CN1203893C - Anti-cancer medicine composition - Google Patents
Anti-cancer medicine composition Download PDFInfo
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- CN1203893C CN1203893C CN 00111126 CN00111126A CN1203893C CN 1203893 C CN1203893 C CN 1203893C CN 00111126 CN00111126 CN 00111126 CN 00111126 A CN00111126 A CN 00111126A CN 1203893 C CN1203893 C CN 1203893C
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Abstract
The present invention relates to an anticancer medical composition which mainly comprises nitric oxide synthesis enzyme inhibitors and oxygen free radical products and/or free radical synergistic agents, wherein the nitric oxide synthesis enzyme inhibitors are mainly used for breaking blood vessels and blood supply of tumors; the free radical products can kill tumor cells and can react with nitric oxide so as to form products with strong toxicity; the free radical synergistic agents comprise acidifying agents, antioxidant inhibitors, valence alternation metal (salt), etc. The anticancer composition can not only kill the tumor cells effectively, but also enhance the damage functions for the blood vessels of the tumors and the sensitivity of the tumor cells for other treatment methods, such as radiotherapy, chemotherapy, etc.
Description
The present invention relates to the anticancer pharmaceutical composition of forming with inhibitors of nitric oxide synthase, free radical product and/or free radical synergist, and the method for the treatment of tumor with this anticancer pharmaceutical composition.
Many non-operative treatment are brought into play antitumor action by the generation of free radical, and the generation of free radical is not only relevant with the complication of radiotherapy and chemotherapy etc., and is the material base of many non-operative treatment killing tumor cells.Just because of this, tumor by local free radical product slowly discharges and is used for tumor treatment as new way.Yet, growth of tumor diffusion and to the sensitivity of medicine by its essence---tumor cell and matter---therebetween tumor vessel determines jointly.Tumor vessel not only provides support for the growth of tumor cell, and the growth for tumor cell simultaneously provides requisite nutrient substance.Therefore, suppressing effectively and destroy its vessel growth is the key factor that influences various therapeutic effect.Suppress and destroy tumor vascular growth with the inhibitors of nitric oxide synthase compositions, have not yet to see open report.
The object of the present invention is to provide a kind of is the anticancer pharmaceutical composition that mainly contains effective constituent with inhibitors of nitric oxide synthase, free radical product and/or free radical synergist.
Another object of the present invention is to, a kind of method of utilizing combinations thereof treatment tumor also is provided.Mainly strengthen non-operative treatment action effects such as tumor radiotherapy and chemotherapy by inhibitors of nitric oxide synthase and free radical product.Because the principal element of decision therapeutic effect is the drug level of tumor by local and the tumor cell sensitivity to medicine.Injection all is difficult to keep long-time active drug concentration at tumor by local in vein, abdominal cavity and artery administration even the tumor body.Simple raising dosage is subjected to the restriction of general reaction again.So seeking effective route of administration and synergist is one of free-revving engine of the present invention.
The present invention finds; inhibitors of nitric oxide synthase and free radical product all have the effect of treatment tumor; inhibitors of nitric oxide synthase is by reduction and disruptive oxidation nitrogen tumor vascular protection and regulating action to be suppressed growth of tumor; and the oxygen-derived free radicals that the free radical product is provided not only can killing tumor cell, and can form the stronger free radical of toxicity with the nitrogen oxide reaction in the tumor vessel.Therefore, the two share killing tumor cell effectively, can destroy tumor vessel effectively simultaneously, thereby provides a kind of new effective measures for treating tumor.
Inhibitors of nitric oxide synthase and free radical product are injected in the band tumor animal body can suppress growth of tumor, but general toxic reaction is also more obvious.If with such matter selective intra-arterial injection, or be injected directly into tumor by local, being that holder is local with the macromolecule polymer particularly discharges, and has not only improved the oncotherapy effect, has significantly reduced general toxic reaction simultaneously.
