CN103720693A - Application of five normal bases of human body in preparation of medicines for cancer treatment - Google Patents
Application of five normal bases of human body in preparation of medicines for cancer treatment Download PDFInfo
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Abstract
The invention discloses application of five normal bases of human body in preparation of medicines for cancer treatment. The five bases are applicable to cancer treatment field, and are prepared into an oral preparation, an injection, a slow-release preparation or a targeting preparation. Standard anti-tumor effect control proves that the five normal bases participating in human metabolism, when achieving a certain concentration in vivo and in vitro, have effects of inducing tumor cell apoptosis and resisting tumor angiogenesis in different degrees. The application disclosed by the invention has the advantages that the five bases, compared to other anti-tumor medicines, have broad-spectrum and low-toxicity anti-tumor effect, and are applicable to chemical treatment of malignant tumors such as gastric cancer, lung cancer, liver cancer, colon cancer, breast cancer, tumors of reproductive system and the like with obvious anti-tumor effect; the five normal bases, in conventional dosage, are free from bone marrow suppression and important organ injury, and are better in anti-tumor effect compared to normal nucleoside.
Description
The application is the divisional application of application number 2011103613136, November 15 2011 applying date, denomination of invention " five kinds of normal bases of human body are in the application of preparing in medicine for treating tumor thing ".
Technical field
The present invention relates to a kind of antitumor drug, specifically five of body metabolism kinds of normal bases, in the application of preparing in medicine for treating tumor thing, belong to tumour medicine field.
Background technology
The normal base of people comprises adenine (Adenine) CAS:73-24-5, molecular formula: C5H5N5, molecular weight: 135.13; Guanine (Guanine) CAS:73-40-5, molecular formula: C5H5N5O, molecular weight: 151.13; Cytosine (Cytosine) CAS:71-30-7, molecular formula: (C4H5N3O), molecular weight: 111.11; Thymus pyrimidine (Thymin) CAS:65-71-4, molecular formula: C5H6N2O2, molecular weight: 126.11; Uracil (Uracil) CAS:66-22-8, molecular formula: C4H4N2O2, molecular weight: 112.09.
Base form mainly with nucleoside monophosphate in DNA and RNA exists, but the formation of its pair relationhip depends primarily on base.The normal base of people is digested and assimilated in process and can be produced at nucleic acid material, is also that nucleic acid material is remedied synthetic important source material.But normal nucleotide metabolism can occur that directly forming metabolic waste excretes without base, as: adenosine → inosine → xanthosine → uric acid excretes.
Above five kinds of bases all can obtain with distinct methods in vitro, are important medicine and health product intermediate.Wherein adenine, claims again adenine phosphate, participates in vivo RNA and DNA synthetic.When leukocyte lacks, it can promote leucocyte hyperplasia, general medication 2～4 weeks, leukocyte number can increase, while being Patients Receiving Chemotherapy leucocytes reduction for the medicine of leukocyte increasing.The adenine of one of five kinds of bases of human body be because can participate in the synthetic of the nucleic acid such as DNA and RNA, can be in the materials such as synthetic ATP its important function, current adenine, claims again adenine phosphate, can be used for the treatment of the leukopenia due to Chemotherapy on Patient with Tumor etc.The external preservation that can be used for blood.
At present, in academia, universally recognized treatment tumor theory is: by add different elements or substituent group in normal base, form normal base analogue and block the synthetic of cell DNA or RNA, thereby suppress the diffusion of tumor.For example, name is called the patent application that " Synergistic anti-cancer compounds ", the patent No. are " CN200480036362.0 ", use antimetabolic base analogue is disclosed as antineoplastic composition, anti-tumor metabolism base analogue is by suppressing nucleus synzyme, and the growth of inhibition or prophylaxis of cancer and interference cell nucleic acid are synthetic.
Summary of the invention
The object of the invention is to, provide five kinds of normal bases of human body in the application of preparing in medicine for treating tumor thing, these five kinds of bases are respectively adenine, guanine, cytosine, thymine and uracil; Above-mentioned five kinds of bases are made to oral formulations, injection, slow releasing agent or targeting preparation, anti-curing oncoma successful, and multiple base combination is used as the ingredient for the treatment of tumor, more independent application can reach obvious raising antitumous effect, reduces toxic and side effects and delays the object that drug resistance occurs.
