CN1326785A - Anti-cancer medicine composition - Google Patents
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- CN1326785A CN1326785A CN 00111126 CN00111126A CN1326785A CN 1326785 A CN1326785 A CN 1326785A CN 00111126 CN00111126 CN 00111126 CN 00111126 A CN00111126 A CN 00111126A CN 1326785 A CN1326785 A CN 1326785A
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Abstract
The anti-cancer medicine composite includes mainly nitric oxide synthease inhibitor, oxygen radical product and/or radical synergist. The nitric oxide synthase inhibitor is used mainly to destroy blood vessel and blood supply of tumor, the oxygen radical product can kill tumor cell alone and react with nitric oxide to produce product with ever stronger toxicity, and the radical synergist includes acidifier, antioxidant inhibitor, valence varying metal(salt), etc. The anti-cancer medicine composite can kill effectively tumor cell while strengthening the destroying effect to tumor blood vessel and the sensitivity of tumor cell to other therapy, such as radiotherapy and chemotherapy.
Description
The present invention relates to an anticancer medicine composition formed from nitrogen oxide synthetase inhibitor, free radical product and/or free radical synergist and its application method for curing tumor.
Many non-surgical therapies exert anti-tumor effects through the generation of free radicals, which are not only associated with complications of radiotherapy and chemotherapy, but are also the material basis for many non-surgical therapies to kill tumor cells. Because of this, the slow release of local free radical production from tumors has been used as a new approach for tumor treatment. However, the growth and spread of tumors and their sensitivity to drugs are determined by their parenchyma, tumor cells and their stroma, tumor blood vessels. The tumor blood vessel not only provides a bracket for the growth of tumor cells, but also provides essential nutrient substances for the growth of the tumor cells. Therefore, effective inhibition and destruction of blood vessel growth is a key factor affecting various therapeutic effects. The nitric oxide synthase inhibitor composition is used for inhibiting and destroying the growth of tumor blood vessels, and no public report is found at present.
The present invention aims at providing one kind of anticancer medicine composition with nitric oxide synthetase inhibitor, free radical product and/or free radical synergist as main effective components.
It is another object of the present invention to provide a method for treating tumors using the above combination. Mainly enhances the effect of non-operative therapies such as tumor radiotherapy, chemotherapy and the like through a nitric oxide synthase inhibitor and a free radical product. The main factors determining the treatment effect are the local drug concentration of the tumor and the sensitivity of tumor cells to the drug. Intravenous, intraperitoneal and arterial administration and even intratumoral injection are difficult to maintain effective drug concentration in tumor parts for a long time. Simply increasing the dosage is limited by systemic reactions. Therefore, the search for effective administration routes and potentiators is one of the important objects of the present invention.
The invention discovers that the nitric oxide synthase inhibitor and the free radical product both have the function of treating tumors, the nitric oxide synthase inhibitor inhibits the growth of the tumors by reducing and destroying the protection and regulation function of nitric oxide on tumor blood vessels, and oxygen free radicals provided by the free radical product can not only kill tumor cells, but also react with the nitric oxide in the tumor blood vessels to form free radicals with stronger toxicity. Therefore, the combination of the two can not only effectively kill tumor cells, but also effectively destroy tumor blood vessels, thereby providing a new effective measure for treating tumors.
The nitric oxide synthase inhibitor and the free radical product can inhibit the growth of tumors when being injected into the bodies of the animals with the tumors, but the whole body toxicity reaction is also obvious. If the substances are selectively injected into arteries or directly injected into local parts of tumors, particularly the high molecular polymer is taken as a support to be locally released, the tumor treatment effect is improved, and the systemic toxic reaction is obviously reduced.
