CN101031301A - Treatment of tumours - Google Patents
Treatment of tumours Download PDFInfo
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- CN101031301A CN101031301A CN 200580030893 CN200580030893A CN101031301A CN 101031301 A CN101031301 A CN 101031301A CN 200580030893 CN200580030893 CN 200580030893 CN 200580030893 A CN200580030893 A CN 200580030893A CN 101031301 A CN101031301 A CN 101031301A
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- metal ion
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- compositions
- chelation agent
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Abstract
The present invention provides the use of a metal ion chelating agent for the manufacture of a medicament for the treatment or prophylaxis of a bacteria-mediated cancerous tumour, wherein said metal ion chelating agent provides a metal ion chelating capacity for at least one metal ion on which said tumorigenic bacteria is dependent for viability. The invention also provides methods for the treatment or prophylaxis of tumours.
Description
The present invention relates to be used for metal-chelating preparation of compositions and application in the cancer lesions of people and non-human animal's treatment bacteria mediated.
Arguement about the source of cancer and origin is still awfully hot strong, and after many years, except basic sign, denies consumingly that still antibacterial may be a cause.The basic research work that causes cancer about antibacterial traced back to for 18th century, at that time even recognize that the antibacterial of certain form may be a cause.Along with the development of recent years about other medical conditions, have realized that antibacterial can change their shape (replica), and because such variation, antibacterial can produce different medical conditions.
Observe, antibacterial becomes another kind of shape (algae shape) from a kind of shape (shaft-like), and vice versa, and finds in these environment, antibacterial accumulation damage, and as if it becomes cancer then.Sometimes, these infringements form the infringement that is called sarcoma (sarcoid), and in many situations, they can become very widely.It is said that these infringements are outbursts of autoimmune system and local environment reaction.Described local environment do not occur and concentrate on many types of antibacterial.
Because replica, when antibacterial changes shape, as if there is not or has only minimum cell wall structure, and when this takes place, as if antibacterial use the calcium biomembrane bag of biomembrane-normally by self, so that self be not subjected to the influence of antibiotic and other chemical compound.
Also seemingly such situation, when antibacterial was subjected to immune system or antibiotic threat, they may lose their cell wall, and taked different growth forms, described growth forms to make them more insensitive for immune attack.This lacking of cell response is why the medical expert finds that antibacterial beyond affordability is the Another reason in cancer source.
Known antibacterial streptococcus pyogenes (Streptococcus pyogene), it mentioned first in 1908, as the reason of a large amount of baby due death, and after 1945, being to form scarlatinous reason, is the reason that forms rheumatic fever and necrotizing fasciitis disease now.This antibacterial shows many types of, and therefore can change its feature and structure, and has the ability that causes many medical conditions.
Show, nano-bacteria (nano-bacteria), it all exists in everyone, and has realized that it exists as impurity in many vaccines, also is many types of, and has biomembrane bag quilt.This is why antibiotic and body immune system can not be handled their reason.Have calcium biomembrane bag quilt, body thinks that described nano-bacteria is a kind of calcium that moves everywhere in system.And as if in some cases, these nano-bacteria are accumulated and are developed into infringement.
Because cause the replica special feature of antibacterial as potential Cancerous disease precursor source, these antibacterials become the target spot of cancerous tumour treatment.As if antibacterial can accumulate in any part of body more or less, and when accumulating like this, can develop into tumor.As and if growth of tumor also relies on a kind of ferric ion dependent bacteria, it is relevant with many types of antibacterial.
Many types of feature can be found in many different types of antibacterials.Therefore, for example, the avirulence antibacterial of usually on skin or mucosa, finding, staphylococcus epidermidis (Staphylococcusepidermis) in thymic tissue, and finds to produce the cancer damage with shaft-like and algae shape perch.Show that Mycobacterium (Mycobacterium sp.) can also change shape and produce various other diseases.
An object of the present invention is to avoid or minimize one or more the problems referred to above.