Technical scheme of the present invention is:
Five kinds of normal bases of human body are in the application of preparing in medicine for treating tumor thing, and described base comprises: adenine, guanine, cytosine, thymine and uracil.
Preferably, described base is one or more in adenine, guanine, cytosine, thymine and uracil;
Preferably, described base is the combination of one or both and adenine in guanine, cytosine, thymus pyrimidine or uracil.
Described medicine is oral tablet, injection or slow releasing agent.
The preparation method of described oral tablet is: add different auxiliary material as starch described base, the part by weight of base and adjuvant is 1:1, make oral tablet, described base total content is 10-30mg/ sheet, the weight size of tablet can be for example 1g, 2g or 5g etc., to its treatment and use, can not exert an influence;
The preparation method of described injection is: described base is dissolved in to the phosphate buffer solution that concentration is 5-25mg/mL, makes the injection that base total concentration is 5-25mg/mL, every injection volume is 2-10mL;
The preparation method of described slow releasing agent is: with medicinal liposome, microcapsule or micelle medicine-releasing system, described base is made to 5-25mg/mL slow releasing agent, then slow releasing agent is made to injection.
Further, the molal quantity of above-mentioned each base combination is identical.
Described tumor comprises the multiple common cancers such as gastric cancer, pulmonary carcinoma, hepatocarcinoma, colon cancer, breast carcinoma, leukemia, genital system tumor.
By research, find: guanine, cytosine, thymine and uracil antitumor action be lower than adenine, because the side effect of adenine very I and other base combine as antineoplastic agent.Different adenine composite reagents reduces than the single medicine concentration in single drug blood, thereby toxic and side effects declines.Multiple medicine composite reagent can delay the generation of drug resistance of tumor simultaneously.By composite reagent, the dosage in the time of can reducing each composition single drug, and the absolute concentration of every kind of concrete nucleoside obviously declines, medicine just declines to the toxic and side effects of body; Meanwhile, two or more chemotherapeutics composite reagent can reduce the generation of drug resistance greatly.By adenosine and other people's normal alkali is basis set close after, be used in the medicine of the above-mentioned tumor of preparation treatment, can add adjuvant and make oral formulations or add its dissolubility of the increases such as buffer salt and make injection, inject use; Injection can be regular injection agent, also various types of slow releasing injection.
Different tumors have different nucleic acid metabolisms and compositing characteristic, every kind of base of different tumor cells is had to different inhibition strengths, but the antitumor action of adenine are the strongest, and experiment in vitro is when concentration reaches 0.3mg/mL, and within 72 hours, tumor control rate is more than 90%.30% of single adenine treatment tumor tumorous size is alleviated completely, and effective percentage is more than 93.0%.
Using dosage is low, is 0.001～0.05mmol/Kg/ days, intramuscular injection or intravenous drip; Oral administration can increase dose 0.5-1.5 doubly.
The invention has the advantages that:
1, the basis set medicine closing for the preparation of multiple common cancers such as treatment gastric cancer, pulmonary carcinoma, hepatocarcinoma, colon cancer, breast carcinoma, genital system tumor of adenine and other people's normal alkali, antitumous effect is obvious, has the feature of efficient, wide spectrum, low toxicity;
2, adenine and the basis set antitumor action closing of other people's normal alkali are apparently higher than all kinds of nucleoside and combination thereof;
3, adenine reduces than the single medicine concentration in single drug blood with other people's normal alkali base composite reagent, thereby toxic and side effects reduces;
4, adenine and other people's normal alkali base composite reagent can delay the generation of drug resistance of tumor.
The specific embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein, only for description and interpretation the present invention, is not intended to limit the present invention.
embodiment 1
The external tumor suppression control experiment of the adenine of variable concentrations and 5-FU.