In view of the above-mentioned findings, the present invention packages nitric oxide synthase inhibitors, radical generators and/or radical synergists, etc. in a polymer, and the sustained-release agent thus prepared is advantageous for topical application. After being placed in a tumor body, the main components of the anticancer composition can be slowly released to the local tumor, so that systemic complications (such as heart and lung injury) are reduced, the local nitric oxide level of the tumor is selectively eliminated, the action effect of free radical products is further enhanced, and a more effective method is provided for radically treating various primary and metastatic solid tumors of human bodies and animals, and the anticancer composition has very high clinical application value and remarkable economic and social benefits. The anticancer composition can enhance the effects of conventional chemotherapy, immunotherapy, hyperthermia, phototherapy, hormone therapy, radiotherapy and the like. Therefore, the slow release of the traditional Chinese medicine composition can be combined with the non-operative treatment at the same time of local slow release, so that the anti-cancer effect of the traditional Chinese medicine composition is further enhanced.
The anticancer medicine composition of the present invention contains mainly effective anticancer amount of nitric oxide synthase inhibitor and oxygen radical product or/and free radical synergist.
Wherein the weight portion of each component is 0.1 to 99.9, preferably 1 to 80, and most preferably 5 to 40.
The anticancer medicine composition of the present invention may be prepared into various preparation forms. Such as injection, suspension, ointment, and solid such as capsule; in various shapes such as granular, flake, spherical, block and film; the slow release is mainly used in various dosage forms. The use of a support for packaging the above-mentioned main ingredients for topical application is the most important form of the invention. The support used in the anti-composition of the present invention may be any material, preferably a polymer or a composite polymer composed of different polymers, more preferably a composite polymer composed of different high molecular weight lactic acid. Supports may also be used with fluids such as, but not limited to, sesame oil, suspensions, distilled water, physiological solutions, and semi-solid substances such as, but not limited to, jellies, pastes, ointments, and the like.
The anticancer pharmaceutical composition can be administered by various routes, preferably topical administration, such as selective arterial injection and direct intratumoral injection, wherein local slow release is most preferred. The anticancer medicine composition may be also released slowly locally for selective arterial injection, and the effective components released locally can kill primary tumor and the anticancer components taken via artery or other way to kill dispersed or diffused tumor cell.
The organic solvent in the present invention may be, but is not limited to, dichloromethane and dimethylformamide.
Nitric oxide synthase inhibitors useful in the present invention include nitric oxide scavengers and nitric oxide synthesis inhibitors. The former includes hemoglobin and its related products; the latter include 7-amino-indazole, canavanine, aminoguanidine, cycloheximide, S-methylisothiourea sulfate, S-2-amino-5- (2-aminoimidazol-1-yl) pentanoic acid, L-N5- (1-iminoethyl) ornithine, N-monomethyl-L-arginine acetic acid, N-amino-arginine methyl ester, N-omega-amino-arginine, NG-amino-L-arginine, L-amino-arginine-p-aminoacanilide, NG-monomethyl-L-arginine and NG-methyl-L-arginine.
The free radical generating substances which can be used in the present invention are:
the first, chemotherapy drugs are commonly used in clinic, such as:
1. platinum compounds, such as: cisplatin, carboplatin and other platinum compounds and their congeners and derivatives.
2. Alkylating agents, such as: oncoclonine, nitrogen mustard, melphalan, ornithromycin, cyclophosphamide and its derivatives such as 4-peroxy-cyclophosphamide, BCNU.
3. Antibiotics, such as: adriamycin, bleomycin, 4-demethoxydaunorubicin, daunorubicin, mitomycin C, actinomycin D, anthranilic acid, tetracycline.
4. Plants, such as: cyclophosphamide and its derivatives such as 4-peroxycyclophosphamide, carcinostatin, daunorubicin, doxycycline, thiotepa and cedar bark extract (taxine).
5. Antimetabolites, such as: 5-fluorouracil, folic acid, amifosthia, 6-mercaptopurine sand fly, 8-aza-guanine sand fly, leukemia, uracil, cytarabine, thiazopyridine sand fly, azaserine, cytosine arabinoside.
6. Others, such as: procarbazine hydrochloride, vincristine and other anthracenyl complexes.
And, quinone complexes, such as (but not limited to): ubiquinone, emodin and other anthraquinone derivatives, benzoquinones and mixtures thereofDerivatives such as anilinomethylaminobenzoquinone, vitamin K3And cistanche naphthoquinone, phenazine methosulfate, triphenol and biosynthetic aminolevulinic acid.
