CN1953748A - A therapeutic agent containing nicotinic acid or its derivatives as an effective ingredient for prevention and treatment of cancer - Google Patents
A therapeutic agent containing nicotinic acid or its derivatives as an effective ingredient for prevention and treatment of cancer Download PDFInfo
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- CN1953748A CN1953748A CNA2005800153487A CN200580015348A CN1953748A CN 1953748 A CN1953748 A CN 1953748A CN A2005800153487 A CNA2005800153487 A CN A2005800153487A CN 200580015348 A CN200580015348 A CN 200580015348A CN 1953748 A CN1953748 A CN 1953748A
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Abstract
The present invention relates to a niacinamide or a derivatives therefrom, specifically, agents for preventing cancer and therapeutics comprising a niacinamide or a derivatives therefrom enhancing the expression of RUNX3 gene, cancer-suppressing gene which is inactivated by methylation. agents for preventing cancer and therapeutics of the present invention is used to cancer which relates to inactivation of RUNX3 such as gastric, lung, liver, larynx, colon, bladdar, prostate, pancreas, uterine and breast cancer.
Description
[technical field]
The present invention relates to a kind of medicament that is used to prevent and treat cancer; it contains the nicotinic acid or derivatives thereof as effective ingredient; more specifically; the present invention relates to a kind of medicament that is used to prevent and treat cancer; it contains the nicotinic acid or derivatives thereof as effective ingredient; described nicotinic acid or derivatives thereof strengthens the RUNX3 gene; a kind of by the expression of the cancer suppressor gene of methylation deactivation, and by preventing that the proteic deacetylation of RUNX3 (deacethylation) from suppressing the proteic decomposition of RUNX3 and activating described gene.
[background technology]
Now, 3 kinds of main Therapeutic Method of cancer are surgical operation, chemotherapy and X-ray therapy.And in fact, carrying out multiplex method with combinations such as said method and laser therapies.Consider the pain of treatment or the probability of transfer, chemotherapy is expected most among them.Therefore, various anticancer agents and they are used for auxiliary chemotherapy been have clinically have been researched and developed.Kill the principle of enlivening splitted cell based on selectivity, researched and developed those medicaments.Yet those medicaments not only kill cancer cell also kill and enliven splitted normal cell, such as immunocyte, hair follicle cell etc., cause serious adverse, so that those medicaments of chronic administration are infeasible.Therefore, it is important researching and developing new anticancer agent based on the basic treatment of cancer cause.
Although the abnormality proliferation of oncogene active inducing cell, tumor suppressor gene suppresses the abnormality proliferation of cell, and hinders the generation of tumor cell sometimes by the special target cell of operation cell death program crash.Even when comprising the oncogene of abnormal activation in cell, the described cell of normal effect by tumor suppressor gene can not grow up to tumor cell.Therefore, in order to produce tumor cell, the deactivation of oncogene active and tumor suppressor gene should take place in cell simultaneously.
Inappropriate cell proliferation, a kind of feature of tumor cell, being determined is that deactivation by oncogene active and tumor suppressor gene causes simultaneously.Especially, the programmed cell death of the dependence of the TGF-β in the normal cell plays an important role in resisting tumor cell.At this moment, the deactivation of tumor suppressor gene promotes cell division, and suppresses the programmed cell death that TGF-β relies on, and this causes the generation of tumor cell.
A kind of crucial viewpoint that causes the tumor suppressor gene deactivation is the unusual dna methylation effect (Jones and Laird, Nature genet.21,163-167,1999) on the CpG island.Methylation in the CpG island is by the dna methylation enzyme induction.When such methylation was carried out, the MeCP2 protein binding caused concentrating of histone deacetylase (deacethylase) in methylated DNA.Then, histone deacetylase removes the acetyl group (acethyl group) that is connected on the histone, and therefore, dna structure on every side is fine and close more, and this causes the inhibition of gene expression.Can express again by the activity of dna methylation enzyme inhibitor or histone deacetylase inhibitor by the gene that the dna methylation effect suppresses.
Acetylation/deacetylation is not only in histone but also in some transcription factor, such as taking place among p53, the RUNX3 etc.For example, when the acetylation in RUNX3 is induced, suppressed proteolysis by ubiquitination, but promoted RUNX3 activity (Jin etc., J.Biol.Chem.2004,279 the volume, the 29409-17 page or leaf).That is, the active promotion of RUNX3 is caused by the inhibition of deacetylated effect.Therefore, acetylation/deacetylation is a kind of very important mechanism of modulin function.
In fact, report recently, RUNX3, it is the tumor suppressor gene that the inventor determines previously, it is expressed in many human cancers and is suppressed by the dna methylation effect, for example, and according to those reports, being expressed in the gastric cancer of RUNX3 60% be suppressed (Li QL etc., Cell.2002109 (1): 113-24; Oshimo Y. etc., Pathobiology.2004,71 (3): 137-43), 25-40% is suppressed (.BBRC.2004 such as LI QL, 314 (1): 223-8 in pulmonary carcinoma; Kim TY etc., Lab Invest.2004,84 (4): 479-84), 62% is suppressed in laryngeal carcinoma, in breast carcinoma, 25% be suppressed (KimTY etc., Lab Invest.2004,84 (4): 479-84), in cancer of pancreas, 70% be suppressed (LiJ etc., JClin Patho1.2004 57 (3): 294-9; Wada M etc., Oncogene.2004,23 (13): 2401-7), 73% is suppressed (Xiao WH and Liu WW, World JGastroenterol.2004,10 (3): 376-80 in hepatocarcinoma; Kim TY etc., Lab Invest.2004,84 (4): 479-84), in cancer of biliary duct, 75% be suppressed (Wada M etc., Oncogene.2004,23 (13): 2401-7), in carcinoma of prostate, 23% be suppressed (Kang GH etc., J.Pathol.2004,202 (2): 233-40; Kim TY etc., Lab Invest.2004,84 (4): 45% be suppressed 479-84) and in colon cancer (Ku JL etc., Oncogene, 2004,23,6736-6742).
