CN102085217B - Pharmaceutical composition containing medicinal calcium salt for early preventing colorectal adenoma or colorectal cancer - Google Patents
Pharmaceutical composition containing medicinal calcium salt for early preventing colorectal adenoma or colorectal cancer Download PDFInfo
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- CN102085217B CN102085217B CN2011100020904A CN201110002090A CN102085217B CN 102085217 B CN102085217 B CN 102085217B CN 2011100020904 A CN2011100020904 A CN 2011100020904A CN 201110002090 A CN201110002090 A CN 201110002090A CN 102085217 B CN102085217 B CN 102085217B
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Abstract
The invention discloses a pharmaceutical composition containing medicinal calcium salt for early preventing colorectal adenoma or colorectal cancer. The pharmaceutical composition contains sodium butyrate and medicinal calcium salt, wherein the mass ratio of the sodium butyrate to elemental calcium in the pharmaceutical composition is (2.47-4.95):1. The pharmaceutical composition disclosed by the invention can reduce cancer genes related to the colorectal cancer and can increase related cancer suppressor genes and signal passages to suppress colorectal cancer cell proliferation and migration capabilities and retard cell growth cycle, thereby achieving the purposes of suppressing the occurrence of the colorectal cancer, lowering the incidence rate of the colorectal cancer of mice, and reducing the tumor volume.
Description
Technical field:
The present invention relates to the pharmaceutical chemistry field, relate in particular to a kind of pharmaceutical composition, the particularly a kind of early prevention large intestine adenoma of medicinal calcium salt or pharmaceutical composition of colorectal cancer of containing.
Background technology:
Colorectal cancer is one of modal in the world three big cancers at present, and in China, along with rhythm of life is accelerated and the life style westernization, the generation of colorectal cancer makes progress and presents the trend that increases year by year.Its generation of the generation of colorectal cancer is relevant unusually with hereditary variation and epigenetic.Although Epidemiological study shows pteroylglutamic acid (pteroylglutamic acid respectively; PGA), n-butyric acie sodium (Sodium butyrate), vitamin D etc. have certain preventive effect to colorectal cancer; But Recent study conclusion as a result differs; We combine result of study in the past, think and to continue period with said medicine foundation level, intervention opportunity and dosage in the body, also have hereditism's variation of tumor-related gene relevant unusually with epigenetic modification.In the prior art, the effect of medicine that is used for prophylactic treatment large intestine adenoma, colorectal cancer is all undesirable, the prevention method that lack effectively, side effect is little and patient dependence is good.
Summary of the invention:
The purpose of this invention is to provide a kind of early prevention large intestine adenoma of medicinal calcium salt or pharmaceutical composition of colorectal cancer of containing, the pharmaceutical composition of described this early prevention large intestine adenoma that contains medicinal calcium salt or colorectal cancer will solve the unfavorable technical problem of effect that is used for the medicine that early prevention large intestine adenoma, colorectal cancer take place in the prior art.
The present invention is a kind of early prevention large intestine adenoma of medicinal calcium salt or pharmaceutical composition of colorectal cancer of containing, and contains n-butyric acie sodium and medicinal calcium salt in the described pharmaceutical composition, and the mass ratio of described n-butyric acie sodium and calcium constituent is at 2.47-4.95: between 1.
Further, also contain vitamin D3 in the described pharmaceutical composition, the quality of described vitamin D3 is the 0.1-1.0IU/mg calcium constituent.
Further, described medicinal calcium salt is medicinal inorganic calcium salt or pharmaceutically acceptable organic acid calcium, or medicinal calcium amino acid chelate or medicinal organism albumen calcium salt.
Further, described medicinal inorganic calcium salt is calcium carbonate or calcium hydroxide or calcium phosphate.
Further, described pharmaceutically acceptable organic acid calcium is calcium lactate or calcium acetate or calcium gluconate or calcium citrate.
Further, described medicinal calcium amino acid chelate is an amino acid calcium.
Further, described medicinal organism albumen calcium is phosphopeptide caseinate calcium.
Further, also contain the carrier of pharmaceutically accepting.
Further, the dosage form of described pharmaceutical composition is pharmaceutically acceptable dosage form.Concrete, described dosage form is tablet, injection, oral liquid etc.