And III, vanadium compounds, such as: vanadate, orthovanadate, and phenanthroline vanadium complex.
And fourthly, the peroxidation reaction products of free radicals and lipid, such as acrolein, α -saturated aldehyde and β -unsaturated aldehyde.
And unsaturated fatty acids such as stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, α -linolenic acid and gamma-linolenic acid.
Sixthly, protein synthesis inhibitors, such as: cycloheximide, emetine, anisomycin and phleomycin.
Hepta, pyridine compounds, such as paraquat.
Eight, electronic carriers, such as, but not limited to, electronic carriers useful in the present invention include (but are not limited to): coenzyme I (reduced form), coenzyme II (reduced form), Dithiothreitol (DTT), 2-mercaptoethanol (2-ME), citric acid, vitamin K3Vitamin C, cysteine hydrochloride, sodium thioglycollate, sodium sulfide, Phenazine Methosulfate (PMS) and ferrous chloride.
Free radical generating species useful in the present invention further include biological oxidation reaction systems such as: amino acid-amino acid oxidase, (chrysopa)/chrysopa oxidase (or) chrysopa dehydrogenase, glucose/glucose oxidase, vitamin C/iron redox couple, hypochlorous acid/myeloperoxidase, flavin oxidoreductase, coenzyme i (ii) oxidoreductase, quinone oxidoreductase, and the like. Any one of the components of the redox couple has no biological toxicity when being singly present, and a series of substance oxygen reactions are triggered only after the components are contacted with each other, so that the generation of reaction oxygen is caused. Therefore, another form of the present invention is to package the active ingredients of the above redox couple individually, for example, chrysopa/chrysopa oxidase, to facilitate local generation of toxic free radicals in the tumor when chrysopa (or) chrysopa oxidase in blood meets chrysopa oxidase (or) locally released from the tumor, thereby selectively killing the tumor. Based on a reaction system capable of generating toxic free radicals, various solid tumors can be selectively attacked. Local therapeutic response can also be more effectively controlled by varying the systemic dose, thus reducing unnecessary damage to normal tissues while treating tumors. The free radical products can be selected singly or in multiple ways, and the effect of the multiple ways is better than that of the single ways. The enzyme in the biological oxidation reaction system, such as glucose oxidase, can also transfect tumor cells by a genetic engineering technology, so as to selectively treat tumors from a gene level.
Many of the non-surgical therapies commonly used in clinical applications, such as radiotherapy, immunotherapy, electrotherapy, chemotherapy, phototherapy and thermotherapy, exert an anti-tumor effect by free radicals, mainly Reactive Oxygen Species (ROS), in which superoxide anion radical (O) is the main radical2-) hydrogen peroxide (H)2O2) And Hydroxyl (HO) are the most important. Because the electrons on the outer layer of the free radical are not paired, the free radical is easy to react with biological structures in cells such as proteins, lipids, nucleic acids and the like, so that the structure and the function of the cells are damaged, and finally the cells die. Therefore, the radical generating substance is one of the main components of the present invention.
The research shows that the activity of antioxidants such as superoxide dismutase (SOD) and catalase is increased in tumor cells, and superoxide anion radical (O) can be generated by the antioxidants such as superoxide dismutase (SOD) and catalase-) And hydrogen peroxide (H)2O2) Detoxify, and convert to non-toxic end products water and carbon dioxide (equations 1 and 2).
Tumor cells are therefore often resistant or rendered congenital insensitive to such non-surgical therapies. Antioxidant inhibitors, such as: aminotriazoles (catalase inhibitors), DDC (superoxide dismutase inhibitors), and the like can break the protective effect of antioxidants. Therefore, as a free radical synergist, an antioxidant inhibitor constitutes one of the most important ingredients of the present invention.