Previous the announcement among the WO 03/032944 in patent more early proposes, and antibiotic-resistance that various local chelating compositionss are suitable for use in opposing skin and open wound infects and pollutes.Yet, do not have such compositions may be applied to the previous prompting of other disease.
Now, we find, based on compositions as the application of disclosed chelate compound in WO 03/032944 (therefore its content incorporates the application into by reference), have the feature of treatment cancerous tumour, in a period of time, reduce the quantity of their the big or small and cancer cell that minimizing exists.Therefore, in a first aspect of the present invention, the application of metal ion chelation agent is provided, the medicine that is used to prepare treatment or prevents the cancerous tumour of bacteria mediated, wherein said metal ion chelation agent provide the metal ion-chelant ability of at least a metal ion that is relied at described tumorigenic bacteria survival.
The present invention also provides metal ion chelation agent to be used for the treatment of the application of medicine that treatment or prevention are selected from the tumor of Kaposi sarcoma and sarcoid.
In another aspect of this invention, be provided for treating or preventing the method for the cancerous tumour of bacteria mediated, it comprises the human or animal who the metal ion chelation agent of effective dose is administered to the such treatment of needs, and wherein said metal ion chelation agent provides the metal ion-chelant ability of at least a metal ion that is relied at described tumorigenic bacteria survival.
Notice that calcium is coated on the existence on the tumorigenic bacteria of wide region, we find, in such circumstances, in order to make bacterial cell can be subjected to the attack of chelating agen, described chelating agen has the sequestering power at one or more essential metal ions of tumor cell survival---such as Mg
2+, Fe
2+, Fe
3+, Cu
2+, Zn
2+, Mn
2+, Ni
2+, and Se
2+, it can be called " nutrition " metal ion expediently, and the chelating agen of using the calcium that exists in the bag quilt based on calcium that is adsorbed on the tumorigenic bacteria film also is essential.Necessarily, in order to attack the ferric ion dependent bacteria of supporting tumor growth, also use the chelating agen that has at the sequestering power of iron ion.Suitable calcium ion chelator is well known in the art, and comprising EDTA.
Therefore, in another aspect of this invention, the application of at least a metal ion chelation agent is provided, be used to prepare the medicine of the cancerous tumour of treatment or prevention bacteria mediated, wherein said metal ion chelation agent provides the metal ion-chelant ability of at least a metal ion that is relied at calcium ion with at described tumorigenic bacteria survival.
In another aspect of this invention, be provided for treating or preventing the method for the cancerous tumour of bacteria mediated, it comprises the human or animal who at least a metal ion chelation agent of effective dose is administered to the such treatment of needs, and wherein said at least a metal ion chelation agent provides the metal ion-chelant ability at calcium ion and at least a metal ion that survival is relied at described tumorigenic bacteria.
Can use the single chelating agen that two or more above-mentioned essential or necessary requirements are provided in principle.In the practice, although we find that different chelating agen has different sequestering powers or the intensity at different metal ions, and necessary usually two or more different chelating agen of using, wherein the sequestering power at various metal ion target spot is maximized to bigger or littler degree.
Notice foregoing, find that oxine has special broad-spectrum activity, except sodium, potassium and calcium, with the most of metal ion (comprising iron ion) of the effectiveness chelating of high level.Therefore, be necessary this chelating agen and secondary calcium ion chelator applied in any combination.Suitable calcium ion chelator is well known in the art, and comprising EDTA.
By the metal ion chelation agent that provides removal can be called each metal ion species of target spot metal ion expediently, can increase the effectiveness of compositions of the present invention.Therefore, about basic " nutrition " metal ion that the attack bacteria cell needs, preferably use can with the metal ion chelation agent that is selected from following multiple metal ion formation chelate: Mg
2+, Fe
2+, Fe
3+, Cu
2+, Zn
2+, Mn
2+, Ni
2+, and Se
2+
Seem the partial action at least of main nutrition metal ion chelation agent be by with main chelating agen with tumor cell bag quilt, thereby contain antibacterial effectively.As if also seem main chelating agen has similar containment effect for the ferric ion dependent bacteria of controlling tumor growth.