One, test method
By human cervical carcinoma Hela tumor cell (Chinese Academy of Sciences's Shanghai cell provides), with containing RPMI 1640 culture medium culturings of 10% new-born calf serum, the cell of the trophophase of taking the logarithm, with after 0.25% trypsinization with 3 × 10
3individual/hole is inoculated in 96 orifice plates, is placed in 37 ℃, 5%CO
2in incubator, cultivate 24 hours, establish 8 multiple holes for every group, test group establishes respectively that multiple hole drug level is 0.005,0.01,0.02,0.04,0.08,0.16,0.32,0.64mg/mL totally 8 total concentrations, the every hole 200 μ L of culture fluid, the 5-FU of matched group is identical with test group concentration, with serum-free medium dilution, the aseptic filtering with microporous membrane of 0.22 μ m.The Measuring Time of drafting 48 hours, inverted microscope observation of cell form was also taken pictures, and then every hole adds the MTT solution 20 μ L of 5mg/mL, is placed in 37 ℃, 5%CO
2in incubator, continue to cultivate 4 hours, stop cultivating, inhale and abandon the supernatant of cultivating in hole, every hole adds 150 μ L DMSO, shakes 10 minutes, after crystal is fully dissolved, with automatic microplate reader (Thermo, model MULTISKAN MK3), measure 570mn place absorbance.Every group of each plate established 8 multiple holes, and each experiment repeats 3 times, and in table 1, data are the average of three experiments.
Growth of tumour cell suppression ratio computing formula is as follows:
The OD value of the actual OD value/negative control hole of tumor cell survival rate (%)=medicine feeding hole;
Growth of tumour cell suppression ratio (%)=100%-cell survival rate.
Table 1: adenine was to 48 of Hela cell hours suppression ratio (%)
Wherein: Adenine is adenine, 5-FU is 5-fluorouracil.
Two, results and analysis
As calculated adenine and 5-FU in 0.005 to 0.64 concentration range 48 hours suppression ratio no difference of science of statistics to Hela cell (
p>0.5); Adenine IC50 is 70ug/mL left and right.
embodiment 2
The external tumor suppression experiment of five kinds of normal bases of people.
One, test method
By people's pulmonary carcinoma SPC tumor cell (Chinese Academy of Sciences's Shanghai cell provides), with containing RPMI 1640 culture medium culturings of 10% new-born calf serum, the cell of the trophophase of taking the logarithm, with after 0.25% trypsinization with 3 × 10
3individual/hole is inoculated in 96 orifice plates, is placed in 37 ℃, 5%CO
2in incubator, cultivate 24 hours, establish 8 multiple holes for every group, test group adds five kinds of bases, and each multiple hole drug level of five kinds of bases and matched group 5-FU is 0.5mg/mL, the every hole 200 μ L of culture fluid, the aseptic filtering with microporous membrane of 0.22 μ m.The Measuring Time of drafting 48 hours, inverted microscope observation of cell form was also taken pictures, and then every hole adds the MTT solution 20 μ L of 5mg/mL, is placed in 37 ℃, 5%CO
2in incubator, continue to cultivate 4 hours, stop cultivating, inhale and abandon the supernatant of cultivating in hole, every hole adds 150 μ L DMSO, shakes 10 minutes, after crystal is fully dissolved, with automatic microplate reader (Thermo, model MULTISKAN MK3), measure 570mn place absorbance.Every group of each plate established 8 multiple holes, and each experiment repeats 3 times, and in table 2, data are the average of three experiments.
Growth of tumour cell suppression ratio computing formula is as follows:
The OD value of the actual OD value/negative control hole of tumor cell survival rate (%)=medicine feeding hole;
Growth of tumour cell suppression ratio (%)=100%-cell survival rate.
Table 2: 48,72 hours suppression ratio (%) of the normal five kinds of base pair people pulmonary carcinoma SPC tumor cells of people
Wherein, A, G, C, T, U represent respectively adenine, guanine, cytosine, thymine and uracil.
Two, results and analysis
From upper table 2, can analyze:
1, guanine is because dissolubility is lower, and some drugs does not dissolve by filtering, actual concentrations 0.3mg/mL;
2, the suppression ratio of adenine is apparently higher than other base, and adenine is exactly adenine phosphate, treated leukopenia.
embodiment 3
A kind of tumor suppression of combination experiment in adenine and other four kinds of bases.