In view of above-mentioned discovery, the present invention is packaged in inhibitors of nitric oxide synthase, free radical product and/or free radical synergist etc. in the macromolecule polymer, and the slow releasing agent of so making helps local the placement.The Main Ingredients and Appearance of anti-cancer composition of the present invention slowly can be released to tumor by local after placing in the tumor body, therefore when reducing whole body complication (after one's own heart injury of lung), optionally remove the nitric oxide levels of tumor by local, and then the action effect of free radical product is further strengthened, thereby provide a kind of more efficient methods for effecting a radical cure former of various human bodies and animal and shifting entity tumor, have very high clinical value and remarkable economical and social benefit.Because anti-cancer composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, phototherapy, hormone therapy and radiotherapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
Anticancer pharmaceutical composition of the present invention mainly contains the inhibitors of nitric oxide synthase and the oxygen-derived free radicals product of effective anticancer, or/and the free radical synergist.
The shared weight portion of wherein various compositions is 0.1～99.9 part, is good with 1～80 weight portion, is the best with 5～40 weight portions.
Anticancer pharmaceutical composition of the present invention can be made into multiple dosage form.Solid-state as injection, muddy suspension, ointment machin as capsule etc.; Be different shape, as granular, lamellar, sphere, bulk and membranaceous; In various dosage forms slowly to be released to the master.With holder above-mentioned Main Ingredients and Appearance being packed the back topical application then is the main form of this invention.The spendable holder of the anti-compositions of the present invention can be any material, and the compound polymer of forming with macromolecule polymer or different macromolecule polymer is good, and the compound polymer of forming with the different molecular weight high molecular lactic is the best.Holder also can use liquid as (but being not limited to) Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid as (but being not limited to) fruit jelly, paste, ointment etc.
This anticancer pharmaceutical composition can with topical, wherein be released to the best with local slow as injection in selective arterial injection and the direct tumor body for good through various administrations.Also can be equipped with local slow during this anticancer pharmaceutical composition selective arterial injection and discharge, the local active ingredient that discharges mainly kills and wounds primary tumo(u)r, and the anticancer composition that tremulous pulse or other approach are taken is used to kill and wound the tumor cell that is dispersed in or has spread.
Organic solvent among the present invention can be, but is not limited to, dichloromethane and dimethyl formamide.
Available inhibitors of nitric oxide synthase comprises nitrogen oxide scavenger and nitrogen oxide synthetic inhibitor among the present invention.The former comprises hemoglobin and associated products thereof: the latter comprises 7-amino-indazole, canavanine, aminoguanidine, cycloheximide, S-methyl isothiourea, S-methyl-isourea, S-2-amino-5-(2-aminooimidazole-1-yl) valeric acid, L-N
5-(1-industry amino-ethyl) ornithine, N-monomethyl-L-arginine acetic acid, N-amino-arginine methyl esters, N-omega-amino--arginine, amino-arginine, NG-amino-L-arginine, L-amino-arginine-p-aminoacyl aniline, NG-monomethyl-L-arginine and NG-methyl-L-arginine.
Available free radical product is among the present invention:
One, clinical chemotherapeutics commonly used, as:
1. platinum-like compounds, as: platinum class complex such as cisplatin, carboplatin ex hoc genus anne thing and derivant.
2. alkylating agent, as: Chlorambucil, chlormethine series pharmaceuticals, Min Erfalan, bird pyrimidine chlormethine, cyclophosphamide and derivant thereof such as 4-peroxide cyclophosphamide, BCNU.
3. antibiotics, as: amycin, bleomycin A5,4-demethoxy daunorubicin, road promise syphilis, ametycin, actinomycin D, anthramycin, tetracycline.
4. plant class, as: cyclophosphamide and derivant thereof such as 4-peroxide cyclophosphamide, new carzinostatin, daunorubicin, powerful red rhzomorph, thio-tepa and Cortex Cunninghamiae Lanceolatae extract (taxine).
5. antimetabolitas, as: 5-fluorouracil, folic acid, ammonia first psychopsid, the fast sandfly of 6-sulfydryl, the fast sandfly of 8-azepine bird, aminopterin, uracil, cytosine arabinoside, the fast sandfly of sulfur azoles, azaserine, cytarabin.
Other, as procarbazine hydrochloride, vincristin, vinblastine and other anthryl complex.
Two, quinones complex is as (but being not limited to): general (partly) quinone, emodin and other anthraquinone derivative, benzoquinone and derivant thereof such as anilino-methylamino benzoquinone, vitamin K
3And plumbagin, azophenlyene metilsulfate, benzenetriol and biosynthetic amino-laevulic acid.