Thus, in another form of the invention, the nitric oxide synthase inhibitor and/or the free radical generator are/is replaced by an antioxidant inhibitor, or an antioxidant inhibitor is added to the complex of nitric oxide synthase inhibitor and free radical generator.
Antioxidant inhibitors useful in the present invention are (but not limited to): catalase inhibitors such as aminotriazole, etc.; superoxide dismutase inhibitors such as diethyldithiocarbamate, and the like; inhibitors of enzymes involved in glutathione synthesis, such as: (1) glutathione reductase inhibitors, such as: ammonium metavanadate, ethylene glycol maleate, cadmium ions, trivalent organic arsenic, glutathione disulfide, tetramethylthiuram disulfide, nitrogen mustard medicaments and the like; (2) glutathione peroxidase inhibitors, such as: butylthionine sulfoximine, [ BSO for short], and the like; (3) glutathione transferase inhibitors, such as: diuretic acid (EA), curcumin, puffball acid, etc., (4) glutathione analogs such as S-hexyl glutathione, etc. An alkyltransferase inhibitor. In addition, a phosphoglycoprotein (P-GP) inhibitor, an adenosine triphosphate (adenosine triphosphate) inhibitor, and the like; nitric oxide synthase inhibitors, uric acid and certain Protein Kinase (PKC) inhibitors, vitamin C inhibitors, vitamin E inhibitors, and the like. In addition, the production of a large amount of free radicals can also reduce the activity of antioxidants, and therefore, the free radical products themselves are also antioxidant inhibitors. The antioxidant inhibitor can be selected singly or in multiple ways, the DDC, the aminotriazole and the BSO have better effect when being selected singly, and the aminotriazole has better effect when being selected in multiple ways, wherein the effect of combining radiotherapy with the aminotriazole is the best.
Among the various Reactive Oxygens (ROS), the hydroxyl radical (HO)-) Most active, one of the most cytotoxic free radicals. Generally, the hydroxyl group (HO) in tumor cells is caused by the action of antioxidants such as superoxide dismutase and catalase-) Is not much generated. When combined with a lower valence metal, e.g. Cu+And Fe++When the reaction is carried out, the superoxide anion radical and hydrogen peroxide can be converted into more toxic Hydroxyl (HO) by Fenton reaction or the like-) (reaction formulas 3 and 4).
Thus, in another form of the invention, the nitric oxide synthase inhibitor and/or the free radical generator described above are substituted with an acidifying agent and/or a valence-altering metal (salt), or the acidifying agent and/or the valence-altering metal (salt) are added to the complex of nitric oxide synthase inhibitor and free radical generator described above.
Acidifying agents useful in the present invention include various substances that inhibit the intracellular pH regulating mechanism and various substances that are capable of directly or indirectly lowering the intracellular and extracellular pH. The former includes: mitochondrial respiratory chain inhibitors such as m-iodophenylguanidine and the like; carbonate/chloride ion exchange inhibitors such as acetazolamide, 4, 4-diisothiocyanatourethane cyanostilbene-2, 2' -disulfonic acid and analogs thereof such as R (+) - [5, 6-dichoro-2, 3,9,9a-tetrahydro-3-oxo-9 a-propyl-1H-fluoro-7-yl]oxy]acetic acid [ B-3(+)]and the like; hydrogen/sodium ion exchange inhibitors such as 3, 5-diamino-6-chloro-N-diaminomethylenebisazinecarboxamide and analogs thereof such as DMA [5- (N, N-dimethyl) amide], HMA [3-amino-6-chloro-5- (1-hoperidyl) -N- (diamidomethyl) pyridocarboxamide], EIBA [5- (N-methyl-N-isobutryl) amide], and EIPA [5- (N-ethyl-N-isopropyl) amide], and the like; energy synthase-dependent hydrogen ion and lactate pump inhibitors and the like. The latter includes: hydrogen/potassium ion exchange promoters such as nigericin and carboxanilium-3-chlorophenylhydrazone; reducing the extracellular sodium ion concentration; other substances capable of indirectly reducing intracellular and extracellular pH, such as lactate, glucose, and vasoactive drugs such as angiotensin, nitric oxide synthase inhibitor and oxygen free radical generator. Theabove acidifying agents can be selected singly or in multiple ways.