One, test method
By people's hepatocarcinoma HepG2 tumor cell (Chinese Academy of Sciences's Shanghai cell provides), with containing RPMI 1640 culture medium culturings of 10% new-born calf serum, the cell of the trophophase of taking the logarithm, with after 0.25% trypsinization with 3 × 10
3individual/hole is inoculated in 96 orifice plates, is placed in 37 ℃, 5%CO
2in incubator, cultivate 24 hours, establish 8 multiple holes for every group, test group adds A+G, A+C, A+T, A+U, and the combination molar ratio of adenine and other 4 kinds of bases is 1:1, and the concentration of two kinds of bases is respectively 0.25mg/mL.Each multiple hole medicine total concentration of 4 kinds of combinations of test group and matched group 5-FU is 0.5mg/mL.The every hole 200 μ L of culture fluid, the aseptic filtering with microporous membrane of 0.22 μ m.The Measuring Time of drafting 48 hours, inverted microscope observation of cell form was also taken pictures, and then every hole adds the MTT solution 20 μ L of 5mg/mL, is placed in 37 ℃, 5%CO
2in incubator, continue to cultivate 4 hours, stop cultivating, inhale and abandon the supernatant of cultivating in hole, every hole adds 150 μ L DMSO, shakes 10 minutes, after crystal is fully dissolved, with automatic microplate reader (Thermo, model MULTISKAN MK3), measure 570mn place absorbance.Every group of each plate established 8 multiple holes, and each experiment repeats 3 times, and in table 3, data are the average of three experiments.
Growth of tumour cell suppression ratio computing formula is as follows:
The OD value of the actual OD value/negative control hole of tumor cell survival rate (%)=medicine feeding hole;
Growth of tumour cell suppression ratio (%)=100%-cell survival rate.
Table 3: the suppression ratio (%) of the combination of adenine and other a kind of base to people's hepatocarcinoma HepG2
Wherein, A, G, C, T, U represent respectively adenine, guanine, cytosine, thymine and uracil.
Two, results and analysis
From table 3:
1, after adenine and any one other base mol ratio 1:1 combination, antitumor action slightly declines, but the absolute concentration of medicine declines 1/2;
2, the external tumor-inhibiting action A+T of four kinds of combinations is the strongest, and A+C is the most weak.
embodiment 4
The tumor suppression experiment of the wantonly two kinds of combinations in adenine and other four kinds of bases.
One, test method
By Human gastric careinoma cells BGC823 tumor cell (Chinese Academy of Sciences's Shanghai cell provides), with containing RPMI 1640 culture medium culturings of 10% new-born calf serum, the cell of the trophophase of taking the logarithm, with after 0.25% trypsinization with 3 × 10
3individual/hole is inoculated in 96 orifice plates, is placed in 37 ℃, 5%CO
2in incubator, cultivate 24 hours, establish 8 multiple holes for every group, test group adds A+C+U, A+G+C, A+C+T, A+T+U, A+U+G, any two kinds of combination mol ratios of adenine and other four kinds of bases are 1:1:1, each multiple hole medicine total concentration is 0.5mg/mL, and the concentration of three kinds of bases is respectively 0.167mg/mL.The concentration of matched group 5-FU is 0.5mg/mL.The every hole 200 μ L of culture fluid, the aseptic filtering with microporous membrane of 0.22 μ m.The Measuring Time of drafting 48 hours, inverted microscope observation of cell form was also taken pictures, and then every hole adds the MTT solution 20 μ L of 5mg/mL, is placed in 37 ℃, 5%CO
2in incubator, continue to cultivate 4 hours, stop cultivating, inhale and abandon the supernatant of cultivating in hole, every hole adds 150 μ L DMSO, shakes 10 minutes, after crystal is fully dissolved, with automatic microplate reader (Thermo, model MULTISKAN MK3), measure 570mn place absorbance.Every group of each plate established 8 multiple holes, and each experiment repeats 3 times, and in table 3, data are the average of three experiments.
Growth of tumour cell suppression ratio computing formula is as follows:
The OD value of the actual OD value/negative control hole of tumor cell survival rate (%)=medicine feeding hole;
Growth of tumour cell suppression ratio (%)=100%-cell survival rate.
Table 4: adenine and other two kinds of bases combine Human gastric careinoma cells BGC823 suppression ratio (%)
Wherein, A, G, C, T, U represent respectively adenine, guanine, cytosine, thymine and uracil.
