CN106265669A - Daidzein and the drug regimen of 10 hydroxy camptothecins and application thereof - Google Patents
Daidzein and the drug regimen of 10 hydroxy camptothecins and application thereof Download PDFInfo
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Abstract
The present invention relates to a kind of pharmaceutical composition, its described pharmaceutical composition contains 10 hydroxy camptothecins and daidzein.The pharmaceutical composition of the present invention has significant synergistic effects in treatment gastric cancer, breast carcinoma, hepatocarcinoma, colon cancer etc., reduces dosage, improves the curative effect of medicine, decreases the generation of side effect.
Description
Technical field
The present invention relates to a kind of antineoplastic pharmaceutical compositions, be specifically related to the medicine of daidzein and 10-hydroxycamptothecine
Compositions and preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovary
Application in the medicine of cancer or breast carcinoma.
Background technology
Along with the raising day by day of people's living standard, the sickness rate of cancer is also in cumulative year after year, and cancer has become threat people
The big killer of the one of class health and lives.One research report of World Health Organization (WHO) shows, 20 years from now on, new tumor patient people
Number will be increased to 15,000,000 by the most annual 10000000.It is annual that because of malignant tumor, the number of death also will be increased to by 6,000,000
10000000.According to Cancer in China report display in 2015, China had more than 2,800,000 people for 2015 and dies from cancer, average every day 7500
People.In addition to pulmonary carcinoma, gastric cancer, hepatocarcinoma, esophageal carcinoma and colon cancer are also modal cancers in Chinese male and women.In China's cancer
Disease has become as first of the disease cause of the death, and M & M is all the most soaring, and public health is caused grave danger.
Therefore, the treatment of cancer becomes problem urgently to be resolved hurrily.The method for the treatment of cancer mainly has operation, radiotherapy and chemotherapy, wherein at present
The most frequently used still chemotherapy, but the dissolubility of most chemotherapeutics itself is poor, and toxic and side effects is strong, and action target spot is single, is easily generated
Drug resistance, thus limit its clinical practice.The most how to improve the drug effect of these chemotherapeutics, reduce the secondary work of its poison simultaneously
With, it is current urgent problem.And for reaching this purpose, most efficient method is through making chemotherapeutics and low toxicity
Or nontoxic Drug combination, thus reach the effect of synergistic antitumor.
10-hydroxycamptothecine is that peculiar from China and that resource is the abundantest Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae), isolated antitumaous effect is the strongest
One of Alkaloid.It is a kind of cell cycle specific agents, mainly acts on S phase cancerous cell, different by suppression topology
The activity of structure enzyme I and make DNA break, thus suppress cell proliferation.This medicine is to multiple human malignant tumor cell such as gastric cancer, liver
Cancer, rectal cancer etc. are respectively provided with lethal effect.Additionally, this kind of medicine and other conventional anticarcinogen are without crossing drug resistant, therefore to resistance to
Medicine tumor has therapeutical effect.But its dissolubility is poor, and the shortcomings such as toxic and side effects are easily caused to limit its clinical practice.In order to solve
These problems, this research and utilization its combine with other low cytotoxic drugs, thus reach the effect of attenuation synergistic.
Daidzein is white powder, is mainly derived from leguminous plant Herba Trifolii Pratentis herb, alfalfa herb, Radix Puerariae, big
The seed of bean.Research shows that it has expansion blood vessel, increases coronary flow, reduces blood pressure, decreasing heart rate and reduction myocardial oxygen consumption
Amount and arrhythmia, antibacterial, estrogen-like effects, treatment climacteric syndrome, osteoporosis, the effect such as anticancer, but greatly
Bean aglycon list medicine antitumaous effect is the most weak, uses the daidzein of high dose just can play anticancer effect, therefore uses daiazi
The single medicine of unit is anticancer and unrealistic.It is used for the most clinically treating climacteric syndrome, heart disease, cardiovascular diseases, sclerotin
Loosen.Its toxicity of this exopathogenic factor is extremely low, cheap, is with a wide range of applications.
Up to the present, about 10-hydroxycamptothecine and daidzein being used in combination in antitumor and the two is anti-
Synergism in tumor have not been reported.
Summary of the invention
It is an object of the invention to provide a kind of highly active antineoplastic pharmaceutical compositions and treat each carcinoid in preparation
Application in the medicine of disease.
The antineoplastic pharmaceutical compositions of the present invention contains 10-hydroxycamptothecine and daidzein.
The structural formula of 10-hydroxycamptothecine, daidzein and puerarin is as shown in I, II, III.
10-hydroxycamptothecine is preferably 0.05～2:1 with the mol ratio of daidzein.