The variable valence metal (salt) used in the present invention is various metal ions and their complexes, among which salts containing copper and iron such as copper sulfate, ferrous sulfate and copper chloride are the most effective.
The existence of hydroxyl can further reduce the pH value of cells, and the low pH value is favorable for the generation of hydroxyl and the inhibition of the regulating function of tumor cells, thereby strengthening the anti-tumor effect of the cells. Therefore, other hydroxyl group-forming substances and hydroxyl group scavenger inhibitors also constitute one of the main components of the present invention.
In addition, the free radical generation enhancer usable in the present invention includes N-acetylcysteine, cytochrome, synonym morpholino hydrochloride, nitric oxide, nitrosoacetyl-clobetanine and the like.
In addition, other medicinal components such as, but not limited to, antibiotics, analgesic, anticoagulant or hemostatic, anti-inflammatory, hormone and related herbal extracts can be added into the anticancer pharmaceutical composition.
The anticancer drug composition of the invention takes free radical products as a main attacking system, because the free radicals are a common mechanism for treating tumors by various non-operative therapies. This discovery provides new theoretical guidance for cancer therapy, particularly the development of new drugs.
The main component of the anticancer compound of the present invention uses a biocompatible material as a support, so that foreign body reaction is not caused. The support can be degraded after being placed in the body, so that the support can not be taken out again after operation. The local drug concentration is selectively increased and prolonged due to the local release of the contained drug in the tumor, and the systemic toxicity reaction caused by the conventional route of administration can be reduced. The released acidifying agent and antioxidant inhibitor can block or destroy the protective regulation mechanism of tumor cell, and can also strengthen the cell toxic reaction of chemotherapeutic medicine, especially free radical product, and the sensitivity of tumor cell to other treatment, so as to strengthen the effect and selectivity.
As mentioned above, the anticancer compound of the invention can be made into various dosage forms, such as injection, turbid suspension, ointment and solid, such as capsule, etc.; the method and procedure for packaging the main components in a topical slow release-based application form is not essential to the present invention, but any substance that enhances free radical toxicity, including the choice of an acidic support, is within the scope of the present invention.
The preparation method of the invention is characterized in that the macromolecule polymer is used as a support and nitric oxide synthase inhibitor, oxygen free radical product or antioxidant inhibitor are dissolved in organic solvent, and then the mixture is fully mixed, pumped and dried. Drying, shaping, sterilizing and packaging. The polymer can be made into various shapes, and the content of various components in the polymer is determined according to different requirements according to the prior art in the same field. Can be 0.1-99.9%, preferably 1-80%, and most preferably 5-40%.
The anticancer pharmaceutical composition can be made into various dosage forms, such as injection, turbid suspension, ointment, and solid such as capsule; in various shapes such as particle-like, flake-like, spherical, block-like and membrane-like; can be administered by various routes, preferably arterial route, and is most preferably directlyplaced in tumor body. The best product of the invention is a solid product which is biologically soluble and can be degraded and absorbed, and can be made into various shapes according to different clinical requirements.
The method for processing the anticancer medicine composition into finished medicine comprises the following steps:
dissolving the weighed solid polymer serving as a support with nitric oxide synthase inhibitor, oxygen free radical product and/or free radical synergist, mixing uniformly, drying, forming, subpackaging and sterilizing to obtain the finished medicine. The method comprises the following specific steps:
1. putting the weighed solid polymer support into a container, adding a certain amount of organic solvent for uniform dissolution, wherein the weight ratio of the solid polymer support to the organic solvent is based on full dissolution.
2. Adding the weighed pharmaceutical composition and shaking up again. The ratio of the pharmaceutical composition to the polymer is determined according to the dosage form and the state of the art.
3. Vacuum drying the drug-containing polymer to remove the organic solvent. Low temperature drying can also be used to remove organic solvent.