Two, results and analysis
From table 4:
1, after adenine and other two kinds other base mol ratio 1:1:1 combinations, antitumor action has decline, but the absolute concentration of medicine declines 2/3;
2, the external tumor-inhibiting action A+T+U of five kinds of combinations is the strongest, and A+G+C is the most weak.
embodiment 5
Oral capsule agent producing process
1, specification and formula
1.1 formulas: 10mg/ grain
Adenine: 10g(is in anhydride)
Microcrystalline Cellulose: 66g
Carboxymethyl starch sodium: 15g
Magnesium stearate: 2g
Make: 1000.
Each component effect in 1.2 formulas
Adenine: principal agent; Microcrystalline Cellulose: diluent; Carboxymethyl starch sodium: disintegrating agent; Magnesium stearate: lubricant.
2, technique
(1) adenine crushed after being dried is crossed to 60 mesh sieves, 80 ℃ of microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate are dry, cross 100 mesh sieves, standby;
(2) take adenine, microcrystalline Cellulose, carboxymethyl starch sodium, the magnesium stearate of formula ratio, mix homogeneously;
(3) encapsulated;
(4) the full review of sampling, packs to obtain finished product after qualified.
Two, using method
For people's using method, 60-120mg/ days, point 3 ante cibum are oral.
embodiment 6
Adenine lotus tumor rabbit MRI pharmacodynamic study
Application background suppresses the Diffusion MR Images technology and hydrogen proton MR spectroscopy study dynamic monitoring adenine and reacts after to the treatment of VX2 liver transplantation tumor; In conjunction with relevant pathological change, inquire into the effect of magnetic resonance molecular imaging in adenine antitumor drug effect is evaluated, its Anticancer Effect and Mechanism of preliminary identification.The leftlobe of liver of the purebred White Rabbit of New Zealand is opened celiophyma piece planting method tumor piece is planted in employing.After inoculation, with size and the growing state of two-dimensional ultrasound monitoring tumor, when tumor is grown to 0.5-1.5cm size, lotus tumor rabbit is divided into totally three groups of adenine group (A group), Endostatin group (B group) and blank groups (C group), 8 every group at random.In lotus tumor, after 14 days, start auricular vein injectable drug, A group gives adenine 4.0mg/kg; B group gives Endostatin 1.0mg/kg; C group gives normal saline 0.3mL/kg, medication every day once, continuous use 10 days.Three groups all after first 1 day of medication and medication the conventional sequence of 2,7,13 days row MR, STIR-EPI-DWI check, after first 1 day of medication and medication, 10 days row 1H-MRS check.Measure respectively each group of tumor tissues compound choline (choline before and after different time points apparent diffusion coefficient ADC value and treatment, Cho) peak and lipid (lipid, Lip) peak height at peak, measures gross tumor volume simultaneously and evaluates the signal characteristic on T1WI, T2WI image.Within after treatment the 14th day, put to death total Test animal and take out tumor piece, the fresh tumor tissues of the aseptic part of drawing materials does the expression of fluorescence real-time quantitative PCR detection tumor VEGF-A mRNA, and remaining tumor tissues is got greatest cross-section, and 4% paraformaldehyde is fixed, paraffin embedding, 5 μ m serial section; Pathological examination is carried out in row HE dyeing respectively, and immunohistochemical staining detects the expression of tumor CD31, and TUNEL method detects the apoptosis of tumor cell.Result shows that the success ratio of inoculation of tumor is 100%, chemotherapy first three groups tumor size do not have statistical significance (
p>0.05).Tumor situation of change sees the following form: table 5: each time point gross tumor volume (cm
3) and relative tumour volume natural logrithm value ln (RTV)
* with matched group comparison
p<0.01,
▲with matched group comparison
p<0.05
Table 6:VEGF-A mrna expression and MVD count distribution and the dependency in each group
* with matched group comparison
p<0.01
Table 7: treat tumor tissues ADC value (× 10 after 13 days
-3mm
2/ s) with AI dependency
* with relatively P<0.01 of matched group, # and Endostatin group be P<0.01 relatively
Conclusion: 1, adenine has the effect that suppresses rabbit VX2 tumor growth; 2, utilize DWIBS and 1H-MRS technology to evaluate dynamically in early days the curative effect of adenine to VX2 liver transplantation tumor in medication; 3, adenine has cell death inducing, suppresses the Anticancer Effect and Mechanism of tumor-blood-vessel growth.
embodiment 7
One, injection production technology
1, specification and formula
1.1 formula: 5mg/mL
Adenine: 50g(is in anhydride)
Sodium chloride: 90g
Water for injection: 10000mL
Make 1000 injections.