Antineoplastic pharmaceutical compositions of the present invention, preferably in the case of, described 10-hydroxycamptothecine and daidzein
Valid density be respectively 0.3～25 μM and 5～20 μMs；In the case of preferred, the most respectively 3～13 μMs and 6～16 μMs.
Antineoplastic pharmaceutical compositions of the present invention, preferably in the case of, described 10-hydroxycamptothecine and daidzein
Retarder thinner be dimethyl sulfoxide or ethanol.
The antineoplastic pharmaceutical compositions of the present invention can be applicable to treat all kinds of tumor, and described tumor includes but not limited to lung
Cancer, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma.
The application of described antineoplastic pharmaceutical compositions, preferably in the case of, described daidzein and 10-hydroxycamptothecine
Add simultaneously；In the case of preferred, after adding, act on 30～50h simultaneously.
The method that the antineoplastic pharmaceutical compositions of the present invention can use this area conventional is made and is suitable to gastrointestinal administration or non-
The preparation of gastrointestinal administration, preferably makes the preparation of gastrointestinal administration by this pharmaceutical composition, and its dosage form can be conventional
Tablet, capsule, controlled or sustained release formulations.
10-hydroxycamptothecine in antineoplastic pharmaceutical compositions of the present invention and/or its derivant and daidzein and/or its
Derivant can directly mix makes preparation；Or make preparation respectively, then according still further to ability with the mixing of corresponding adjuvant respectively
The mode of territory routine is packed or combines；Or after mixing with corresponding adjuvant respectively, remix and make preparation.Preparation uses
Adjuvant can use the conventional adjuvant in this area, but react with pharmaceutical composition of the present invention of getting along well or do not affect medicine of the present invention
Premised on the curative effect of compositions.
According to dosage form and the difference of preparation specification, pharmaceutical composition of the present invention content in the formulation can be at 1-
It is adjusted between 99wt%, preferably 10-90wt%.Additionally, the dosage of pharmaceutical composition of the present invention can be right according to being administered
As the dosage form of, route of administration or medicine suitably changes, but to ensure this pharmaceutical composition energy in mammal body
Premised on enough reaching effective blood drug level.
The pharmaceutical composition of the present invention has significant synergistic effects in treatment gastric cancer, breast carcinoma, hepatocarcinoma etc., improves
The curative effect of medicine, reduces dosage, decreases the generation of side effect.
Accompanying drawing explanation
Fig. 1 is to show the two prescription used time variable concentrations figure to MCF7 cell inhibitory effect Yu fit equation；Wherein: A: big
Bean aglycon is to MCF7 cell inhibitory effect figure；B: according between dosage and the breast carcinoma MCF7 cell survival rate of daidzein
Relation be fitted the rectilinear that obtains；C:10-hydroxy camptothecin is to MCF7 cell inhibitory effect figure；D: according to 10-hydroxyl
Relation between dosage and the MCF7 cell survival rate of camptothecine is fitted the rectilinear obtained；
Fig. 2 is to show that when 10-hydroxycamptothecine share from daidzein, variable concentrations is thin to MCF7 with different administration timing of drug
The figure of born of the same parents' Proliferation Ability；Wherein: significance analysis is only to add HCPT medicine for comparison often organizing, if P < 0.05, then be significantly, table
It is shown as " * "；If P < 0.01, then it is extremely notable, is expressed as " * * ".
Fig. 3 is to show the two prescription used time variable concentrations figure to gastric cancer BGC823 cell inhibitory effect Yu fit equation；Its
In: A: daidzein is to BGC823 cell inhibitory effect figure；B: according to dosage and the BGC823 cell survival of daidzein
Relation between rate is fitted the rectilinear obtained；C:10-hydroxy camptothecin is to BGC823 cell inhibitory effect figure；D: according to
Relation between dosage and the BGC823 cell survival rate of 10-hydroxycamptothecine is fitted the rectilinear obtained；
Fig. 4 is to show that when 10-hydroxycamptothecine share from daidzein, variable concentrations and different administration timing of drug are to BGC823
The figure of cell inhibitory effect；Wherein: significance analysis is only to add HCPT medicine for comparison often organizing, if P < 0.05, then be significantly,
It is expressed as " * "；If P < 0.01, then it is extremely notable, is expressed as " * * ".
Fig. 5 is the figure showing two prescription used time variable concentrations to proliferation of hepatocellular carcinoma HepG 2 cell line suppression with fit equation；Its
In: A: daidzein is to HepG2 cell inhibitory effect figure；B: according to dosage and the HepG2 cell survival rate of daidzein
Between relation be fitted the rectilinear that obtains；C:10-hydroxy camptothecin is to HepG2 cell inhibitory effect figure；D: according to 10-
Relation between dosage and the HepG2 cell survival rate of hydroxy camptothecin is fitted the rectilinear obtained；
Fig. 6 is to show that when 10-hydroxycamptothecine share from daidzein, variable concentrations is thin to HepG2 with different administration timing of drug
The figure of born of the same parents' Proliferation Ability；Wherein: significance analysis is only to add HCPT medicine for comparison often organizing, if P < 0.05, then be significantly, table
It is shown as " * "；If P < 0.01, then it is extremely notable, is expressed as " * * ".
