CN1093763C - Anticancer substance suppressing cancerous metastasis - Google Patents
Anticancer substance suppressing cancerous metastasis Download PDFInfo
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- CN1093763C CN1093763C CN96194213A CN96194213A CN1093763C CN 1093763 C CN1093763 C CN 1093763C CN 96194213 A CN96194213 A CN 96194213A CN 96194213 A CN96194213 A CN 96194213A CN 1093763 C CN1093763 C CN 1093763C
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- sialic acid
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Abstract
The present invention aims to provide an anticancer agent which can suppress the diversion of cancer cells solely, and even if the anticancer agent is taken for a long time, the anticancer agent has small side effects and small toxicity. The anticancer agent for suppressing the diversion of the cancer cells of the present invention is characterized in that the anticancer agent contains sialic acid, sialate, and the salt of sialic polymers and/or sialic acid polymers for being used as effective components.
Description
Technical field
The present invention relates to significantly stop the anticarcinogen of cancer cell metastasis, provide, cure the medicament of cancer more perfectly by stoping cancer cell metastasis.
Background technology
In recent years, the treatment method for cancer can adopt the chemotherapy that gives various anticarcinogen, promote the immunotherapy that the antibody of anticancer cell produces, the surgical treatment of extracing cancerous cell and the actinotherapy by the irradiation kill cancer cell etc., because the development of these Therapeutic Method, surgical operation and actinotherapy are restricted on means, can not stop the transfer of cancer effectively.In addition, the chemotherapy of using anticarcinogen is direct and cancerous cell effect, but this moment, often the normal cell to the host has also produced deleterious side effect, and is not necessarily effective for preventing cancerometastasis.And then the immunotherapy of the immunocompetence treatment cancer by improving the host is preventing in the cancerometastasis, does not also find good result.The effect of treatment primary carcinoma has improved significantly now, even but cured primary carcinoma fully, because of cancer cell metastasis causes that dead situation is quite a few.For suppressing cancerometastasis, strong hope exploitation can stop the medicament of cancer cell metastasis.Can think that cancerous cell is by with the adhesion of cell membranes in tissue such as mesentery and extensively shift.
Pharmaceuticals as anticancer shifts will split
Rhzomorph and chemotherapeutics agent and time spent, can see the effect that has anticancer to shift, but the pharmaceuticals of anticancer transfer do not have also separately commercially available.In addition, open the spy that clear 60-190791, spy open clear 61-83125 and special opening discloses the effect that suppresses cancerometastasis about sialic acid derivative among the clear 62-223124, but do not narrate the sialic acid or derivatives thereof that uses as effective ingredient among the present invention and their inhibition cancerometastasis effect.
The problem that solves
The present invention in view of the above problems, the anticarcinogen that its purpose is to provide anticancer separately to shift.In addition, take the anticarcinogen that the anticancer that side effect is also little and toxicity is very little shifts even the object of the present invention is to provide for a long time.
Solve the means of problem
The present invention finishes by the medicament that shifts from nature screening anticancer, relate to sialic acid and/or its salt as effective ingredient, the anticarcinogen that suppresses the cancerometastasis effect arranged.
In addition, the present invention relates to the salt of sialic polymer and/or this polymer as effective ingredient, the anticarcinogen that suppresses the cancerometastasis effect arranged.
Above-mentioned sialic polymer is preferably by polymer that 2 molecules～13 molecule sialic acides constitute.Owing to can be separated to 13 aggressiveness fractions effectively, thus will on be defined as 13 aggressiveness.Can expect that the saliva polymer and the salt thereof of 2～13 aggressiveness have the pharmacological effect identical with sialic acid and salt thereof.In addition,, can use pharmaceutically permissible various salt,, can use sodium salt, potassium salt, calcium salt, magnesium salt, in addition,, can use sodium salt as the salt of sialic acid polymer as the monomeric salt of sialic acid as the salt of sialic acid or its polymer.In addition, said sialic acid is meant (N-acetyl neuraminic acid) in present specification.
Preparation of the present invention can be enumerated the injection of transdermic absorbent, subcutaneous administration, intraperitoneal administration and intravenous administrations such as oral agents such as tablet, capsule and powder, suppository and vaginal suppository.When the prevention of disease, preferred oral agent, but when emergency, preferably injection.
The compound method of oral agents, transdermic absorbent and injection can be carried out with common compound method, below is the formulation example of enumerating oral agents and injection.