Three, vanadium compounds, as: vanadate, adjacent vanadate and phenanthroline vanadium complex.
Four, free radical and lipid peroxidation product close aldehyde and aldehyde is closed in β-insatiable hunger as: acrylic aldehyde, α-full.
Five, fatty acid is closed in insatiable hunger, as: parinaric acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexenoic acid, alpha-linolenic acid and gamma-Linolenic acid.
Six, protein synthesis inhibitor, as: cycloheximide, hippo alkali, anisomycin and fast sandfly mycin.
Seven, than pyridine class complex, as N,N'-dimethyl-.gamma..gamma.'-dipyridylium.
Eight, electron carrier, as, but be not limited to, available electron carrier includes, but is not limited among the present invention: nadide (reduced form), coenzyme II (reduced form), dithiothreitol, DTT (DTT), 2 mercapto ethanol (2-ME), citric acid, vitamin K
3, vitamin C, cysteine hydrochloride, sodium thioglycolate, sodium sulfide, methyl-sulfuric acid azophenlyene (PMS) and ferrous chloride.
Available free radical product more comprises the biooxidation reactions system among the present invention, as: aminoacid-amino acid oxidase, (yellow fast sandfly)/yellow fast sandfly oxidase (or) yellow fast sandfly dehydrogenase, means of glucose/glucose oxidase, vitamin C/ferrum redox couple, hypochlorous acid/myeloperoxidase, flavin oxidoreductase, nadide (II) oxidoreductase and quinone oxidoreductase etc.Do not have bio-toxicity during arbitrary composition individualism in the above-mentioned redox couple, just trigger a series of thing oxygen reactions after only being in contact with one another, cause reacting the generation of oxygen.Therefore, another kind of form of the present invention is that the active ingredient in the above-mentioned redox couple is packed separately, with the fast sandfly of Huang/yellow fast sandfly oxidase is example, when the yellow fast sandfly in the blood (or) the yellow fast sandfly oxidase that discharges of yellow fast sandfly oxidase and tumor by local (or) is convenient to tumor by local toxigenicity free radical when yellow fast sandfly meets, thus killing tumor cells optionally.But, can optionally attack various entity tumors based on the reaction system of toxigenicity free radical.Can also control local therapeutic response more effectively by the change amount of being administered systemically, therefore, in the treatment tumor, reduce unnecessary damage normal structure.Above free radical product can singly select or multiselect, and multiselect more singly is elected to be with effective.Enzyme in the biooxidation reactions system such as glucoseoxidase etc. also can be through technique for gene engineering transfection tumor cells, and then optionally treat tumor from gene level.
Many clinical non-operative treatment commonly used such as radiotherapy, immunization therapy, electrotherapy, chemotherapy, phototherapy and thermotherapy etc. are by free radical performance antitumor action, based on reaction oxygen (ROS), wherein with superoxide anion base (O
2 -), hydrogen peroxide (H
2O
2) and hydroxy (HO) be most important.Because the free radical outer-shell electron is unpaired, thus very easily with reactions such as intracellular biological structure such as protein, lipid and nucleic acid, thereby the 26S Proteasome Structure and Function of destruction cell finally causes cell death.Therefore, the free radical product is one of Main Ingredients and Appearance of the present invention.
Discover that antioxidant activity in tumor cell such as superoxide dismutase (SOD) and catalase increase, because superoxide dismutase and catalase etc. can be with superoxide anion base (O
-) and hydrogen peroxide (H
2O
2) detoxifcation, be transformed into nontoxic end-product water and carbon dioxide (reaction equation 1 and reaction equation 2).
Therefore tumor cell often produces toleration or congenital insensitive to above-mentioned non-operative treatment.Antioxidant inhibitor, as: aminotriazole(ATA) (hydrogen peroxide enzyme inhibitor) and DDC (superoxide dismutase inhibitor) etc. can be broken the protective effect of antioxidant.So as the free radical synergist, antioxidant inhibitor constitutes one of main composition of the present invention.