Each component effect in 1.2 formulas
Adenine: principal agent
Sodium chloride: osmotic pressure regulator
Water for injection: solvent.
2, technique
(1) glass ampule is first slightly washed rear water for injection fine purifiation, the dry for standby used by injection requirement;
(2) in material-compound tank, inject water 6000mL, add the sodium chloride stirring and dissolving of formula ratio;
(3) add 0.05% needle-use activated carbon, 60 ℃ of stirring and adsorbing 30 minutes, coarse filtration takes off charcoal; Be heated to 80 ℃ and add again above formula ratio adenine stirring and dissolving, add to the full amount of water for injection;
(4) stir, cooling, fine straining;
(5) sample examination;
(6) be filled in ampoule sealing by fusing; 115 ℃ of pressure sterilizings 30 minutes.
(7) lamp inspection, packing, warehouse-in.
Two, using method: 40-100mg/ days, adds slowly intravenous drip in 250mL or 500mL normal saline.
Three, pharmacodynamic study
1. experiment material and method
Laboratory animal: 30 of BALB/c mouse, female ♀, body weight 22 ± 2g, purchased from Shandong Province's Experimental Animal Center.
Cell strain: mouse junction cancer CT-26 cell strain, by The 2nd Army Medical College, be so kind as to give.
Experimental agents: by the preparation of above-mentioned formula Shandong University's new drug evaluation center.Endostatin: purchased from Yantai, Shandong Mai get Jin biological engineering limited company.
Method: with the RPMI-1640 culture medium cellar culture CT-26 cell containing 10% calf serum, carry out cell inoculation in 37 ℃ containing being cultured to cell log trophophase in 5%CO2 constant incubator, with 1.5 × 10
6it is subcutaneous that the density 0.2mL of/mL is inoculated in right side of mice armpit.Lotus tumor after 5 days 30 mices all see that grain of rice size tumor grows, 30 tumor-bearing mices are divided into 3 groups at random, in lotus tumor the 5th day respectively at the each 0.4mL of left side armpit subcutaneous injection normal saline, Endostatin (2ug/ days/only), adenine (2mg/ days/only).After continuous use 14 days, MR viviperception tumor growth situation, evaluates therapeutic effect.After experiment in 16 days finishes, put to death mice, take tumor and weigh and measure tumor size and carry out pathology and SABC detection.
2. experimental result
Mouse inoculation is all shown in tumor growth after 5 days, lotus tumor success rate 100%.
Table 8: the inhibitory action of different pharmaceutical to mouse tumor
Conclusion:
1, adenine is obvious to mouse-borne tumor model tumor inhibition effect;
2, adenine tumor inhibition effect is better than endostatin.
embodiment 8
One, release injectable agent producing process
1, specification and formula
1.1 formulas: 5mg/ props up
Adenine: 50g(is in anhydride)
Copolymer of poly lactic acid: 50g
Dichloromethane: 500mL
Sodium carboxymethyl cellulose: 15g
0.9% sodium chloride solution: 10000mL
Make 1000 slow releasing injection.
Each component effect in 1.2 formulas
Adenine: principal agent
Copolymer of poly lactic acid: slow-release auxiliary material
Sodium carboxymethyl cellulose: cosolvent
Dichloromethane: solvent
0.9% sodium chloride solution: solvent.
2, production technology
(1) cillin bottle, bottle stopper and aluminium lid are first slightly washed rear water for injection fine purifiation, the dry for standby used by injection requirement;
(2) copolymer of poly lactic acid of formula ratio is added in container, the appropriate dissolving that add methylene chloride mixes, then the adenine that adds formula ratio mixes, and prepares injectable microsphere with spray drying method;
(3) injectable microsphere making is dissolved in sodium carboxymethyl cellulose normal saline, makes suspension;
(4) suspension is respectively charged into cillin bottle ,-80 ℃ after freezing 24 hours, is placed in freeze dryer vacuum drying 48 hours;
(5) sample examination;
(6) tamponade, jewelling lid;
(7) check, packing, warehouse-in.