4. The dried solid polymer was immediately formed. Can be made into various shapes according to different requirements.
5. Sterilizing with radiation after packaging, and the radiation dosage varies with volume. Other methods may also be used to strain the bacteria. The polymer product produced by this process is a solid, yellow or silvery white in color, depending on the concentration of the drug to be packaged and the type of drug.
The present invention will be furtherdescribed with reference to the following examples, but is not limited thereto.
Example 1: lactic acid 100 mg with molecular weight of 50000
Methylene chloride 100 ml
Nitric oxide synthase inhibitor 40 mg
20 mg of medicine for curing tumor
The drug-containing polymer is prepared according to the above process.
Example 2: lactic acid 50 mg having molecular weight of 20000
Lactic acid 50 mg with molecular weight of 80000
Dimethylformamide 200 ml
Diethyldithiocarbamate 5 mg
Cisplatin 20 mg
30 mg of aminotriazole
5 mg of m-iodophenylguanidine
The drug-containing polymer is prepared according to the above process.
Example 3: lactic acid 50 mg having molecular weight of 20000
Lactic acid 40 mg with molecular weight of 80000
Dimethylformamide 100 ml
Diethyldithiocarbamate 5 mg
40 mg of medicine for curing tumor
The drug-containing polymer is prepared according to the above process.
Example 4: lactic acid 50 mg having molecular weight of 20000
Lactic acid 40 mg with molecular weight of 80000
Dimethylformamide 100 ml
Diethyldithiocarbamate 5 mg
40 mg of medicine for curing tumor
Nitric oxide synthase inhibitor 40 mg
The drug-containing polymer is prepared according to the above process.
Example 5: lactic acid 50 mg with molecular weight of 80000
Dimethylformamide 200 ml
Diethyldithiocarbamate 5 mg
Cisplatin 20 mg
Nitric oxide synthase inhibitor 20 mg
30 mg of aminotriazole
5 mg of m-iodophenylguanidine
Ferrous sulfate 1 mg
The drug-containing polymer is prepared according to the above process.
The drug-containing polymer is placed on the local part of the tumor, so that the treatment effect on the brain tumor is greatly improved, the systemic toxicity is reduced, and in addition, the anti-tumor effect is obviously enhanced when different components are combined compared with the single use.
As described above, the drug-containing support is biocompatible and does not cause a foreign body reaction. Can be degraded and absorbed after being placed in the body, so the surgical operation is not needed to be taken out again. The encapsulated drug is slowly released during degradation and absorption, thereby selectively increasing and prolonging the local drug concentration of the tumor. Local placement not only improves therapeutic efficacy, but also reduces systemic toxic effects caused by conventional routes of administration. Besides local placement, the drug can be administered in various forms and by various routes. In addition to being used alone, it can also be used in combination with a number of therapeutic measures. For example:
(1) can be used for treating various solid tumors of human and animals
The local placement and application of the anti-cancer composition after the operation has unique effect on radically curing the tumor. Some tumors growing in key parts of human body (such as brainstem and the like) can not be removed by operation, and local medicine is slowly released to replace the excision of the operation. In some malignant tumors, the operation may promote the tumor spread, and the slow release of local drugs may be a more scientific choice.
(2) Use in combination with hyperthermia treatment:
hyperthermia can lower the pH of the tumor, while the presence of an acidifying agent can enhance the sensitivity of tumor cells to hyperthermia treatment. As a hyperthermic sensitizer, many drugs have been shown to have an acidifying effect on tumors. The acidifier can not only enhance the inhibition effect of tumor growth caused by high fever, but also inhibit the occurrence of tumor heat tolerance phenomenon of human body, and the latter is a main factor for limiting high fever treatment. In addition, low pH can enhance the production of toxic free radicals, which can further lower the pH.
(3) Use in combination with radiotherapy:
survival of tumor cells depends on the regulatory mechanisms of the underground cells themselves. Inhibiting or blocking this regulatory mechanism reduces the tumor cell's ability to tolerate radiation therapy. The pH value of the tumor affects the effect of thermal radiation therapy. The heat radiation therapy kills the tumor by generating free radicals, and if the acidifying agent, the antioxidant inhibitor and the like are locally and slowly released, the effect of the radiation therapy can be enhanced and is more selective.