1) formulation example of injection:
With sialic acid or its polymer 50g, be dissolved in the distilled water (pyrogen-free) of 1000ml after, use soda lye, pH is transferred to 7.0, filter, sterilize with usual method, then, under aseptic condition, enclose in the 20ml ampoule, make injection.
2) formulation example of oral agents:
With 60 order sieving 280mg of sialic acid or its polymer, insert in No. 3 ' Yanming ' capsules for clearing, make capsule.
Dosage changes according to patient's age, sex, ill degree etc., so cannot treat different things as the same, but as being contained in the sialic acid in the injection or the sodium salt of its polymer, the adult is 1～2000mg/kg, 10～500mg/kg preferably every day, administration number of times was advisable with 1～6 time on 1st, and the intravenous drip drug administration by injection also is an effective method.
Because sialic acid is distributed in the sugar-chain end of the glycoprotein that exists in sugar-chain end on the cell surface that constitutes human body and blood, the body fluid mostly, so be for the few medicament of the adverse effect of human body.
Sialic acid used in the present invention and polymer thereof; the enzymatic synthesis product that can be synthetic, use acetylneuraminate aldolase or cytosine phosplate-N-acetyl neuraminic acid (CMP-NANA) synzyme and CMP-NANA transferring enzyme to obtain; and acid decomposes any in the water decomposition product of adding of cholodinic acid that cholodinic acid (コ ロ シ Application) obtains, but the present invention is not limited by these.
The accompanying drawing summary
Fig. 1 is the adhesion inhibition effect of expression sialic acid for cancerous cell rat M cell.
Fig. 2 is the sialic interaction partners LFA-1 antibody of expression suppresses effect to the adhesion of cancerous cell-rat M cell influence.
The preferred plan that carries out an invention
According to the present invention, in this anticarcinogen as the salt of the contained sialic acid of effective ingredient, sialate, sialic polymer, sialic acid polymer, but outer cell membrane adhesion such as anticancer and mesentery prevents cancer cell metastasis thus.In addition, as effective ingredient, sialic acid, sialate, sialic acid polymer and sialic acid polymer salt can use separately, in addition, also it can be used in combination more than 2 kinds.
By anticarcinogen of the present invention, can suppress cancerometastasis effectively.
Embodiment
Present inventors adopt system that most evil property cancerous cell-rat ascites hepatocarcinoma adheres to rat mesentery as measuring the inhibiting model system of cancer cell metastasis, use the cell line of easier maneuver.The former cancerous cell uses the AH66F-cell, and the latter's mesentery cell uses the M-cell.
State in the use when measuring screening system and being present in the various material of occurring in nature, can see that sialic acid and polymer anticancer thereof are adhered to the mesentery cell activity, and then, when the rat that use suffers from AH66F ascites hepatocarcinoma carries out zoopery, also can see the effect of significant prolongation life.Below, at length be illustrated with embodiment.
The effect of sialic acid and the adhesion of sialic acid polymer anticancer
Use Tissue Culture Plate, in the Eagle ' s of the improvement that reaches the ear Bake that contains 5% hyclone (FCS) culture medium (DMEM), cultivate mesentery cell (M-cell) from rat, cell be paved with the institute porose after, with the DMEM washing that does not contain FC3, and then, with the DMEM that contains sialic acid 10 μ g/ml or 100 μ g/ml, under 37 degree, cultivate.After 45 minutes, use the DMEM washing hole, add rat AH66F cell (4 * 10
4Individual/hole) and sialic acid (concentration shown in Figure 1) after, add DMEM, under 37 degree, cultivated 1 hour.After the cultivation, stirred for 30 seconds, culture supernatant is moved on in the probe tube.In each hole, add the new DMEM of 200 μ l, similarly stir 15 seconds, washing.Carry out this washing operation again 2 times, cleaning mixture and the culture supernatant that obtains merged.With it with 12,000rpm centrifugalize 5 minutes, remove supernatant after, add the new DMEM of 100 μ l, behind the suspension cell, at microscopically, calculate cell number (Abherent cell number) with blood counting chamber.
In addition, only cultivate cancerous cell in contrast, carry out identical operations after, measure cell number (control cells number).
Can obtain the adhesion rate of cancerous cell by following calculating formula.Its result as shown in Figure 1, but it is the meansigma methods of the concentration of 4 each acylneuraminate of hole.