Therefore, another kind of form of the present invention be above-mentioned inhibitors of nitric oxide synthase and (or) the free radical product replaces by antioxidant inhibitor, or add antioxidant inhibitor in the above-mentioned complex of being made up of inhibitors of nitric oxide synthase and free radical product.Therefore, anticancer pharmaceutical composition of the present invention contains 2 classes or the 3 class medicines in inhibitors of nitric oxide synthase, oxygen-derived free radicals product and the free radical synergist of being selected from of effective anticancer.
The available antioxidant inhibitor of the present invention is (but being not limited to): the hydrogen peroxide enzyme inhibitor, as aminotriazole(ATA) etc.; The superoxide dismutase inhibitor is as diethyldithio carbamate etc.; The inhibitor of the enzyme synthetic relevant with glutathion, as: (1) glutathion reductase inhibitor, as: ammonium metavanadate, maleic acid second two fat, cadmium ion, trivalent organo-arsenic, glutathione bisulphide, tetramethylthiuram disulfide and chlormethine series pharmaceuticals etc.; (2) glutathion peroxidase inhibitor, as: DL-Buthionine-(S,R)-sulfoximine BSO, [being called for short BSO] etc.; (3) glutathione transferase inhibitor, as: acidum ethacrynicum (EA), curcumin, cavatic acid etc., (4) glutathione analogs is as S-basic glutathion etc.The transalkylation enzyme inhibitor.In addition, phosphoglucoprotein (P-GP) inhibitor and the fast sandfly nucleosidic inhibitors of gland etc.; Inhibitors of nitric oxide synthase, uric acid and some protein kinase (PKC) inhibitor, vitamin C inhibitor and vitamin E inhibitor etc.In addition, the generation of a large amount of free radicals also can make the activity of antioxidant reduce, and therefore, free radical product itself also is an antioxidant inhibitor.Above antioxidant inhibitor can singly select and multiselect, and better with DDC, aminotriazole(ATA) and BSO action effect when singly selecting, multiselect more singly is elected to be with effective, and is wherein best with the action effect of aminotriazole(ATA) combination with radiotherapeutic.
In various reaction oxygen (ROS), hydroxy (HO
-) the most active, be one of the strongest free radical of cytotoxicity.Generally, because of the effect of antioxidants such as superoxide dismutase and catalase, hydroxy (HO in the tumor cell
-) generation few.When with the low price metal, as Cu
+And Fe
++, superoxide anion base and hydrogen peroxide just can be converted into the stronger hydroxy (HO of toxicity by reactions such as Fenton's reactions in when reaction
-) (reaction equation 3 and reaction equation 4).
In reaction equation 3 and reaction equation 4, metal has played very important catalytic action at a low price, and sour environment helps metal from the conversion of high price to low price, therefore, generate reinforcing agent as free radical, acidulant and variable valency metal (salt) constitute another Main Ingredients and Appearance of the present invention.
Therefore, another kind of form of the present invention be above-mentioned inhibitors of nitric oxide synthase and (or) the free radical product by acidulant and (or) variable valency metal (salt) replaces, or in the above-mentioned complex of forming by inhibitors of nitric oxide synthase and free radical product, add acidulant with (or) variable valency metal (salt).
Available acidulant comprises the various materials of interior pH value regulatory mechanism capable of inhibiting cell and the various materials that can directly or indirectly reduce the inside and outside pH value of cell among the present invention.The former comprises: the mitochondrial respiratory chain inhibitor, as-iodobenzene guanidine and analog; Carbonate/chloride ion exchanger inhibitor, as acetazolamide, 4,4-two different sulfo-polyurethane cyanato-stilbenes-2,2 '-disulfonic acid and analog thereof such as R (+)-[5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl] oxyI] acetic acid[B-3 (+)] etc.; Hydrogen/sodium ion exchanger inhibitor, as 3,5-diaminourea-6-chloro-N-diamino methylene than piperazine carbon oxamides and analog thereof such as DMA[5-(N, N-dimethyl) amiloride], HMA[3-amino-6-chloro-5-(1-homopiperidyl)-N-(diaminomethylene) pyrazimecarboxamide], EIBA[5-(N-methyl-N-isobutyl) amiloride] and EIPA[5-(N-ethyl-N-isopropyl) amiloride] etc.; Hydrion and lactic acid pump inhibitor and analog thereof etc. that the energy synzyme relies on.The latter comprises: hydrogen/potassium ion exchange promoter, as nigericin and phosphinylidyne cyanogen-3-chlorobenzene hydrazone etc.; Reduce the extracellular Na ion concentration; Other can reduce the various materials of the inside and outside pH value of cell indirectly, as lactate, glucose and vasoactive agent such as angiotensin, inhibitors of nitric oxide synthase and oxygen-derived free radicals product etc.Above acidulant can singly select or multiselect.