In addition, the activation that proves the RUNX3 gene suppress significantly tumor cell proliferation (Li etc., Cell, 109 (1), 113-24,2002; Balmain, Nature 417 (6886), 235-7,2002).Based on this proof, be used to prevent and the research and development for the treatment of the medicament of cancer have concentrated on the research of RUNX3 gene activation.
Therefore, the inventor attempts finding out the factor that can activate RUNX3, and described RUNX3 is a kind of tumor suppressor gene, and it is inactivated in cancer cell in vivo.Therefore, the inventor finds such fact, that is, nicotinic acid and derivant thereof can activate by the RUNX3 gene of methylation deactivation, and increases the proteic amount of RUNX3.And in addition, the inventor can be used for prevention effectively by definite nicotinic acid and derivant thereof and treat cancer and finish the present invention.
[disclosure]
[technical problem]
The purpose of this invention is to provide and contain the nicotinic acid or derivatives thereof is used to prevent and treat cancer as effective ingredient medicament, it can activate the RUNX3 gene, a kind of tumor suppressor gene that in tumor cell, is inactivated by methylation, and promotion is derived from the proteic activity of RUNX3 of described gene.
[technical scheme]
To achieve these goals, the invention provides the medicament that is used to prevent and treat cancer, it contains the nicotinic acid or derivatives thereof as effective ingredient.
Hereinafter, describe the present invention in detail.
The invention provides the medicament that is used to prevent and treat cancer, it contains the nicotinic acid or derivatives thereof as effective ingredient.
The medicament that inventor's expectation can activate the tumor suppressor gene RUNX3 that is inactivated in vivo again has antitumaous effect.Therefore, the inventor has found a kind of material that can activate the RUNX3 gene, and the result has determined that nicotiamide can activate RUNX3.
Inventor's research, RUNX3, whether a kind of tumor suppressor gene is methylated in tumor tissues, with the relation of tumor development and methylation among the check cancer patient.As a result, the RUNX3 gene is usually methylated in cancer patient's tissue, and proves that demonstrating methylated those patients' groups of RUNX3 has a high proportion of cancer return and transfer (referring to table 1-table 3).
The above results shows that activating by the RUNX3 of methylation deactivation is a kind of method of prophylaxis of cancer development again.And this idea impels the inventor to seek the material that can activate the RUNX3 gene, as the effort that detects the medicament that hinders cancer generation and development.As a result, determine that nicotiamide can activate by the RUNX3 of methylation deactivation (referring to Fig. 2) again.
Also study nicotiamide and whether can increase the proteic amount of RUNX3.The result; because RUNX3 is by being decomposed by the inductive deacetylation of histone deacetylase, the proteic amount of RUNX3 reduces, yet; using of nicotiamide causes the acetylizad increase of RUNX3 albumen, and this causes the increase (referring to Fig. 3 and Fig. 4) of described proteic amount.
In order to determine the vivo antitumor effect of nicotiamide, in the mice that suffers from the cancer of bringing out, observe the inhibition that tumor forms by carcinogen.This paper is used as carcinogen with N-butyl-N-4-(hydroxyl butyl)-nitrosamine (BBN), and take place with the tumor that is provided to BBN and nicotinamide soln continues as drinking water between the mice in 20 weeks by relatively being provided to BBN solution continued for 20 weeks as drinking water mice, analyze the inhibition (referring to Fig. 5 and Fig. 6) of tumor formation.As a result,, in the CpG island in RUNX3 exons 1 zone, induce to methylate, mean the activity inhibited of RUNX3 in the BBN processed group.Therefore, 100% has developed bladder cancer in described group, and 80% is that infiltrating carcinoma and 23% is for shallow table cancer in them.In contrast, in BBN and nicotiamide processed group, in the CpG island in RUNX3 exons 1 zone, methylation is reduced significantly, the minimizing (58%) that this causes bladder cancer to take place, and the pernicious of cancer also reduced.Therefore, have only 23% in them for infiltrating carcinoma, and 77% be shallow table cancer in them.The above results shows, nicotiamide suppresses the deactivation of the RUNX3 that caused by BBN, and this shows that it can suppress the tumor that BBN causes and take place.
From The above results, confirm that nicotiamide of the present invention can activate the RUNX3 of the deactivation that methylated again, and therefore suppress tumor growth significantly.
According to The above results, find tumor suppressor gene RUNX3, in fact, at various human cancers, in gastric cancer, pulmonary carcinoma, laryngeal carcinoma, breast carcinoma, cancer of pancreas, hepatocarcinoma, cancer of biliary duct, carcinoma of prostate, colon cancer etc., by methylation be inactivated (Li QL etc., Cell.2002109 (1): 113-24; Oshimo Y. etc., Pathobiology.2004,71 (3): 137-43); .BBRC.2004 such as LI QL, 314 (1): 223-8; Kim TY etc., Lab Invest.2004,84 (4): 479-84; Li J etc., J Clin Pathol.2004 57 (3): 294-9; Wada M etc., Oncogene.2004,23 (13): 2401-7; Xiao WH and Liu WW World J Gastroenterol.2004,10 (3): 376-80; Kang GH etc., J.Pathol.2004,202 (2): 233-40; Ku JL etc., Oncogene, 2004,23,6736-6742), and the activation of proof RUNX3 gene significantly the propagation of anticancer (Kim etc., Lab Invest.84 (4), 479-84,2004; Wada etc., Oncogen, 23 (13), 2401-7,2004; Li etc., Biochem Biophys Res Commun, 314 (1) .223-8,2004; Li etc., Cell, 109 (1), 113-24,2002; Li etc., Cell, 109 (1), 113-24,2002; Balmain, Nature, 417 (6886), 235-7,2002).Therefore, the pharmaceutical composition that comprises the nicotinic acid or derivatives thereof as effective ingredient of the present invention, can activate the RUNX3 gene again, therefore described compositions can be used to effectively prevent and treat many inductive cancers of deactivation by RUNX3, for example gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, carcinoma of prostate, cancer of pancreas, uterus carcinoma or breast carcinoma.