Adhesion rate=(1-(Abherent cell number)/(control cells number)) * 100
As described in embodiment 1, when sialic acid concentration is 10 μ g/ml and 100 μ g/ml, stop the adhesion of 27% and 31% cancerous cell respectively to the mesentery cell.
Embodiment 2
The effect of acylneuraminate anticancer adhesion under the antibody coexistence of anti-LFA-1
In the cultivation that makes M-cell and AH66F cells contacting, except sialic concentration is 0 and 100 μ g/ml, simultaneously with anti-LFA-1 antibody 10 μ g/ml coexistence outside, other and embodiment 1 are identical.
Its result as shown in Figure 2.
Have in the presence of the rat anti LFA-1 antibody (antibody of anti-leukocyte function dependency antigen β chain) that stops the cancerous cell tackability known, do not add sialic acid and can suppress 40%, and, demonstrate the adhesion of prevention 70% when adding sialic acid 100 μ g/ml.This represents that anti-LFA-1 antibody stops the mechanism of cancerous cell adhesion different with sialic acid, has shown that also two kinds of materials have cooperative effect simultaneously.
Embodiment 3
In the test of model system, disclose the effect that acylneuraminate has the anticancer adhesion, so sialic acid and polymer thereof are studied the effect of the rat of trouble metastatic carcinoma (AH66F).Acylneuraminate is to suffering from the life prolongation effect of cancer rat
With AH66F cancerous cell (1 * 10
6Cells), be administered to east stream (Donryu) and be the intraperitoneal of male rat (6 age in week 100-120g, 6 every group) after, give 0.5ml sialic acid solution (administered dose: 10mg/kg and 100mg/kg) or normal saline (matched group) to intraperitoneal immediately.Then, give sialic acid or normal saline solution after 2 days, observe the existence natural law of rat at intraperitoneal.
Calculate life-delaying rate with following formula, its result is as shown in table 1.
Life-delaying rate=((the existence natural law of treatment group)-(the existence natural law of matched group)/
(the existence natural law of matched group)) * sialic life prolongation effect processed group existence natural law life-delaying rate contrast 7.3 ± 0.3-sialic acid 10mg/kg * 3 days 11.5 ± 0.4 58% in the carcinogenic rat of 100 table 1 AH66F cancerous cell
100mg/kg * 3 days 13.4 ± 0.4 84%
The result confirms, the existence natural law that does not give the acylneuraminate group is 7.3 ± 0.3 days, give sialic acid 10mg/kg group 1.6 times life prolongation effect, give the 100mg/kg group 1.8 times life prolongation effect is arranged.
Acute toxicity test
Obtaining and using Wister is the LD50 value of the intravenous administration of rat (male), and sialic acid and sialic trimerical sodium salt (pH 7.0) all are 2, more than the 000mg/kg.
Claims (3)
1. sialic acid or its salt application in the preparation anticarcinogen.
2. the application in the preparation anticarcinogen of sialic polymer or its salt.
3. the described application of claim 2, wherein sialic polymer are the polymer that the sialic acid by 2 molecules～13 molecules constitutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96194213A CN1093763C (en) | 1996-02-08 | 1996-02-08 | Anticancer substance suppressing cancerous metastasis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96194213A CN1093763C (en) | 1996-02-08 | 1996-02-08 | Anticancer substance suppressing cancerous metastasis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1185738A CN1185738A (en) | 1998-06-24 |
| CN1093763C true CN1093763C (en) | 2002-11-06 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96194213A Expired - Fee Related CN1093763C (en) | 1996-02-08 | 1996-02-08 | Anticancer substance suppressing cancerous metastasis |
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| Country | Link |
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| CN (1) | CN1093763C (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1158571A (en) * | 1995-05-25 | 1997-09-03 | 日本碍子株式会社 | Remedy for endotoxinemia andmultiple organ failure induced thereby |
-
1996
- 1996-02-08 CN CN96194213A patent/CN1093763C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1158571A (en) * | 1995-05-25 | 1997-09-03 | 日本碍子株式会社 | Remedy for endotoxinemia andmultiple organ failure induced thereby |
Non-Patent Citations (1)
| Title |
|---|
| 《中国医药工业杂志》20(10) 1989.10.31 冯万祥等唾液酸抗炎作用初步探讨 * |
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| Publication number | Publication date |
|---|---|
| CN1185738A (en) | 1998-06-24 |
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