Main and one of accessory chelating agen or both make that also with the free ion of chelating iuntercellular medium they can not support bacteria growth and growth.Then, the resulting damage of antibacterial for the iron ion regulation and control begins induced tumor to dwindle.Continue to use chelate compound compositions of the present invention during a period of time, this tumorigenic bacteria with many types of that will not regulate and control to iron ion constantly provides any food, fully eliminates up to them.
The remarkable benefit of another of chelate compound compositions of the present invention is that their wrap by the neuroreceptor of tumor region, and thereby the minimizing pain that the patient stood.As if this effect also further strengthen the treatment of tumor or Cancerous disease and render a service.
Preferred chelating agen can the various metal ion of chelating, and thereby by multiple, direct and indirect approach attack tumorigenic bacteria.More specifically, for used chelating agen, preferably be selected from Mg
2+, Fe
2+, Fe
3+, Cu
2+, Zn
2+, Mn
2+, Ni
2+, and Se
2+Multiple metal ion form chelate.Have been found that oxine has special broad-spectrum activity, except sodium, potassium and calcium, the most of metals of its chelating.
Preferably, mainly " nutrition " metal ion chelation agent is a heteropolar compound, it comprises at least one undersaturated heterocycle hexatomic ring, wherein at least one heteroatom moiety act as hydrogen acceptor, and wherein said chemical compound also comprises at least one hydrogen donor part, be hydroxyl expediently, described heteropolar compound does not have such replacement, promptly, described replacement itself or replace with other and to produce such steric restriction and/or to make described molecule be alkalescence or acid, perhaps change the space geometry of molecule, with hydrogen donor and the hydrogen donor of acceptor portion and another described heteropolar compound molecule and the interaction of acceptor portion that prevents a heteropolar compound molecule.
Usually, preferred " nutrition " metal ion chelation agent is a heteroaryl compound, has at least 1 nitrogen in its heterocycle structure, and has at least 1 hydroxyl replacement on ring structure, so that chelating function is provided jointly.Preferred metal ion chelation agent is selected from 2 of optional replacement, 3-dihydroxy-pyridine; 4, the 6-dihydroxy-pyrimidine; 2-pteridine alcohol; 2, the 4-quinoline diol; 2,3-dihydroxy quinoxaline; 2,4-pteridine glycol; 6-purine alcohol; 3-phenanthridines alcohol; 2-phenanthroline alcohol; 2-azophenlyene alcohol, and oxine most preferably.Oxine has the advantage that forms metallo-chelate with the different metal ion of special wide region.
Another aspect of the present invention is provided for the pharmaceutical composition that inside, outside or injection are used, and at its pharmaceutical carrier, is preferably in the carrier based on aqueous, and it comprises described main and accessory chelating agen.The suitable carrier based on aqueous also comprises intermediate diluent usually, wetting agent, the words thickening agent that needs and ideally, pH controlling agent.Described compositions is usually with the form of liquid, gel or paste, and will comprise 0.0031%-0.20%w/w usually, (main with accessory) chelating agen of 0.02-0.1%w/w preferably, and this depends on wherein used concrete route of administration.
In people's situation, in order to be controlled at the tumor of stomach, liver and intestinal, expediently, described compositions is taken 2 times with the ratio of every dose of 5mls every day.Keep this dosage, begin to dwindle, and finally disappear then up to cancerous tumour.For laryngeal carcinoma, take the 10mls aqueous mixture in one glass of water, and gargle with it then.
In order to control isolating tumor, (desirably) is injected directly into chelant composite in the tumor then ideally.The particular location that depends on tumor assisting down of suitable scanner, can advantageously be injected by remote control mode, to guarantee that described mixture is expelled to suitable zone.Alternative is that a kind of inculcating or syringe pump is installed, and it will be assigned to the time durations of chelate solution at needs in the tumor at interval with preset time.Usually by the suitable monitoring of tumor is determined, dwindle during injection or the administration to guarantee tumor.