The nicotinic acid or derivatives thereof can be used to prevent and treat the effective ingredient of the medicament of cancer as the present invention, and described nicotinic acid derivates can comprise nicotiamide, nicotinic acid, 6-aminonicotinamide, Pyrazinamide, isonicotinic acid hydrazide (isonicotinohydrazide), N-methylnicotinamide, nicorandil (nicorandil), pyridine-2-carboxylic acid amides (pyridine-2-carboxamide), Thionicotinamide (thionicotin amide) or 6-chloro-nicotinamide.
The nicotinic acid derivates that contains of the present invention can oral or parenteral as the pharmaceutical composition of effective ingredient, and can use with the general type of pharmaceutical preparation.
Pharmaceutical composition of the present invention can be used for oral or parenteral by preparing with common used filler, supplement, binding agent, wetting agent, disintegrating agent, diluent such as surfactant or mixed with excipients.The solid preparation that is used for oral administration is tablet, pill, face powder, granule and capsule.These solid preparations are prepared such as mixing such as starch, calcium carbonate, sucrose, lactose, gelatin by with one or more appropriate excipients.Except described simple excipient, can be with lubricator, for example magnesium stearate, Talcum etc.The liquid preparation that is used for oral administration is suspension, solution, Emulsion and syrup, and preparation mentioned above is except containing used simple diluent usually, outside water and liquid paraffin, can comprise various excipient, such as wetting agent, sweeting agent, aromatic and antiseptic.The preparation that is used for parenteral is aseptic aqueous solution, water-insoluble excipient, suspension, Emulsion and suppository.Water-insoluble excipient and suspension can contain propylene glycol except containing one or more reactive compounds, Polyethylene Glycol, and vegetable oil such as olive oil, injectable ester, as ethyl oleate (ethylolate), etc.Except one or more reactive compounds, suppository can comprise witepsol, Polyethylene Glycol, tween 61, cocoa butter, laurin fat, glycerin jelly (glycerogelatin) etc.
The effective dose of nicotinic acid derivates of the present invention is 1～50mg/kg, and 10～30mg/kg more preferably, and administration frequency is every day 1～3 time.
In mice, carry out the acute toxic test that carries out with nicotinic acid derivates.In the group of handling with nicotinic acid derivates, up to the dosage of 2g/kg, do not observe any variation, and, compare with the group of application of water only, do not observe any pronounced side effects yet.
The present invention also provides the method that prevents and/or treats for cancer, and it comprises the step that nicotinic acid derivates is administered to target subject.The present invention also provides the application that nicotinic acid derivates is used to prepare the medicament that prevents and/or treats cancer.
[accompanying drawing description]
Figure 1A be show by PCR confirm the RUNX3 gene in normal structure not by methylated electrophoresis photo,,
M: methylated DNA U: unmethylated DNA
Figure 1B be show by PCR confirm the RUNX3 gene in Bladder Cancer by methylated electrophoresis photo,,
M: methylated DNA U: unmethylated DNA
Fig. 2 is that demonstration is handled the activated electrophoresis photo of methylated RUNX3 by nicotiamide,
Fig. 3 shows the photo that the proteic amount of RUNX3 is reduced by combination histone deacetylase (Sirt2),
Fig. 4 is such photo; its demonstration, the proteic minimizing of RUNX3 that is caused by histone deacetylase (Sirt2) is relevant with the inhibition of RUNX3 acetylation, and on the contrary; interior proteic acetylation of RUNX3 of cell and the proteic increase of RUNX3 that causes thus are inductive by using nicotiamide
Fig. 5 is the photo by the Bladder Cancer that is observed visually, it is presented at and is provided to a kind of carcinogen N-butyl-N-4-(hydroxyl butyl)-nitrosamine (BBN) solution continued for 20 weeks as drinking water group, and be provided to BBN and nicotinamide soln as tumorigenic comparison between another group in lasting 20 weeks of drinking water
Fig. 6 A shows to be provided to BBN solution, and a kind of carcinogen continues the microphotograph of bladder body of the mice in 20 weeks as drinking water,
Fig. 6 B shows to be provided to BBN and nicotinamide soln continue the mice in 20 weeks as drinking water the microphotograph of bladder body.
[best mode]
Embodiment preferred practicality of the present invention and present is illustrated as in the following embodiments.
Yet, should be appreciated that consider the disclosure of invention, those skilled in the art can carry out various changes and improvement within the spirit and scope of the present invention.
＜embodiment 1〉RUNX3 methylates and the mutual relation of tumor between taking place
In order to determine whether the RUNX3 gene is methylated in cancer patient's tissue, extract the tissue of bladder cancer patients and research methylating wherein.Particularly, from normal bladder tissue and Bladder Cancer, extract genomic DNA, be purified then, then use 3M NaSO
2(sodium bisulfite, (sodium bisulfite)) handled 16 hours at 50 ℃.In above-mentioned processing procedure, the cytosine among the DNA becomes not by methylated uracil.
After the processing, purify DNA once more.Then, application is carried out PCR based on two groups of primers of the sequence preparation on the CpG island of RUNX3 genomic DNA; One group of primer forming by SEQ.ID.No 1 and SEQ.ID.No2 methylated DNA that is used to increase, another group primer of forming by SEQ.ID.No 3 and the SEQ.ID.No 4 unmethylated DNA that is used to increase.PCR is undertaken by following; 94 ℃ of degeneration 14 seconds, 60 ℃ of annealing 50 seconds, 40 circulations are carried out in 72 ℃ of polymerizations 58 seconds from the degeneration to the polymerization.