Available variable valency metal (salt) is each metal ion species and complex thereof among the present invention, and is wherein best with the salt such as the effects such as copper sulfate, ferrous sulfate and copper chloride of cupric ferrum.
The existence of hydroxy (hydroxyl) can further reduce the pH value of cell, and low pH value helps the generation of hydroxy and to the inhibition of tumor cell regulatory function, thereby its antitumor action is strengthened mutually.Therefore, other hydroxy product and hydroxy scavenger inhibitor have also constituted one of Main Ingredients and Appearance of the present invention.
In addition, available free radical generation reinforcing agent also comprises N-acetylcystein, cytochrome, hydrochloric acid different name morpholino, nitrogen oxide and nitroso-group acetyl penicillamine etc. among the present invention.
In addition, also can add other medicinal component in this anticancer pharmaceutical composition, as, but be not limited to antibiotic, antalgica, anticoagulant medicine or hemorrhage, antibiotic medicine, hormone and relevant Chinese herbal medicine extract.
Anticancer pharmaceutical composition of the present invention is main attacking system with the free radical product, because free radical is the common mechanism of multiple non-operative treatment treatment tumor.This is found to be treatment of cancer, and particularly the research and development of new drug provide new theoretical direction.
The Main Ingredients and Appearance of anticancer compound of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.Acidulant of being released and antioxidant inhibitor are except that the protectiveness regulatory mechanism of capable of blocking or broken tumor cell; also can strengthen chemotherapeutics; particularly the cytotoxic reaction of free radical product and tumor cell (particularly toleration tumor cell) be to the sensitivity of other therapies, thereby its action effect is strengthened and have more selectivity.
As mentioned above, anticancer compound of the present invention can be made into various dosage forms, and is solid-state as capsule etc. as injection, muddy suspension, ointment machin; Be released to main application form with local slow, the packing method of its Main Ingredients and Appearance and step are not main contents of the present invention, but any material that can strengthen free radical toxicity comprises and selects for use acid holder all to belong to category of the present invention.
The characteristics of technology of preparing of the present invention are the macromolecule polymer is dissolved in the organic solvent as holder and inhibitors of nitric oxide synthase, oxygen-derived free radicals product or antioxidant inhibitor, and abundant mixing is bled afterwards, the universe is dry.Treat that the universe is shaped immediately after dry and sterilizes packing.The macromolecule polymer can be made into different shape, and the content of various compositions is decided by the same domain prior art because of different needs in the macromolecule polymer.Can be good with 1%～80% from 0.1%～99.9%, be the best with 5%～40%.
This anticancer pharmaceutical composition can be made into various dosage forms, and is solid-state as capsule etc. as injection, muddy suspension, ointment machin; Be different shape, as granular, lamellar, sphere, bulk and film sample; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Best product of the present invention is the solid product that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.
The method that anticancer pharmaceutical composition of the present invention is processed to finished medicines is as follows:
The solid polymer of weighing as holder and inhibitors of nitric oxide synthase, oxygen-derived free radicals product and/or free radical synergist dissolving mixing, dry forming, packing sterilization, medicine gets product.Concrete steps are as follows:
1. the solid polymer holder of weighing is put into container, it is even to add the certain amount of organic solvent dissolving, and the two body weight is than being as the criterion with abundant dissolving.
2. adding the pharmaceutical composition of weighing shakes up again.The ratio of pharmaceutical composition and polymer is decided by the same domain prior art according to dosage form.
3. pastille polymer vacuum drying is removed organic solvent.Also available cold drying is removed organic solvent.
4. dried solid polymer is shaped immediately.Can make different shape according to different needs.