The situation of tumor externally, similar tumor and in the popular sarcoma of Malaysia and China in Kaposi sarcoma, opening tumor (open toptumours), blind tumor (blind tumours) or the animal such as the mankind, it is favourable using the nutrition paste-like preparation.Nutritive proportion depends on that tumor is tumor opening or blind in the position of body and it, and the latter needs higher basically dose ratio, even only obtain general success then.For the opening tumor, such as sarcoma, paste-like preparation is used 2 times common every day, continues several days, typically is 10 days.In week, we find that sarcoma has disappeared at 6-8, only stay little lump on the skin that they once existed.
In the situation of oral cancer, for example, gum cancer is advantageously used the paste-like preparation clip affected site, expediently every day 2 times.
Should be appreciated that the selection of other composition of the present invention may be subjected to the restriction of the character of metal ion chelation agent.Therefore, for example, because preferred metal ion chelation agent oxine is insoluble usually in aqueous solution, or utmost point indissoluble.Can such as polyhydric alcohol, comprise ethylene glycol by using intermediate flux based on the aqueous solution of oxine compositions, preferably propylene glycol, glycerol or Sorbitol and wetting agent and prepare.It should be appreciated by those skilled in the art, the wetting agent of adaptable wide region can obtain, it will give the dissolubility of described metal ion chelation agent in ethylene glycol, comprising polyoxyethylene sorbitan aliphatic ester T20, T40, T60 and T80 (Spheron MD 30/70 (Polysorbate)) and C9-C11 fat alcohol ethoxyl compound (Symperonic91/8, or more preferably, Symperonic 91/6).
Should be appreciated that can use the different proportion based on the various compositions of the compositions of aqueous, it depends on the dissolubility of used metal ion chelation agent, the final concentration that needs etc.Usually, we find that the consumption of used wetting agent is responsive relatively.In the situation of intermediate flux (ethylene glycol etc.), in case list the minimum amount that is enough to the needs that described metal ion chelation agent is water-soluble, so, the consumption of this intermediate flux can further increase at an easy rate, and even now is done does not have special benefit usually.
Advantageously,, most preferably, guarantee pH, also comprise the pH controlling agent in the 9.2-9.4 zone in order to ensure the alkaline pH of compositions.The pH controlling agent can be KOH or NaOH.But, preferably, use EDTA, it is expediently with the form of disodium or tetrasodium salt.
In the situation of oxine, we have found that the suitable ratio of the compositions based on liquid, aqueous solution of the present invention that can be used to be suitable for to be used for to treat tumor will have following compositions usually:
Composition weight
1 part of main chelating agen (oxine)
0.1 part of less important chelating agen (EDTA)
Wetting agent 4+/-5% part
Diluent at least 20, preferred 40
The final concentration that the deionized water acquisition needs is needed
It is required that pH controlling agent (DSEDTA or TSEDTA) obtains pH 9.2-9.4
Other preferable feature of the present invention and advantage will appear in the following detailed example, and its mode that certain preferred embodiments is described by way of example provides.
Embodiment 1-prepares the method for concentrate
With 10gm oxine (main chelate compound) and 0.5 gram ethylenediaminetetraacetic acid (less important chelate compound), restrain the water-soluble non-aqueous diluent that is selected from propylene glycol, glycerol and Sorbitol with 200, be dissolved in the 50 gram wetting agents at 70 degrees centigrade, described wetting agent is selected from: polyoxyethylene sorbitan aliphatic ester T20, T40, T60 and T80 (Spheron MD 30/70) and C9-C11 fat alcohol ethoxyl compound (Symperonic 91/6).Solution adds more ethylene glycol or the glycerol or the sorbitol diluent of volume in case form, and making the solution of 500 grams, and cooling then, makes the 500g concentrate that contains 2.10% main and less important chelate compound.