The PCR that uses above-mentioned primer can determine that whether the RUNX3 gene is by the deactivation that methylates.If DNA means so that with primer sets SEQ.ID.No 1 and SEQ.ID.No 2 amplifications RUNX3 is by the deactivation that methylates.Similarly, if DNA means so that with primer sets SEQ.ID.No 3 and SEQ.ID.No 4 amplifications RUNX3 is not methylated.
As shown in FIG. 1, methylation is not observed in the promoter region of the RUNX3 gene in the normal bladder tissue that extracts from 20 normal individuals.Simultaneously, in the bladder cancer patients tissue, observe 74% methylation (having 88 in 119 individualities).About the bladder tumor recurrence rate, in their cancerous tissue, make the RUNX3 gene do not demonstrated 61.11% relapse rate, and those make the RUNX3 gene be demonstrated 88% relapse rate by methylated patient in their cancerous tissue by methylated patient.That is, have among the patient of methylated RUNX3 gene at those, the chance of cancer return is very high (table 1).
[table 1]
RUNX3 methylate and the cancer return rate between mutual relation
| Do not methylate | Methylate | |
| Not recurrence (%) | 14(38.89) | 6(12.00) |
| Recurrence (%) | 22(61.11) | 44(88.00) |
p＝0.0036，OR＝4.6667，95％CI＝1.5774-13.8064
As shown in the table 2, RUNX3 is fast by the progress of cancer in the methylated cancerous tissue therein.94.74% the patient who suffers from terminal cancer has methylated RUNX3 gene, and this shows that methylating of RUNX3 gene plays an important role in the progress of cancer.
[table 2]
RUNX3 methylate and cancer progression between mutual relation
| Do not methylate | Methylate | |
| Do not make progress (%) | 21(33.33) | 42(66.67) |
| Progress (%) | 1(5.26) | 18(94.74) |
p＝0.0155，OR＝9.00，95％CI＝1.1236-72.0598
In a word, do not have derivative cancer cell to compare with the methylation of RUNX3 gene wherein, the methylation of RUNX3 gene takes place that tumor increase by 109 times in the cancer cell, and with the cancer return rate with cancer progression increases by 500 respectively and 9 times.
＜embodiment 2〉nicotiamide is to the activation of RUNX3
Based on from above-mentioned＜embodiment 1〉result that obtained, the inventor seeks the material of the methylation that can suppress tumor suppressor gene RUNX3, and result, the inventor have determined that nicotiamide and derivant thereof can suppress the methylation of RUNX3 gene.
With the culture solution of nicotiamide managing cancer cell line, wherein the RUNX3 gene is by dna methylation effect deactivation.This processing continues 4 days, and final concentration is adjusted to 1mg/ml.Application is carried out reverse transcriptase-polymerase chain reaction (RT-PCT) by the Ps-CA of SEQ.ID.No 5 representative with by the primer sets of the Ps-CB of SEQ.ID.No 6 representatives, to detect the RUNX3 expression of gene.As shown in FIG. 2, be SUN16 and MKN74 at stomach cancer cell, lung cancer cell line NCl-H226 among NCl-H460 and Sq-1 and the bladder cancer cell lines T24, confirms that nicotiamide activates the RUNX gene by the methylation deactivation again.
＜embodiment 3〉decompose RUNX3 albumen by deacetylation
In order to study the mutual relation between deacetylation and the RUNX3 albuminolysis, the gene that will express Sirt2 (III type histone deacetylase) and RUNX3 respectively is inserted in the cell line of expressing Sir2 and RUNX3 independently or together.Carry out immunoprecipitation and Western blotting, with the effect of studying described insertion (Janeway etc., the 5th edition .Garland Publishing of Immunobiology., 2001).
The result, (IP:RUNX3 detects in IB:Sirt2) Sirt2 albumen, and the immunoprecipitation (IP:Sirt2 of RUNX3 albumen from carrying out with Sirt2 from the immunoprecipitation that carries out with RUNX3, IB:RUNX3) detect (Fig. 3) in, this shows that RUNX3 and Sirt2 are relevant physically.Also confirm the proteic amount of RUNX3 reduced by Sirt2 (Fig. 3, IB:RUNX3).
＜embodiment 4〉increase the proteic amount of RUNX3 by nicotiamide
Induce the cell inner expression of RUNX3, Acetylase (p300) and deacetylase (Sirt2), and nicotiamide is added in the cell culture medium, to study the variation of the RUNX3 protein level that causes by nicotiamide.In order to study, carry out immunoprecipitation and Western blotting.As a result, express the proteic minimizing of RUNX3 (Fig. 4, swimming lane 1 and 2) that causes by Sirt2 and be resumed (Fig. 4, swimming lane 3,4 and 5) by using nicotiamide.
＜embodiment 5〉the vivo antitumor effect of nicotiamide
In order to determine the anticancer effect of nicotiamide, suffer from mice by application by the inductive cancer of carcinogen, carry out tumor test takes place to suppress.Mice is divided into 2 groups: give one group 0.05% (w/w) N-butyl-N-4-(hydroxyl butyl)-nitrosamine (BBN) solution is provided, a kind of carcinogen, continued for 20 weeks as drinking water, provide 0.05%BBN and 1% (w/w) nicotiamide (10mg/ml) solution to continue for 20 weeks as drinking water to another group.And between these 2 groups, compare.Here, the C3H/HE female mice with 6 ages in week is used as test animal.Provide water or 1% (W/W) nicotinamide soln to continue for 20 weeks to control group mice.In the last day of experiment, mice is put to death, and extract bladder, with the methylation of research RUNX3 gene and the formation and size of tumor.