5. ray sterilizing is standby after the packing, and roentgendosis is different because of volume.The tight bacterium of also available other method.The polymer product made from this method is a solid, is yellow or silvery white, and its color is relevant with the drug level and the medicament categories of packaging.
Below in conjunction with embodiment the present invention further is illustrated, but is not limited thereto.
Embodiment 1: molecular weight is 100 milligrams of 50000 lactic acid
100 milliliters of dichloromethane
40 milligrams of inhibitors of nitric oxide synthase
20 milligrams of Chlorambucils
It is made the pastille polymer by above-mentioned flow process.
Embodiment 2: molecular weight is 50 milligrams of 20000 lactic acid
Molecular weight is 50 milligrams of 80000 lactic acid
200 milliliters of dimethyl formamides
5 milligrams of diethyldithio carbamate
20 milligrams of cisplatin
30 milligrams of aminotriazole(ATA)s
Between-5 milligrams of iodobenzene guanidines
It is made the pastille polymer by above-mentioned flow process.
Embodiment 3: molecular weight is 50 milligrams of 20000 lactic acid
Molecular weight is 40 milligrams of 80000 lactic acid
100 milliliters of dimethyl formamides
5 milligrams of diethyldithio carbamate
40 milligrams of Chlorambucils
It is made the pastille polymer by above-mentioned flow process.
Embodiment 4: molecular weight is 50 milligrams of 20000 lactic acid
Molecular weight is 40 milligrams of 80000 lactic acid
100 milliliters of dimethyl formamides
5 milligrams of diethyldithio carbamate
40 milligrams of Chlorambucils
40 milligrams of inhibitors of nitric oxide synthase
It is made the pastille polymer by above-mentioned flow process.
Embodiment 5: molecular weight is 50 milligrams of 80000 lactic acid
200 milliliters of dimethyl formamides
5 milligrams of diethyldithio carbamate
20 milligrams of cisplatin
20 milligrams of inhibitors of nitric oxide synthase
30 milligrams of aminotriazole(ATA)s
Between-5 milligrams of iodobenzene guanidines
1 milligram in ferrous sulfate
It is made the pastille polymer by above-mentioned flow process.
Above-mentioned pastille polymer is placed on tumor by local has improved therapeutic effect to the cerebral tumor greatly, reduced general toxicity simultaneously, in addition, single time spent of the antitumous effect when different components share obviously strengthens.
As mentioned above, the pastille holder is a bio-capacitivity, so do not cause foreign body reaction.Place the back degradable in the body and absorb, so the taking-up of need not performing the operation again.Drug slow with institute's bag in the process of degraded and absorbed discharges, thereby optionally improves and prolong the local drug concentration of tumor.The local placement not only improved therapeutic effect, and reduced the general toxic reaction that is caused by the conventional route administration.Except that place the part, can also the administration of various ways medicine number of ways.Except that independent application, also can with many treatment measure use in conjunction.For example:
(1) is used for the treatment of people and the various entity tumors of animal
The local application anti-cancer composition of placing in operation back has unique effect to the radical cure tumor.Some tumor growth can not exenterate at the key position (locating as brain stem etc.) of human body, and the slow release of topical remedy can replace excision.Some malignant tumor, operation technique may promote the tumor diffusion, and the slow release of topical remedy may be the more selection of science.
(2) with high thermal therapeutical use in conjunction:
Hyperpyrexia can reduce the pH of tumor, and the existence of acidulant can strengthen the sensitivity life of tumor cell to high thermal therapeutical.As high thermal therapeutical sensitizer, many medicines have demonstrated the acidization to tumor.Acidulant not only can be strengthened the inhibitory action of the tumor growth that hyperpyrexia causes, and can suppress the generation of human tumor heat tolerance phenomenon, and the latter is the principal element of the high thermal therapeutical of restriction.In addition, low pH value can strengthen the generation of toxicity free radical, and the toxicity free radical can further reduce pH.
(3) with the radiotherapy use in conjunction:
The existence of tumor cell relies on the regulatory mechanism of ground cell itself down.Suppress or block this regulatory mechanism and reduced tumor cell radiocurable tolerance.The height of human tumor pH affects the action effect of heat emission treatment.The killing tumor cells by the generation that produces free radical is treated in heat emission, if acidulant and antioxidant inhibitor are waited until that the release of material local slow may make radiocurable effect enhancing and have more selection.