Fig. 7 is to show the two prescription used time variable concentrations figure to colon cancer Caco2 cell inhibitory effect Yu fit equation；Its
In: A: daidzein is to Caco2 cell inhibitory effect figure；B: according to dosage and the Caco2 cell survival rate of daidzein
Between relation be fitted the rectilinear that obtains；C:10-hydroxy camptothecin is to Caco2 cell inhibitory effect figure；D: according to 10-
Relation between dosage and the Caco2 cell survival rate of hydroxy camptothecin is fitted the rectilinear obtained；
Fig. 8 is to show that when 10-hydroxycamptothecine share from daidzein, variable concentrations is thin to Caco2 with different administration timing of drug
The figure of born of the same parents' Proliferation Ability；Wherein: significance analysis is only to add HCPT medicine for comparison often organizing, if P < 0.05, then be significantly, table
It is shown as " * "；If P < 0.01, then it is extremely notable, is expressed as " * * ".
Fig. 9 is to show the variable concentrations figure to MCF7 cell inhibitory effect Yu fit equation when puerarin is alone；Wherein: A:
Puerarin is to MCF7 cell inhibitory effect figure；B: enter according to the relation between dosage and the MCF7 cell survival rate of puerarin
The rectilinear that row matching obtains；
Figure 10 is to show that when 10-hydroxycamptothecine share from puerarin, variable concentrations and different administration timing of drug are to MCF7 cell
The figure of Proliferation Ability；Wherein: significance analysis is only to add HCPT medicine for comparison often organizing, if P < 0.05, then be notable, expression
For " * "；If P < 0.01, then it is extremely notable, is expressed as " * * ".
In each figure, Daidzein represents that daidzein, Puerarin represent that puerarin, HCPT represent 10-hydroxycamptothecine.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further elaborated, but the present invention is not limited to this, without departing from this
In the case of the thought of invention and objective, any change being done technical scheme all should fall into right of the present invention and want
In seeking book limited range.
Biomaterial, medicine and experimental technique used in embodiment 1～5 are as follows:
Cell: MCF-7 (Breast cancer lines), BGC823 (human stomach cancer cell line), HepG2 (human hepatoma cell strain),
Caco2 cell (human colon cancer cell strain) is commercially middle to be obtained, such as Shanghai Inst. of Life Science, CAS
Cellular resources center.
Medicine: (Sichuan is tieed up for precise 10-hydroxycamptothecine (Dalian Mei Lun Bioisystech Co., Ltd), daidzein
Ke Qi bio tech ltd) and puerarin (Wei Keqi bio tech ltd, Sichuan), with dimethyl sulfoxide or ethanol
Dissolving respectively, being made into 10-hydroxycamptothecine concentration is 100mmol/L, and daidzein concentration is 800mmol/L, puerarin concentration
Stock solution for 400mmol/L preserves at-20 DEG C, is diluted in table 1～14 cited during use by fresh culture medium
Suitably concentration, the culture medium used in embodiment 1～4 is DMEM high glucose medium.
MTT detects cell proliferation: cell is in containing 10% hyclone, 100kU/L penicillin, 100mg/L streptomycin
In DMEM high glucose medium, 37 DEG C, 5%CO2Under conditions of cultivate.After cell trypsinization, enter with blood cell counting plate
Row counting.(cell inoculum concentration 8000-10000/hole, according to cell to be inoculated in 96 porocyte culture plates by every hole 100 μ L volume
Size and the speed of growth select), 5%CO2, 37 DEG C of incubators cultivate 24h after add the testing sample of variable concentrations gradient,
5%CO2, 37 DEG C of incubators hatch 48 hours.Discarding culture medium, wash once with PBS, then every hole adds containing 0.5mg/mL
The serum-free medium 100 μ L, 5%CO of MTT2, 37 DEG C of incubators hatch 4h.Culture medium in 96 orifice bores is sucked, so
Rear every hole adds 100 μ L dimethyl sulfoxide.Detecting by microplate reader, detection wavelength is 570nm, and reference wavelength is 630nm.
The calculating of Combination index (CI):
(1) relational expression between dosage (D) and cell survival rate (fu) is determined
Survival rate (fu)=Medicine group OD value/Matched group OD value
Suppression ratio (fa)=1-survival rate (fu)
According to middle efficacious prescriptions formula: fa/fu=(D/Dm)m, taking the logarithm in both sides, obtains
Log (fa/fu)=m logD-m log Dm,
If b=m, a=-m be logDm, Y=log (fa/fu), X=logD,
Then dosage and cell survival rate relational expression are Y=bX+a (Dm is middle effect dosage).