Two, using method
For people's using method, 40-100mg/ days, adds 250mL normal saline medium-sized vein drop.
embodiment 9
HT-29 colorectal cancer chick chorioallantoic membrane transplantation model is set up and antineoplastic vascular generates, the research of histiocyte mechanism of proliferation.
One, set up stable colorectal cancer chick chorioallantoic membrane transplantation model
Observe the dynamic change of chick chorioallantoic membrane vascular development, clearly set up the optimal condition of colorectal cancer chick chorioallantoic membrane transplantation model.While selecting the highest tumor formation rate, inoculate the desirable inoculating cell quantity that the minimum quantity of HT-29 cell is set up as model; The HT-29 cell of identical ideal quantity is inoculated in to the relative avascular area of different days chick chorioallantoic membrane, determines best inoculation embryo age; The cell of ideal quantity is inoculated into the relative avascular area of the suitableeest age in days chick chorioallantoic membrane, understands tumor bulk-growth and the angiogenesis Changing Pattern of colorectal cancer chick chorioallantoic membrane transplantation model.
Two, antitumor mechanism is inquired into
If adenine group, PBS do blank group, the positive matched group of rhEndostatin, the negative matched group of VEGF totally 4 groups.Select to have inoculated the one-tenth tumor Embryo Gallus domesticus of HT-29 cell after 3 days, at one-tenth, pretreated gelfoam is placed at tumor place, experimental group medicine and matched group PBS are respectively got on the gelfoam that 10 μ l are added on respectively each group, hatch 5 days, fixedly get film, observe different experiments group vascularization feature, calculate selected areas blood vessel Area Ratio, and calculate angiogenesis suppression ratio.Qu Liu soma is fixed, paraffin embedding, routine paraffin wax section, and HE staining is observed the histologic characteristics of tumor body, adopts immunohistochemistry technology to detect the expression of Proliferating cell nuclear antigen PCNA.Result shows that the adenine of 5 μ g/ Embryo Gallus domesticus can suppress the angiogenesis of colorectal cancer chick chorioallantoic membrane transplantation model, it is the propagation by direct inhibition tumor cell that adenine antineoplastic mechanism has more than, but by suppressing the propagation of vascular endothelial cell, and then suppress tumor tissues vascularization, thereby further suppress tumor growth.
Conclusion:
1, adenine has the effect of obvious inhibition Embryo Gallus domesticus tumor vascular growth;
2, its effect that suppresses Embryo Gallus domesticus tumor-blood-vessel growth is strong compared with Endostatin;
3, adenine can suppress tumor new vesselses generations at different levels.
Claims (7)
1. five kinds of normal bases of human body are in the application of preparing in medicine for treating tumor thing, and described five kinds of bases comprise adenine, guanine.
2. five kinds of normal bases of human body according to claim 1 are in the application of preparing in medicine for treating tumor thing, and wherein, described base is that adenine is or/and guanine.
3. five kinds of normal bases of human body according to claim 1 are in the application of preparing in medicine for treating tumor thing, and wherein, described tumor is pulmonary carcinoma, colon cancer, gastric cancer, the esophageal carcinoma, hepatocarcinoma, cancer of pancreas, breast carcinoma, genital system tumor or glioma.
According to five kinds of normal bases of the human body described in claim 1-3 in the application of preparing in medicine for treating tumor thing, wherein said medicine is oral tablet, injection, slow releasing agent or targeting preparation.
5. five kinds of normal bases of human body according to claim 4 are in the application of preparing in medicine for treating tumor thing, the preparation method of described oral tablet is that described base is added in adjuvant, the part by weight of base and adjuvant is 1:1, and making base contents is 10-30mg/ sheet oral tablet.
6. five kinds of normal bases of human body according to claim 4 are in the application of preparing in medicine for treating tumor thing, the preparation method of described injection is that described base is directly dissolved in phosphate buffer solution, make the injection that base total concentration is 5-25mg/mL, every injection volume is 2-10mL.
7. five kinds of normal bases of human body according to claim 4 are in the application of preparing in medicine for treating tumor thing, the preparation method of described slow releasing agent is: with medicinal liposome, microcapsule or micelle medicine-releasing system, described base is made to slow releasing agent, then slow releasing agent is made to injection.
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