(4) with the immunization therapy use in conjunction:
Many immunocytes are brought into play its antitumor action by the generation of free radical, and weakly acidic condition not only can lure in the lymphocyte outer room matter and move, and can promote the release with the link coupled medicine of monoclonal antibody.Many cytotoxic factors are influenced by the pH of environment also as the performance of the cytotoxicity of tumor necrosis factor etc., effect strengthens under acid situation.If material local slow such as acidulant and antioxidant inhibitor are discharged the effect enhancing that may make immunization therapy and have more selectivity.
(5) with the other therapies use in conjunction: as synergist, anticancer compound of the present invention is except that share with above-mentioned therapy, its Main Ingredients and Appearance also can strengthen the action effect of phototherapy, electrotherapy, hormone therapy, chemotherapy and gene therapy etc., therefore has unique advantage and very high clinical value.
Claims (3)
1. anti-cancer composition contains 2 classes or the 3 class medicines in inhibitors of nitric oxide synthase, oxygen-derived free radicals product and the free radical synergist of being selected from of effective anticancer, wherein:
Described inhibitors of nitric oxide synthase is selected from 7-amino-indazole, canavanine, aminoguanidine, S-methyl isothiourea, S-methyl-isourea, S-2-amino-5-(2-aminooimidazole-1-yl) valeric acid, L-N5-(1-imino group ethyl) ornithine, N-monomethyl-L-arginine acetic acid, N-amino-arginine methyl esters, N-omega-amino--arginine, amino-arginine, NG-amino-L-arginine, L-amino-arginine-p-aminoacyl aniline, NG-monomethyl-L-arginine or NG-methyl-L-arginine;
Described oxygen-derived free radicals product is selected from Chlorambucil, Min Erfalan, BCNU, cyclophosphamide, 4-peroxide cyclophosphamide, cisplatin, carboplatin, amycin, bleomycin A5, daunomycin, ametycin, actinomycin D, new carzinostatin, daunorubicin, powerful red rhzomorph, thio-tepa, taxine, 5-fluorouracil, folic acid, ammonia first psychopsid, the fast sandfly of 6-sulfydryl, the fast sandfly of 8-azepine bird, aminopterin, uracil, cytosine arabinoside, procarbazine hydrochloride, vincristine, vincaleucoblastine;
Described free radical synergist comprises antioxidant inhibitor and/or acidulant and/or variable valency metal, wherein:
Antioxidant inhibitor is selected from aminotriazole(ATA), diethyldithio carbamate, DL-Buthionine-(S,R)-sulfoximine BSO, the fast sandfly of O6-benzyl bird or the fast sandfly of O6-methyl bird,
Between acidulant is selected from-the iodobenzene guanidine and
Variable valency metal comprises ferrum, copper metal ion and salt thereof.
2. the anticancer pharmaceutical composition according to claim 1 is characterized in that, also contains the macromolecule polymer as holder.
3. the anticancer pharmaceutical composition according to claim 2 is characterized in that, it is 20000,50000,80000 lactic acid that described holder is selected from molecular weight.
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|---|---|---|---|
| CN 00111126 CN1203893C (en) | 2000-06-01 | 2000-06-01 | Anti-cancer medicine composition |
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|---|---|---|---|
| CN 00111126 CN1203893C (en) | 2000-06-01 | 2000-06-01 | Anti-cancer medicine composition |
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| CN1203893C true CN1203893C (en) | 2005-06-01 |
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| CN108210931A (en) * | 2016-12-15 | 2018-06-29 | 深圳大学 | Nanometer diagnosis and treatment agent, preparation method and application |
| CN107823644B (en) * | 2017-11-07 | 2021-03-02 | 福州大学 | Application of NO donor compound in preparation of drugs for inhibiting invasion and transfer capacity of tumor cells rich in sulfhydryl molecules |
| CN110980915B (en) * | 2019-12-23 | 2022-08-02 | 解冰 | Application of nano oxygen free radical water in anticancer medicine |
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