By the development of bladder cancer in naked eyes and the microscopic examination experimental group, as shown in Fig. 5 and Fig. 6 A.Definitely, BBN induces in the CpG island in RUNX3 exons 1 zone and methylates, and this causes the active inhibition to RUNX3.Therefore, in the group of handling with BBN, 100% has developed bladder cancer.Especially, be infiltrating carcinoma by 80% in the inductive cancer of BBN, 20% is shallow table cancer (table 3) in them.
[table 3]
The carcinogenic pattern of 0.05%BBN processed group
| Individual | The tumor number | Tumor size (mm) | |
| 1 | 1 | 4×3 | |
| 2 | All | 6×5 | |
| 3 | 1 | 5×5 | |
| 4 | 1 | 1×3 | |
| 5 | All | 5×5 | Wellability |
| 6 | 4 | Little | Shallow |
| 7 | 1 | 5×3 | Wellability+shallow |
| 2 | 1×1 | ||
| 8 | Little | Shallow | |
| 9 | All | 7×6 | |
| 10 | 1 | 3×2 | Shallow |
| 11 | All | 6×5 | Wellability |
| 12 | All | 9×8 | Wellability |
| 13 | 1 | 4×3 | Wellability |
| 14 | 1 | 3×2 | Wellability |
| 15 | 1 | 3×2 | Wellability |
| 16 | All | 10×9 | Wellability |
| 17 | All | 5×4 | Wellability |
| 18 | All | 4×4 | Wellability |
| 19 | 1 | 2×2 | Shallow |
| 20 | 1 | 2×2 | Wellability |
In the group of handling together with BBN and nicotiamide, the methylation in RUNX3 exons 1 zone C pG island has reduced significantly.In described group, the development rate of bladder cancer is low to moderate 58% (Fig. 5 and Fig. 6 B), and has perniciously also reduced (23% cancer be infiltrating and 77% for shallow) (table 4).The above results shows that nicotiamide suppresses the deactivation of BBN to RUNX3, this means that the tumor that nicotiamide can suppress to be brought out by BBN takes place.
[table 4]
The carcinogenic pattern of 0.05%RRN and nicotiamide processed group
| Individual | The tumor number | Tumor size (mm) | |
| 1 | 1 | 3×3 | |
| 2 | 0 | ||
| 3 | 0 | ||
| 4 | 0 | ||
| 5 | 1 | 2×2 | Shallow |
| 6 | 0 | ||
| 7 | 1 | 5×5 | Wellability |
| 8 | 0 | ||
| 9 | 1 | 1×1 | |
| 10 | 0 | ||
| 11 | Little | 1×1 | Shallow |
| 12 | 4 | 1×1 | Shallow |
| 13 | 0 | ||
| 14 | 1+ is little | 7×5 | Wellability/shallow |
| 15 | 1 | 3×1/1×1 | Shallow |
| 16 | 0 |
| 17 | 1 | 1×1 | Shallow |
| 18 | 2 | 1×1 | Shallow |
| 19 | 1 | 3×2 | Shallow |
| 20 | 0 | ||
| 21 | 0 | ||
| 22 | 0 | ||
| 23 | 0 | ||
| 24 | 1+ is little | 3×3/1×1 | Shallow |
| 25 | 0 | ||
| 26 | 1 | 3×3 | Shallow |
| 27 | 2 | 2×2 | Shallow |
| 28 | 1 | 1×1 | Shallow |
| 29 | 3 | 2×1/1×1 | Shallow |
| 30 | 4/5 | 6×5 | Wellability |
| 31 | 3 | 4×2/1×1 | Wellability/shallow |
| 32 | 1 | 3×3 | Shallow |
| 33 | 1 | 4×4 | Wellability |
| 34 | 0 | ||
| 35 | 1 | 2×1 | Shallow |
| 36 | 1 | 2×1 | Shallow |
| 37 | 0 | ||
| 38 | 0 | ||
| 39 | 0 | ||
| 40 | 0 |
＜embodiment 6〉suppress methylation in the body by nicotinic acid and derivant thereof
The inventor studies the inhibition to methylation in the body of nicotinic acid and derivant thereof, and the result is as follows.
[table 5]
Nicotinic acid derivates is to the inhibition of methylation in the body
| Group | Individual number | Methylate | Do not methylate |
| The BBN+ nicotiamide | 28 | 5(17.9％) | 23(82.1％) |
| BBN+ nicotinic acid | 28 | 8(28.6％) | 20(71.4％) |
| The BBN+ aminonicotinamide | 27 | 7(25.9％) | 20(74.1％) |
| The BBN+ Pyrazinamide | 27 | 11(40.7％) | 16(59.3％) |
| The BBN+ isonicotinic acid hydrazide | 29 | 15(51.7％) | 14(48.3％) |
| The BBN+ methylnicotinamide | 26 | 6(23％) | 20(77％) |
| The BBN+ nicorandil | 27 | 18(66.7％) | 9(33.3％) |
| BBN+ pyridine-2-carboxylic acid amides | 28 | 10(35.7％) | 18(64.3％) |
| The BBN+ Thionicotinamide | 28 | 15(53.6％) | 13(46.4％) |
| The BBN+ picolinic acid | 27 | 16(59.3％) | 11(40.7％) |
| The BBN+ chloro-nicotinamide | 30 | 8(26.7％) | 22(73.3％) |
In the group of handling with BBN, the methylation of RUNX3 gene is induced by 100% ground, but in the group of handling together with BBN and nicotinic acid or derivatives thereof, described methylation is suppressed, as shown in the table 4.Therefore, think that the nicotinic acid or derivatives thereof has active anticancer.