(4) Use in combination with immunotherapy:
many immune cells exert their anti-tumor effects through the production of free radicals, and the weak acid environment not only induces movement in the extracellular matrix of lymphocytes, but also promotes the release of drugs conjugated to monoclonal antibodies. The cytotoxic action of many cytotoxic factors, such as tumor necrosis factor, is also affected by the pH of the environment and is enhanced in acidic conditions. If the substances such as the acidifier and the antioxidant inhibitor are locally and slowly released, the effect of the immunotherapy is enhanced and more selective.
(5) Use in combination with other therapies: as synergist, the anticancer compound of the present invention may be used in combination with the said therapy and has also the main components of phototherapy, electrotherapy, hormone therapy, chemotherapy, gene therapy, etc. and thus has unique advantages and high clinical application value.
Claims (10)
1. An anticancer pharmaceutical composition is characterized by mainly comprising an anticancer effective amount of nitric oxide synthase inhibitor and oxygen radical generator, or/and free radical synergist.
2. The anticancer pharmaceutical composition of claim 1, wherein the oxygen radical generator comprises: (1) chemotherapy drugs are commonly used in clinic, such as: platinum-based complexes and analogues and derivatives thereof; alkylating agents, such as: oncoclonine, melphalan, cyclophosphamide and its derivatives such as 4-peroxycyclophosphamide and BCNU; antibiotics, such as: adriamycin, bleomycin, 4-demethoxydaunorubicin, daunorubicin, mitomycin C, actinomycin D, kanamycin, anthranomycin and tetracycline; plants, such as: neocarzines, daunorubicin, doxycycline, thiotepa, and taxines; antimetabolites, such as: 5-fluorouracil, folic acid, methotrexate butterfly sand fly, 6-sulfhydryl butterfly sand fly8-azaguanine, leucinolone, uracil, cytarabine, others such as procarbazine hydrochloride, vincristine and other anthracenyl complexes, (2) quinone complexes such as ubiquinone, emodin and other anthraquinone derivatives, benzoquinones and their derivatives such as anilino-methylamino benzoquinone-naphthoquinone, phenazine methosulfate and benzenetriol, (3) vanadium compounds such as vanadate, o-vanadate and phenanthroline vanadium complexes, (4) free radical and lipid peroxidation products such as acrolein, α -saturated aldehyde and β -unsaturated aldehyde, (5) unsaturated fatty acids such as decatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, α -linolenic acid and gamma-linolenic acid, (7) protein synthesis inhibitors such as cycloheximide, emetine, anisomycin and reduced phleomycin, (8) pyridine coenzyme complexes such as paraquat (9) biological oxidation system such as xanthocerase oxidase, xanthinin, glucose oxidase, glucose dehydrogenase, vitamin I/or glucose oxidoreductase, glucose reductase, glucose dehydrogenase, glucose reductase3Vitamin C, cysteine hydrochloride, sodium thioglycollate, sodium sulfide, phenazine methosulfate and ferrous chloride; the above radical generating substances may be singly or multiply selected.
3. The anticancer pharmaceutical composition according to claim 1, wherein the nitric oxide synthase inhibitor comprises hemoglobin and its related products, 7-amino-indazole, canavanine, aminoguanidine, S-methylisothiourea sulfate, S-2-amino-5- (2-aminoimidazol-1-yl) pentanoic acid, L-N5- (1-iminoethyl) ornithine, N-monomethyl-L-arginine acetic acid, N-amino-arginine methyl ester, N- ω -amino-arginine, NG-amino-L-arginine, L-amino-arginine-p-aminoacyl-ide, NG-monomethyl-L-arginine and NG-methyl-L-arginine.
4. The anticancer pharmaceutical composition according to claim 1, wherein said radical synergist comprises an antioxidant inhibitor, an acidifying agent and/or a valence-variablemetal.