Embodiment 2-prepares Orally administered composition
Take the 2.1% chelating concentrate of 1 part of embodiment 1, and in 159 parts of deionized waters, dilute, then, by adding tetrasodium ethylenediamine tetraacetate, and with the pH regulator of this compositions to pH9.2/9.4.The intensity of this preparation is the chelate compound of 131.25ppm, makes every doses of the 5mls that contains 656 micrograms.
The suitable dose ratio of this compositions is 10mls every day, consumes the chelate compound of 1312 micrograms every day, based on average adult's body weight of 70kg, and about 18.75 micrograms of the corresponding every kg body weight of this dose ratio.
Embodiment 3-prepares injectable composition
Take the 2.1% chelating concentrate of 1 part of embodiment 1, and in 319 parts of deionized waters, dilute, then, by adding tetrasodium ethylenediamine tetraacetate, and with the pH regulator of this compositions to pH9.2/9.4.The intensity of this preparation is the chelate compound of 62.5ppm, makes every part of injection volume of the 5mls that contains 312.5 micrograms.
Based on 2 injections every day, each 5mls, this will provide the dose ratio of 625 microgram chelate compounds every day, based on average adult's body weight of 70kg, about 8.93 micrograms of the corresponding every kg body weight of this dose ratio.
This solution can be expediently by being placed in human external or the inner pump of inculcating be used, by external electronic control administration frequency and time, in this method, this administration is automatically, and speed and frequency can externally be controlled.
Embodiment 4-preparation is used for the paste of external tumor
Take the 2.1% chelating concentrate of 1 part of embodiment 1, and in 9 parts of deionized waters, dilute.Then, add suitable thickening agent with 2% ratio, Amaze XT normally, to make the viscosity paste, then, by adding tetrasodium ethylenediamine tetraacetate (TSEDTA), and with the pH regulator of this compositions to pH 9.2/9.4.
Tumor and the people who relates to are depended in the application of this paste, and during still each the application, paste layer 2-3mm at least is thick.The paste that is necessary to remain on the tumor is moistening, therefore, if necessary, suitable dressing or overcover (expediently, with disposable cloth material form) is placed the zone of twining with plastic foil, in case paste suppressing agent becomes dry.
Embodiment 5-treatment Equus caballus (L.) tumor
Typically, these are present in the fold place of lower limb and health, and in this case, when using 2 times every day, it is moistening that described paste tends to keep.Typically, treatment continue 10 days during.
Claims (24)
1. the application of metal ion chelation agent, the medicine that it is used to prepare treatment or prevents the cancerous tumour of bacteria mediated, wherein said metal ion chelation agent provide the metal ion-chelant ability of at least a metal ion that is relied at described tumorigenic bacteria survival.
2. the application of metal ion chelation agent, it is used to prepare the medicine for the treatment of or preventing to be selected from the tumor of Kaposi sarcoma and sarcoid.
3. according to the application of claim 1 or claim 2, wherein said metal ion chelation agent is used with the calcium ion chelator that has at the sequestering power of calcium ion.
4. according to each application among the claim 1-3, wherein said metal ion chelation agent is a heteropolar compound, it comprises at least one undersaturated heterocycle hexatomic ring, wherein at least one heteroatom moiety act as hydrogen acceptor, and wherein said chemical compound also comprises at least one hydrogen donor part, described heteropolar compound does not have such replacement, promptly, described replacement itself or replace with other and to produce such steric restriction and/or to make described molecule be alkalescence or acid, perhaps change the space geometry of molecule, with hydrogen donor and the hydrogen donor of acceptor portion and another described heteropolar compound molecule and the interaction of acceptor portion that prevents a heteropolar compound molecule.
5. according to each application among the claim 1-4, wherein said metal ion chelation agent is a heteroaryl compound, has at least 1 nitrogen in its ring structure, and has at least 1 hydroxyl replace on ring structure, so that chelating function is provided jointly.
6. according to the application of claim 5, wherein said metal ion chelation agent is selected from 2 of randomly replacement, 3-dihydroxy-pyridine; 4, the 6-dihydroxy-pyrimidine; 2-pteridine alcohol; 2, the 4-quinoline diol; 2,3-dihydroxy quinoxaline; 2,4-pteridine glycol; 6-purine alcohol; 3-phenanthridines alcohol; 2-phenanthroline alcohol; 2-azophenlyene alcohol, and oxine.