Action principle of the present invention: the n-butyric acie sodium that the present invention selects for use (Sodium butyrate) molecular formula C
4H
7NaO
2, relative molecular mass is 110.09, calcium (Ca) form of calcium ion in the present invention absorbs.N-butyric acie sodium can impel mitochondrion to discharge cytochrome C through reducing transmembrane potential, improves the proteolytic activity of caspase3, finally causes the apoptosis of colon cancer cell.Ruemmele etc. find also that under study for action sodium butyrate can improve CaCO
3The expression of cell mitochondrial apoptosis-related protein bak reduces anti apoptotic protein bcl x level, and impels mitochondrion to discharge cytochrome C, finally causes the activation of a series of apoptotic pathways.See that from the effect of present in vitro tests and clinical practice n-butyric acie sodium is for the good efficacy that has of prevention colorectal cancer.
About calcium preparation the preventive effect of colorectal cancer is had report repeatly, but the studies result exists dispute.Think inventor aspect calcium prevention colorectal cancer machine-processed: calcium can reduce its stimulation to big intestinal mucosa through being combined with the material that toxic secondary bile acid forms slightly solubility; Calcium can suppress the calcium channel TRPV6 on the colon epithelial cell and suppress the generation of its atypical hyperplasia; Perhaps directly through inducing differentiation, suppress propagation and apoptosis-induced and bring into play its preventive effect.It is similar for the tumor-related gene action target spot that n-butyric acie sodium and calcium have, and both help the Normocellular vicious transformation of early stage blocking-up large intestine in time in the Combined application of effective dosage ranges, and the duplicating of tumor cell, Invasion and Metastasis.
The present invention is combined with n-butyric acie sodium (Sodium butyrate) and calcium; The vicious transformation that can effectively suppress the large intestine normal mucosa; The expression of the relevant oncogene of downward modulation colorectal cancer, thus the colorectal cancer cells proliferation activity suppressed, blocked the colorectal cancer cells growth cycle; Stop Invasion and Metastasis, thereby play incidence rate that lowers mice colorectal cancer and the effect that reduces gross tumor volume.Pharmaceutical composition of the present invention (when colorectal cancer does not produce as yet), capacity and omnidistance preventive effect of intervening in early days is better.
The present invention compares with prior art, and its effect is actively with tangible.The present invention is with n-butyric acie sodium (Sodium butyrate) and calcium (containing vitamin D3) combination; Prevent colorectal cancer to compare with independent use n-butyric acie sodium (Sodium butyrate) or calcium; The vicious transformation that can obviously suppress the normal colonic mucosa cell; Suppress growth of tumour cell, significantly lower the incidence rate of mice colorectal cancer and reduce gross tumor volume.
Description of drawings:
Fig. 1 is that the cardinal principle of DMH modeling 24 all mice colorectal cancer is at the body sketch map.Wherein, A is n-butyric acie sodium+DMH modeling group, and B is calcium+DMH modeling group.
Fig. 2 is the stripped photo of mice large intestine.Wherein, A is DMH modeling figure, and B is n-butyric acie sodium+DMH modeling figure, and C is n-butyric acie sodium+DMH modeling figure, and D is calcium+n-butyric acie sodium+DMH modeling figure.
Fig. 3 is the mice BIAO and BEN HE dyeing picture (200*) in the embodiments of the invention.
Fig. 4 is the mice BIAO and BEN HE dyeing picture (400*) in the embodiments of the invention.
Fig. 5 is the chip of expression spectrum cluster analysis quality control collection of illustrative plates in the embodiments of the invention.
Fig. 6 is that the chip of expression spectrum in the embodiments of the invention is intervened medicine tumor-related gene influenced collection of illustrative plates 1.
Fig. 7 is that the chip of expression spectrum in the embodiments of the invention is intervened medicine tumor-related gene influenced collection of illustrative plates 2.
Fig. 8 is intervention mainly influences about n-butyric acie sodium forms the coherent signal path and shift relevant core gene TGF β 1 with tumor invasion with tumor.
Fig. 9 is intervention mainly influences about n-butyric acie sodium forms the coherent signal path and shift relevant core gene PI3K with tumor invasion with tumor.
Figure 10 is reaching and tumor and the relevant core gene NF-κ B of chronic inflammatory disease with tumor formation coherent signal path that intervention mainly influences about calcium.