＜embodiment 7〉by the oral acute toxic test that is applied in the mice
Carry out following experiment, in mice (C3H/HE6), whether have acute toxicity as the pharmaceutical composition of effective ingredient to observe the nicotinic acid or derivatives thereof that contains of the present invention.Drug composition oral of the present invention is administered to every group of 2 mices, and as drinking water, the dosage of 2g/kg continues 5 months with every day.Observe death, clinical symptoms and the body weight change of mice, carry out the hematology's test and the biochemical test of blood, and in the obduction process, with any unusual sign among the gastrointestinal organ in eye detection thoracic cavity and abdominal cavity.The result shows that pharmaceutical composition of the present invention does not cause any special clinical symptoms, weight change or death in Mus.In hematology's test, biochemical test and the obduction of blood, do not observe any variation.Therefore,, the level that reaches 2g/kg at pharmaceutical composition described in the mice do not change owing to causing any toxicity, and the LD of its estimation
50Value much larger than 5g/kg, estimates that pharmaceutical compositions for use is a safe material in this experiment in mice.
[industrial usability]
The present invention relates to be used to prevent and treat the medicament of cancer, it contains the nicotinic acid or derivatives thereof as effective ingredient, more properly, the present invention relates to be used to prevent and treat the medicament of cancer, it contains the nicotinic acid of the RUNX3 gene that can activate the deactivation that methylated again and derivant thereof as effective ingredient.Of the present inventionly be used to prevent to be used for the treatment of the entity cancer relevant with the deactivation of RUNX3 gene effectively, such as gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, carcinoma of prostate, cancer of pancreas, uterus carcinoma or breast carcinoma with prevention with the medicament for the treatment of cancer.The conventional anticarcinogen that shows very active fissional cell is different with being designed to kill, medicament of the present invention is based on the principle exploitation that activates the tumor suppressor gene in the cancerous cell, and this makes it become a kind of material standed for likely with new type anticancer agent of side effect still less.
[sequence list text none]
SEQ.ID.No 1 and SEQ.ID.No 2 are used to increase the primer of methylate DNA,
SEQ.ID.No 3 and SEQ.ID.No 4 are used to increase the not primer of methylate DNA,
SEQ.ID.No 5 is Ps-CA primers,
SEQ.ID.No 6 is Ps-CB primers.
Those skilled in the art should be appreciated that, can easily the basis that makes an amendment or design identical other embodiment of purpose of implementation the present invention be used in disclosed design in aforementioned detailed description and specific embodiment.Those skilled in the art be also to be understood that these embodiments of equal value do not deviate from the spirit and scope of the present invention as proposing in accompanying Claim.
Sequence table
＜110〉biological as this Zhu Shi commercial firm of Encke
＜120〉contain the nicotiamide or derivatives thereof and be used for prevention and the agent of treatment treatment for cancer as effective ingredient
<160>6
<170>Kopatent In 1.71
<210>1
<211>24
<212>DNA
＜213〉artificial sequence
<220>
＜223〉be used for the primer that methylate DNA increases
<400>1
ttacgagggg cggtcgtacg cggg 24
<210>2
<211>24
<212>DNA
＜213〉artificial sequence
<220>
＜223〉be used for the primer that methylate DNA increases
<400>2
aaaacgaccg acgcgaacgc ctcc 24
<210>3
<211>24
<212>DNA
＜213〉artificial sequence
<220>
＜223〉be used for the not primer of methylate DNA amplification
<400>3
ttatgagggg tggttgtatg tggg 24
<210>4
<211>24
<212>DNA
＜213〉artificial sequence
<220>
＜223〉be used for the not primer of methylate DNA amplification
<400>4
aaaacaacca acacaaacac ctcc 24
<210>5
<211>25
<212>DNA
＜213〉artificial sequence
<220>
<223>Ps-CA
<400>5
gagtttcacc ctgaccatca ctgtg 25
<210>6
<211>25
<212>DNA
＜213〉artificial sequence
<220>
<223>Ps-CB
<400>6
gcccatcact ggtcttgaag gttgt 25
Claims (according to the modification of the 19th of treaty)
1. medicament that is used to prevent and treats the cancer that the inactivation by tumor suppressor gene RUNX3 causes, it comprises nicotinic acid, its derivant or its pharmaceutical salts with following formula as effective ingredient:
Wherein, R
1Be oxygen or sulfur, R
2Be H, OH, C
1～C
10Alkyl, NH
2, NH-NH
2, NH-C
2H
4-O-NO
2-or OR
3, R
3Be C
1～C
5Alkyl, X are H, NH
2Or halogen atom, and Y is H or CH
3
2. according to the medicament of claim 1, wherein said R
2Be C
1～C
5Alkyl.
3. according to the medicament of claim 1, wherein said halogen atom is F or Cl.
4. according to the medicament of claim 1, wherein said R
2Be CH
3Or C
2H
5
5. according to the medicament of claim 1, wherein said nicotinic acid derivates is selected from the group of being made up of following: nicotiamide, nicotinic acid, 6-aminonicotinamide, Pyrazinamide (isonicotinamide), isonicotinic acid hydrazide (isonicotinohydrazide), the N-methylnicotinamide, nicorandil (nicorandil), pyridine-2-carboxylic acid amides (pyridine-2-carboxamide), Thionicotinamide (thionicotin amide) and 6-chloro-nicotinamide.
6. according to the medicament of claim 1, wherein said cancer is selected from the group of being made up of following: gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, cancer of pancreas, cancer of pancreas, uterus carcinoma, the esophageal carcinoma and breast carcinoma.
7. method for cancer that the inactivation that prevents and/or treats by tumor suppressor gene RUNX3 causes, it comprises to target subject uses nicotinic acid, its derivant or its pharmaceutical salts.