5. The anti-cancer pharmaceutical composition of claim 4, wherein the antioxidant inhibitor is: catalase inhibitors such as aminotriazole; superoxide dismutase inhibitors, such as: diethyldithiocarbamate, chromium and triethylenetetramine; glutathione inhibitors, such as: ammonium metavanadate, butyl thionine sulfoximine, diuretic acid and S-nitrosoglutathione; alkyltransferase inhibitors, such as: o6-benzyl guanine sand fly and O6-methyl guanine sand fly; vitamin C inhibitors and vitamin E inhibitors; the antioxidant inhibitor can be selected singly or in multiple ways.
6. The anticancer pharmaceutical composition according to claim 4, wherein said acidifying agent comprises substances that inhibit the intracellular pH regulation mechanism and substances that directly or indirectly lower the intracellular and extracellular pH,
various substances that may inhibit the intracellular pH regulation mechanism include: mitochondrial respiratory chain inhibitors such as m-iodophenylguanidine and the like; carbonate/chloride ion exchange inhibitors such as acetazolamide, diisothiourethane cyanostilbene-2, 2' -disulfonic acid and the like; hydrogen/sodium ion exchange inhibitors such as 3, 5-diamino-6-chloro-N-diaminomethylenediazine carbooxamide and its analogs; energy synthase-dependent hydrogen ion and lactate pump inhibitors and the like,
various substances that can directly or indirectly reduce the pH inside and outside the cell include: hydrogen/potassium ion exchange promoters such as nigericin and carboxan-3-chlorophenylhydrazone; reducing the extracellular sodium ion concentration; other substances capable of indirectly reducing intracellular and extracellular pH, such as lactate, glucose, and vasoactive drugs such as angiotensin, nitric oxide synthase inhibitor and oxygen free radical generator,
the above acidifying agents can be selected singly or in multiple ways.
7. The anticancer pharmaceutical composition of claim 4, wherein said valence-change metal includes metal ions such as iron and copper, and related compounds thereof.
8. The anticancer pharmaceutical composition of claim 1, further comprising other auxiliary pharmaceutical ingredients including antibiotics, analgesic, anticoagulant or hemostatic, anti-inflammatory agents, hormones and herbal extracts.
9. The anticancer pharmaceutical composition of claim 1, wherein the composition is formulated as an injection, a suspension, an ointment, or a solid such as a capsule; in various shapes such as granular, flake, spherical, block and film; can be administered by various routes, preferably arterial route, and is most preferably directly placed in tumor body.
10. A method of treating tumors comprising administering the anti-cancer composition of claim 1 in combination with chemoimmunization, therapy, thermotherapy, phototherapy, hormone therapy, electrotherapy, gene therapy, and radiotherapy to treat primary or secondary tumors in humans and animals.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108210931A (en) * | 2016-12-15 | 2018-06-29 | 深圳大学 | Nanometer diagnosis and treatment agent, preparation method and application |
| WO2019091013A1 (en) * | 2017-11-07 | 2019-05-16 | 福州大学 | Use of no donor compound for preparing drug for inhibiting invasion and metastasis ability of tumor cell rich in mercapto molecules |
| CN110980915A (en) * | 2019-12-23 | 2020-04-10 | 解冰 | Nano oxygen radical water for directionally repairing variant cells and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108210931A (en) * | 2016-12-15 | 2018-06-29 | 深圳大学 | Nanometer diagnosis and treatment agent, preparation method and application |
| WO2019091013A1 (en) * | 2017-11-07 | 2019-05-16 | 福州大学 | Use of no donor compound for preparing drug for inhibiting invasion and metastasis ability of tumor cell rich in mercapto molecules |
| CN110980915A (en) * | 2019-12-23 | 2020-04-10 | 解冰 | Nano oxygen radical water for directionally repairing variant cells and preparation method thereof |
| CN110980915B (en) * | 2019-12-23 | 2022-08-02 | 解冰 | Application of nano oxygen free radical water in anticancer medicine |
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| CN1203893C (en) | 2005-06-01 |
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