Figure 11 is reaching and tumor and the relevant core gene FOXM1 of chronic inflammatory disease with tumor formation coherent signal path that intervention mainly influences about calcium.
The specific embodiment:
Buy 352 of mices of S-ICR (SCXK (Shanghai) 2003-0003) from laboratory animal base, Chinese Academy of Sciences Songjiang, the cleaning level, female, outbreeding system, body weight 18～20g is divided into 16 groups at random, 22 of every treated animals.Raise a week back (0week) and begin experiment.
Concrete grouping and delivery time, mode are following:
1) n-butyric acie sodium effect: 1.5% concentration gives drinking water every day continuously.Intervened late period in the 13rd week and intervene medicine (13-24week); Early stage whole process is intervened in the 1st week beginning (1-24week).
2) calcium you strange (available from U.S. Hui Shi-hundred palace pharmaceutical Co. Ltd) acts on: 1.82mg/ is (containing vitamin D3 0.38iu) only, and drink every day continuously.Intervened late period in the 13rd week and intervene medicine (13-24week); Early stage whole process is intervened in the 1st week beginning (1-24week).
3) unite the addition that is that gives: the effect of n-butyric acie sodium: 1.5% concentration gives in the 3-6ml drinking water every day continuously; You very act on calcium: 1.82mg/ is (containing vitamin D3 0.38iu) only, and drink every day continuously; Intervened late period in the 13rd week and intervene medicine (13-24week); Early stage whole process is intervened in the 1st week beginning (1-24week).The mass ratio of n-butyric acie sodium and calcium (containing vitamin D3 0.21iu) is 2.47: 1 to 4.95: 1 a scope.
4) DMH modeling: DMH is with physiological saline solution, subcutaneous injection DMH (20mg/kg, 1 time/week, continuous 20 weeks)+corresponding medicine.
5) NS normal saline contrast: subcutaneous injection NS (20mg/kg, 1 time/week, continuous 20 weeks).To 24 weeks put to death laboratory animal in batches, observe the large intestine pathological changes after dissecting, BIAO and BEN is seen Fig. 1 and Fig. 2 substantially, specifically intervenes grouping and result and sees table 1.Obviously draw materials at the place from pathological changes, the fixing back making of neutral formalin paraffin section, HE dyeing back is observed DMH success modeling generation large intestine adenoma and is seen (Fig. 3 and Fig. 4).
The result is intervened in table 1 zoopery
Annotate: relatively adopt X 2 test between the tumor formation rate group,
△Each group compares P＜0.05 with DMH modeling group in the later stage intervention,
*Early stage omnidistance intervention groups and DMH modeling group be P＜0.05 relatively.
Known that by above the present invention can be lowered the incidence rate of mice colorectal cancer, reduces gross tumor volume, its early stage, omnidistance combined effect is superior to independent intervention group.And the movable nothing of the normal growth of mice is obviously suppressed.
Embodiment 2 tissue specimen Agilent chip of expression spectrum are analyzed
The chip of expression spectrum that present embodiment adopts, from Anjelen Sci. & Tech. Inc, concrete experimental technique is with reference to the experimental procedure of Agilent company:
www.agilent.com/chem/dnamanuals-protocols。
1 quality control: use TRIzol (Invitrogen) and extract total RNA; RNasey Mini kit (Qiagen p/n 74104) washs total RNA, Quick Amp label ing kit, onecolor (Agilent p/n 5190-0442) labelling; The RNA of RNasey Mini kit (Qiagen p/n74104) purification labelling; NanoDrop ND-1000 carries out quality testing, then with full chip gene expression profile whole genome oligo microarray (AgilentTechnologies, Palo Alto available from Agilent company; CA; USA) hybridization, operate according to recommendation step: hybridize well and use Agilent microarray scanner (Agilent p/n G2565BA) after the washing and scan chip, application Agilent Feature Extraction Software (version 10.5.1.1) carries out graphical analysis and data fetch; Cluster analysis shows that specimen quality is feasible, Fig. 5.
2 screening group difference genes (TwoClassDif): utilize Tobin's mean variance model (RVM) at random; The multiple comparisons check; Calculate significance level (P-value) and the False Rate (FDR) of gene differences, obtain the medication intervention group and the gene of intervention group differential expression not thereby screen.Differential gene between group is used Fold-change calculating and T-test check and is drawn, those Fold change>=1.5, and P value≤0.05 are considered to be in the differential gene that remarkable change is arranged between two groups in the T check.