8. according to the method for claim 7, wherein said nicotinic acid derivates is selected from the group of being made up of following: nicotiamide, nicotinic acid, 6-aminonicotinamide, Pyrazinamide, isonicotinic acid hydrazide, N-methylnicotinamide, nicorandil, pyridine-2-carboxylic acid amides, Thionicotinamide and 6-chloro-nicotinamide.
9. according to the method for claim 7, wherein said cancer is selected from the group of being made up of following: gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, cancer of pancreas, cancer of pancreas, uterus carcinoma, the esophageal carcinoma and breast carcinoma.
10. nicotinic acid, its derivant or its pharmaceutical salts are used to prepare the application of the medicament that prevents and/or treats the cancer that the inactivation by tumor suppressor gene RUNX3 causes.
11. according to the application of claim 10, wherein said nicotinic acid derivates is selected from the group of being made up of following: nicotiamide, nicotinic acid, 6-aminonicotinamide, Pyrazinamide, isonicotinic acid hydrazide, N-methylnicotinamide, nicorandil, pyridine-2-carboxylic acid amides, Thionicotinamide and 6-chloro-nicotinamide.
12. according to the application of claim 10, wherein said cancer is selected from the group of being made up of following: gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, cancer of pancreas, cancer of pancreas, uterus carcinoma, the esophageal carcinoma and breast carcinoma.
13. a method that is used to activate the gene of RUNX3 or coding RUNX3, it comprises to the experimenter uses nicotinic acid, its derivant or its pharmaceutical salts, and described patient suffers from the cancer that the inactivation by tumor suppressor gene RUNX3 causes.
14. according to the method for claim 13, the wherein said experimenter who suffers from cancer has the RUNX3 of deacetylation (deacethylated).
15. according to the method for claim 13, wherein the inactivation of tumor suppressor gene RUNX3 is caused by the methylation of described gene RUNX3.
16. according to the method for claim 13, wherein said cancer is selected from the group of being made up of following: gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, cancer of pancreas, cancer of pancreas, uterus carcinoma, the esophageal carcinoma and breast carcinoma.
Claims (16)
1. medicament that is used to prevent and treat cancer, it contains nicotinic acid or derivatives thereof with following formula as effective ingredient:
Wherein, R
1Be oxygen or sulfur, R
2Be H, OH, C
1～C
10Alkyl, NH
2, NH-NH
2, NH-C
2H
4-O-NO
2-or OR
3, R
3Be C
1～C
5Alkyl, X are H, NH
2Or halogen atom, and Y is H or CH
3
2. the medicament that is used to prevent and treat cancer that proposes in the claim 1, wherein said R
1Be C
1～C
5Alkyl.
3. the medicament that is used to prevent and treat cancer that proposes in the claim 1, wherein said halogen atom is F or Cl.
4. the medicament that is used to prevent and treat cancer that proposes in the claim 1, wherein said R
2Be CH
3Or C
2H
5
5. the medicament that is used to prevent and treat cancer that proposes in the claim 1, wherein said nicotinic acid derivates is selected from the group of being made up of following: nicotiamide, nicotinic acid, 6-aminonicotinamide, Pyrazinamide (isonicotinamide), isonicotinic acid hydrazide (isonicotinohydrazide), the N-methylnicotinamide, nicorandil (nicorandil), pyridine-2-carboxylic acid amides (pyridine-2-carboxamide), Thionicotinamide (thionicotin amide) and 6-chloro-nicotinamide.
6. the medicament that is used to prevent and treat cancer that proposes in the claim 1, wherein said cancer is selected from the group of being made up of following: gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, cancer of pancreas, cancer of pancreas, uterus carcinoma, the esophageal carcinoma and breast carcinoma.
7. one kind prevents and/or treats method for cancer, and it comprises to target subject uses the nicotinic acid derivates of claim 1 or the step of its pharmaceutical salts.
8. what propose in the claim 7 prevents and/or treats method for cancer, wherein said nicotinic acid derivates is selected from the group of being made up of following: nicotiamide, nicotinic acid, 6-aminonicotinamide, Pyrazinamide, isonicotinic acid hydrazide, the N-methylnicotinamide, nicorandil, pyridine-2-carboxylic acid amides, Thionicotinamide and 6-chloro-nicotinamide.
9. what propose in the claim 7 prevents and/or treats method for cancer, and wherein said cancer is selected from the group of being made up of following: gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, cancer of pancreas, cancer of pancreas, uterus carcinoma, the esophageal carcinoma and breast carcinoma.
10. the nicotinic acid derivates of claim 1 or its pharmaceutical salts application that is used to prepare the medicament that prevents and/or treats cancer.
11. the application that proposes in the claim 10, wherein said nicotinic acid derivates is selected from the group of being made up of following: nicotiamide, nicotinic acid, 6-aminonicotinamide, Pyrazinamide, isonicotinic acid hydrazide, N-methylnicotinamide, nicorandil, pyridine-2-carboxylic acid amides, Thionicotinamide and 6-chloro-nicotinamide.
12. the application that proposes in the claim 10, wherein said cancer is selected from the group of being made up of following: gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, cancer of pancreas, cancer of pancreas, uterus carcinoma, the esophageal carcinoma and breast carcinoma.
13. a method that is used to activate the gene of RUNX3 or coding RUNX3, it comprises the step of using the nicotinic acid derivates of claim 1 to the experimenter who suffers from cancer.
14. the method that proposes in the claim 13, the wherein said experimenter who suffers from cancer has the RUNX3 of deacetylation (deacethylated).
15. the method that proposes in the claim 13, the wherein said experimenter who suffers from cancer has the gene of methylated coding RUNX3.
