimental group received radiation did not appear obvious redness, swelling and ulceration. It can be seen that Dasatinib Spray application as a spray can also play a certain role in radiation prevention and treatment.

Based on the foregoing examples and the existing application of dasatinib, quercetin, and soybean isoflavones, dasatinib, quercetin, and soybean isoflavones can generally be used as Src/Abl inhibitors, while Src and Abl is a non-receptor tyrosine kinase in cells, which plays an important role in cell life activities. The inventors of the present invention found in the course of research that Src and Abl kinase activities play a role in tissue damage caused by ionizing radiation. The key role, by inhibiting their activity, can effectively protect normal tissue from radiation damage.

Therefore based on the teachings of the above-mentioned embodiments, it can also be extended to imatinib, nilotinib, bosutinib, KX2-391, etc., which are also Src/Abl inhibitors, and should also have the effect of preventing and treating radiation damage drugs. ability, and its mode of administration is not limited to oral, subcutaneous injection and spray forms, intramuscular injection, intravenous injection, transdermal administration, intranasal administration or rectal administration should also be able to achieve a certain effect, while the drug The dosage forms are not limited to sprays and solutions, and capsules, tablets, inhalants, buccal tablets, sprays, medicinal beverages or food and drug additives should also be used as pharmaceutical dosage forms for the prevention and treatment of radiation. The timing of the medicine should not be limited to before receiving radiation, while receiving radiation and after receiving radiation, it should also have a certain curative effect. Side effects are the premise.

The foregoing is only an illustration of the present invention. For those skilled in the art, according to the teaching of the present invention, without departing from the principle and spirit of the present invention, all equivalent changes made according to the patent scope of the present invention, Modifications, replacements and variations all shall fall within the scope of the present invention.

Claims (7)

1.Src/Abl inhibitor is used as the application for preventing or treating radiation injury medicine.

2. application according to claim 1, it is characterised in that：Radiation, cancer when described radiation is radiodiagnosis are controlled Treat under radiotherapy radiation, cat scan radiation, radionuclide scanning radiation, CT or the fluorescence microscope guiding in link Tissue incorporation the radiating of radionuclide, exposure caused by the radiation of interventional radiological treatment, the food of intake pollution or water The ionising radiation of radiation, the radiation of radioactive substance leakage or cosmic radiation on the nuclear weapon periphery for not adding control.

3. application according to claim 1, it is characterised in that：Described radiation injury includes radiation injury of skin, radiation Oral cavity, alimentary canal mucous membrane damage caused by the alopecia or radiation of induction.

4. application according to claim 1, it is characterised in that：Described Src/Abl inhibitor is Imatinib, replaced up to sand Buddhist nun, AMN107, Bosutinib, KX2-391, Quercetin or isoflavones.

5. application according to claim 1, it is characterised in that：The administering mode of the medicine is oral, hypodermic injection, flesh Meat injection, intravenous injection, cutaneous penetration, intranasal administration or rectally.

6. application according to claim 1, it is characterised in that：The formulation of the medicine is capsule, tablet, inhalant, contained Piece, spray, medicine beverage or food medicated premix.

7. application according to claim 1, it is characterised in that：The administration time of the medicine is to receive before radiation, When receiving to radiate or after receiving radiation.