3 chip of expression spectrum GO-Signet analyze
3.1 differential gene imported carry out gene function classification among the Gene Ontology (www.geneontology.org), be the GO clauses and subclauses that the boundary filters out remarkable change with P≤0.05.
3.1.1 what intervention mainly influenced about n-butyric acie sodium forms (cell differentiation, CDC, cell proliferation, apoptosis, cell adhesion, angiogenesis, cell invasion) relevant gene with tumor, sees Fig. 6.
3.1.2 what intervention mainly influenced about calcium forms (cell differentiation, CDC, cell proliferation, apoptosis, cell adhesion, angiogenesis, cell invasion) relevant gene with tumor, sees Fig. 7.(calcium salt of this experiment employing is a calcium carbonate)
3.2 based on the signal transmission path among the data bases such as KEGG, Reactome, Biogrid; And the interactively between the gene, protein, chemical compound; Construct the signal delivery network between target gene and gene outcome; Thereby obtain the server gene, the key gene in the promptly above-mentioned target gene; Obtain intergenic interaction relationship through the signal transduction network simultaneously, the regulatory mechanism of reflected sample.(Signal-Net)
3.2.1 what intervention mainly influenced about n-butyric acie sodium forms the coherent signal path and shifts relevant core gene TGF β 1, PI3K with tumor invasion with tumor, sees Fig. 8-9.
3.2.2 what intervention mainly influenced about calcium reaches and tumor and relevant core gene NF-κ B, the FOXM1 of chronic inflammatory disease with tumor formation coherent signal path, sees Figure 10-11.
4 are analyzed and can be found out by above-mentioned GO; N-butyric acie sodium influences colorectal cancer with calcium and forms oncobiology action processes such as relevant cell differentiation, CDC, cell proliferation, apoptosis, cell adhesion, angiogenesis, cell invasion; Pharmaceutical composition of the present invention helps strengthening both curative effects, the generation and the progress of prevention colorectal cancer.Filter out the tumor-related gene that n-butyric acie sodium and calcium Combined application prevention large intestine adenoma, colorectal cancer mainly influence by chip results, like table 2.
The tumor-related gene that table 2 chip of expression spectrum is mainly regulated and control by n-butyric acie sodium and calcium Combined application is tabulated
Claims (3)
1. one kind contains the early prevention large intestine adenoma of medicinal calcium salt or the pharmaceutical composition of colorectal cancer; It is characterized in that: contain n-butyric acie sodium, calcium carbonate and vitamin D3 in the described pharmaceutical composition; The mass ratio of described n-butyric acie sodium and calcium constituent is at 2.47-4.95: between 1, the quality of described vitamin D3 is the 0.1-1.0IU/mg calcium constituent.
2. the early prevention large intestine adenoma of medicinal calcium salt or the pharmaceutical composition of colorectal cancer of containing as claimed in claim 1 is characterized in that: also contain the carrier of pharmaceutically accepting.
3. the early prevention large intestine adenoma of medicinal calcium salt or the pharmaceutical composition of colorectal cancer of containing as claimed in claim 1, it is characterized in that: the dosage form of described pharmaceutical composition is pharmaceutically acceptable dosage form.
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| KR101683635B1 (en) * | 2014-12-29 | 2016-12-09 | 가천대학교 산학협력단 | Pharmaceutical composition for treating cancer comprising lactate metallic salts |
| CN106974934A (en) * | 2017-03-16 | 2017-07-25 | 华中科技大学 | A kind of epirubicin based on calcium agent is combined chemotherapeutics and its application |
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Non-Patent Citations (3)
| Title |
|---|
| H. M. HAMER et. al..《the role of butyrate on colonic function》.《Alimentary Pharmacology & Therapeutics》.2008,第27卷(第2期),第104–119页. * |
| W. Scheppach et. al..《Role of short chain fatty acids in the prevention of colorectal cancer》.《European touranal of cancer》.1995,第31A卷(第7/8期),第1077-1080页. * |
| 张亚历,张振书,杨希山.《短链脂肪酸诱导的大肠肿瘤细胞凋亡》.《大肠癌的基础与临床》.1999,第94页. * |
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