16. the method that proposes in the claim 13, wherein said cancer is selected from the group of being made up of following: gastric cancer, pulmonary carcinoma, hepatoma, laryngeal carcinoma, colorectal carcinoma, bladder cancer, cancer of pancreas, cancer of pancreas, uterus carcinoma, the esophageal carcinoma and breast carcinoma.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20040033323 | 2004-05-12 | ||
| KR1020040033323 | 2004-05-12 | ||
| PCT/KR2005/001399 WO2005115388A1 (en) | 2004-05-12 | 2005-05-12 | A therapeutic agent containing nicotinic acid or its derivatives as an effective ingredient for prevention and treatment of cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1953748A true CN1953748A (en) | 2007-04-25 |
Family
ID=35450646
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800153487A Pending CN1953748A (en) | 2004-05-12 | 2005-05-12 | A therapeutic agent containing nicotinic acid or its derivatives as an effective ingredient for prevention and treatment of cancer |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1753425A4 (en) |
| JP (1) | JP2007537246A (en) |
| KR (1) | KR100775549B1 (en) |
| CN (1) | CN1953748A (en) |
| WO (1) | WO2005115388A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016062281A1 (en) * | 2014-10-24 | 2016-04-28 | 朗齐生物医学股份有限公司 | Applications of cardiovascular disease medicaments in preparing cancer-inhibiting pharmaceutical composition |
| CN108478573A (en) * | 2018-03-30 | 2018-09-04 | 浙江中医药大学 | A kind of 1- methylnicotinamides prepare prevent or treatment alcoholic fatty liver drug in application |
| CN108514561A (en) * | 2018-05-21 | 2018-09-11 | 复旦大学 | Application of the niacinamide in preventing and treating signet ring cell cancer |
| CN109364074A (en) * | 2018-11-01 | 2019-02-22 | 重庆医科大学 | 6-aminonicotinamide is preparing the purposes in therapeutic agent for hepatitis B as effective component |
| CN109942566A (en) * | 2019-03-19 | 2019-06-28 | 厦门稀土材料研究所 | Isonicotinic acid derivatives and its preparation method and application |
| CN115176998A (en) * | 2016-04-14 | 2022-10-14 | 可劳迈戴斯有限公司 | Use of nicotinamide riboside, nicotinic acid riboside, nicotinamide mononucleotide and nicotinyl compound derivatives in infant formula |
| CN117281804A (en) * | 2023-11-14 | 2023-12-26 | 北京大学 | New application of nicotinic acid and new derivatives thereof in preparation of medicines for preventing or treating liver cancer |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7611847B2 (en) | 2005-06-01 | 2009-11-03 | Agency For Science, Technology And Research | Method for identifying an intestinal phenotype |
| WO2011113300A1 (en) * | 2010-03-15 | 2011-09-22 | Yan Xiaojing | Medicines for inhibiting toxicity or side effects caused by chemotherapeutic agents |
| TWI648403B (en) * | 2016-07-29 | 2019-01-21 | 臺北醫學大學 | Diagnosis of gynecological tumors |
| GB2586745B (en) * | 2018-03-13 | 2023-04-05 | Nuchido Ltd | Compositions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0534097A (en) * | 1991-07-30 | 1993-02-09 | Mitsubishi Heavy Ind Ltd | Composite guidance device for missile |
| AU2090099A (en) * | 1997-12-16 | 1999-07-05 | William Darwin Garner | Reduction of uv induced skin cancer by topical amines |
| US7241743B2 (en) * | 2001-06-15 | 2007-07-10 | The Trustees Of Columbia University In The City Of New York | Sir2α-based therapeutic and prophylactic methods |
-
2005
- 2005-05-12 JP JP2007513069A patent/JP2007537246A/en not_active Withdrawn
- 2005-05-12 CN CNA2005800153487A patent/CN1953748A/en active Pending
- 2005-05-12 KR KR1020050039767A patent/KR100775549B1/en active IP Right Grant
- 2005-05-12 EP EP05764719A patent/EP1753425A4/en not_active Withdrawn
- 2005-05-12 WO PCT/KR2005/001399 patent/WO2005115388A1/en active Application Filing
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016062281A1 (en) * | 2014-10-24 | 2016-04-28 | 朗齐生物医学股份有限公司 | Applications of cardiovascular disease medicaments in preparing cancer-inhibiting pharmaceutical composition |
| CN115176998A (en) * | 2016-04-14 | 2022-10-14 | 可劳迈戴斯有限公司 | Use of nicotinamide riboside, nicotinic acid riboside, nicotinamide mononucleotide and nicotinyl compound derivatives in infant formula |
| CN108478573A (en) * | 2018-03-30 | 2018-09-04 | 浙江中医药大学 | A kind of 1- methylnicotinamides prepare prevent or treatment alcoholic fatty liver drug in application |
| CN108514561A (en) * | 2018-05-21 | 2018-09-11 | 复旦大学 | Application of the niacinamide in preventing and treating signet ring cell cancer |
| CN109364074A (en) * | 2018-11-01 | 2019-02-22 | 重庆医科大学 | 6-aminonicotinamide is preparing the purposes in therapeutic agent for hepatitis B as effective component |
| CN109364074B (en) * | 2018-11-01 | 2021-05-07 | 重庆医科大学 | Application of 6-aminonicotinamide as effective component in preparing medicament for treating hepatitis B |
| CN109942566A (en) * | 2019-03-19 | 2019-06-28 | 厦门稀土材料研究所 | Isonicotinic acid derivatives and its preparation method and application |
| CN117281804A (en) * | 2023-11-14 | 2023-12-26 | 北京大学 | New application of nicotinic acid and new derivatives thereof in preparation of medicines for preventing or treating liver cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1753425A1 (en) | 2007-02-21 |
| EP1753425A4 (en) | 2009-08-05 |
| JP2007537246A (en) | 2007-12-20 |
| KR20060047820A (en) | 2006-05-18 |
| WO2005115388A1 (en) | 2005-12-08 |
| KR100775549B1 (en) | 2007-11-16 |
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Open date: 20070425 |