7. according to the application of claim 6, wherein said metal ion chelation agent is an oxine.
8. according to each application among the claim 1-7, it comprises wetting agent in described compositions.
9. according to the application of claim 8, wherein said wetting agent is selected from polyoxyethylene sorbitan aliphatic ester T20, T40, T60 and T80 (Spheron MD 30/70), with C9-C11 fat alcohol ethoxyl compound (comprising Symperonic 91/8 and Symperonic 91/6).
10. according to each application among the claim 1-9, wherein said compositions contains intermediate flux, and it is the form of non-aqueous water-soluble solvent in described compositions.
11. according to the application of claim 10, wherein said intermediate flux is a polyhydric alcohol.
12. according to the application of claim 11, wherein said intermediate flux is selected from monoethylene glycol, propylene glycol, glycerol, and Sorbitol.
13., wherein in described compositions, comprise thickening agent according to the application of claim 1-12.
14. according to the application of right 13, wherein said thickening agent is the hydroxypropyl cellulose thickening agent.
15. according to the application of claim 13, wherein said thickening agent is a dehydrogenation xanthan gum thickening agent.
16. according to each the application of claim 1-15, it comprises the oxine of 1 part of weight, the wetting agent of 4 ± 5% parts of weight, the dihydroxylic alcohols of at least 20 parts of weight, and water in described medicine.
17. according to each the application of claim 1-16, wherein said compositions is the form of liquid, spray, unguentum or paste.
18. according to each application among the claim 1-17, wherein said metal ion chelation agent concentration with the chelating agen of 0.0031%-0.20%w/w in compositions exists.
19. according to the application of claim 18, wherein said metal ion chelation agent concentration with the chelating agen of 0.02-0.1%w/w in compositions exists.
20. according to each application among the claim 1-19, wherein said compositions comprises the pH controlling agent, so that described compositions has the pH of 7.5-10 scope.
21. according to the application of claim 20, wherein said combination comprises the pH controlling agent, so that described compositions has the pH of 9.2-9.4 scope.
22. according to each application among the claim 1-21, wherein said calcium ion chelator comprises EDTA.
23. method for the treatment of or preventing the cancerous tumour of bacteria mediated, it comprises gives the metal ion chelation agent of effective dose with the human or animal who gives the such treatment of needs, and wherein said metal ion chelation agent provides the metal ion-chelant ability of at least a metal ion that is relied at described tumorigenic bacteria survival.
24. method for the treatment of or preventing the cancerous tumour of bacteria mediated, it comprises the human or animal who at least a metal ion chelation agent of effective dose is administered to the such treatment of needs, and wherein said at least a metal ion chelation agent provides the metal ion-chelant ability at calcium ion and at least a metal ion that survival is relied at described tumorigenic bacteria.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0415768A GB0415768D0 (en) | 2004-07-15 | 2004-07-15 | Methods of manufacture, applications and delivery of chelating substances or compounds for the purpose of treating bacteria associated with cancerous lesions |
| GB0415768.1 | 2004-07-15 | ||
| GB0508411.6 | 2005-04-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101031301A true CN101031301A (en) | 2007-09-05 |
Family
ID=32893566
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580030893 Pending CN101031301A (en) | 2004-07-15 | 2005-07-15 | Treatment of tumours |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101031301A (en) |
| GB (1) | GB0415768D0 (en) |
| ZA (1) | ZA200703882B (en) |
-
2004
- 2004-07-15 GB GB0415768A patent/GB0415768D0/en not_active Ceased
-
2005
- 2005-07-15 CN CN 200580030893 patent/CN101031301A/en active Pending
-
2007
- 2007-05-14 ZA ZA200703882A patent/ZA200703882B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200703882B (en) | 2009-07-29 |
| GB0415768D0 (en) | 2004-08-18 |
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Open date: 20070905 |