The cell survival rate that when can record certain drug given alone by experiment, different dosing dosage is corresponding.To be administered
Dosage and cell survival rate data substitute into above-mentioned Equation for Calculating and go out Y and X.These group data are carried out linear fit, calculates correspondence
B value, a value, i.e. obtain the equation Y=bX+a of the dosage corresponding to this medicine and suppression ratio relation.
(2) Combination index (CI) is calculated
Middle effect dosage (Dm) and m value is tried to achieve by a, b value in aforesaid equation.
Efficacious prescriptions formula D=Dm (fa/fu) in utilization1/m, individually make when calculating the depression effect reaching two kinds of drug combinations
With the theoretical dosage (D of two kinds of medicinesSingle 1、DSingle 2、DSingle 2)。
Combination index (CI): CI=D is calculated by following equationClose 1/DSingle 1+DClose 2/DSingle 2
(DClose 1And DClose 2It is two medicines every kind of medicine the most respective dosage when share, for testing actually used administration
Dosage.)
Embodiment 1
(1) with containing 10% hyclone, 100kU/L penicillin, the DMEM high glucose medium culture medium of 100mg/L streptomycin
Dilution daidzein and the concentration that 10-hydroxycamptothecine is table 1～5, the daidzein of variable concentrations and 10-hydroxy-camptothecin respectively
During alkali alone, the experimental result to MCF7 inhibited proliferation is shown in Fig. 1 and table 1-2.
Table 1 daidzein MCF7 cell survival Relation Parameters under different dosing dosage calculates
Table 2 10-hydroxycamptothecine MCF7 cell survival Relation Parameters under different dosing dosage calculates
As a example by table 1, carry out calculation specifications, first show that daidzein acts on the survival rate of MCF7 cell, then according to giving
Relation between pharmaceutical quantities and cell survival rate is fitted obtaining equation Y=1.12X-3.07, then b=1.12, a=-3.07,
M=b=1.12, Dm=10(-a/m)=550.90
The relational expression of the theoretical dosage and cell survival rate of thus deriving daidzein is: DSingle 1=Dm (fa/fu
)1/m=550.9 [(1-fu)/fu)]1/1.12
The relational expression of the theoretical dosage and cell survival rate that in like manner can obtain 10-hydroxycamptothecine is: DSingle 2=Dm (fa/
fu)1/m=16.91 [(1-fu)/fu)]1/0 . 92
(2) with the combination Synergistic of 10-hydroxycamptothecine, daidzein promotes that the experimental result of MCF7 cell death is divided
It is not shown in Table 3 and Fig. 2.
Table 3 daidzein and 10-hydroxycamptothecine alone with drug combination time MCF7 cell survival rate and CI value
A: represent and add 10-hydroxycamptothecine effect 24h again after first adding daidzein effect 24h
B: represent that daidzein acts on 48h after 10-hydroxycamptothecine dosing simultaneously
C: represent and add daidzein effect 24h again after first adding 10-hydroxycamptothecine effect 24h
Drug combination has 3 kinds of results: cooperative effect, antagonistic effect and additive effect.The general Combination index CI of employing comes
Judge concrete effect, CI value<1 thinks have cooperative effect, and CI thinks value=1 have additive effect, CI value>1 think have short of money
Antiatherosclerotic effect, < 0.7 thinks have significant cooperative effect to CI value.It can be seen from the results above that daidzein and the happiness of 10-hydroxyl
When tree alkali is administered simultaneously, CI value can reach between 0.2-0.5 under doses and proportioning, and now, Papillary is to MCF7
The lethal effect of cell has preferable synergism.If first with adding 10-hydroxycamptothecine work after daidzein effect 24h again
The effect of antagonism is then presented with 24h, on the contrary then synergism, but its synergy is less than synergy during dosing simultaneously.Institute
With, it should it is best that both are administered simultaneously then curative effect.
The calculating of explanation CI value as a example by group 4b in table 3:
12.5 μm ol/L daidzeins and 6.25 μm ol/L 10-hydroxycamptothecines share, cell survival rate during dosing simultaneously
Fu is 40.8 ± 1.50%, then D closes 1=12.5 μM, and D closes 2=6.25 μM.
The above-mentioned theory dosage that fu=40.8% substitutes into daidzein and 10-hydroxycamptothecine respectively is deposited with cell
In the relational expression of motility rate, can obtain
The mono-1=550.90 of D [(1-fu)/fu)] 1/1.12=768.09 μM
The mono-2=16.91 of D [(1-fu)/fu)] 1/0.92=25.34 μM
Substitute into the computing formula of Combination index (CI), can obtain
CI=D closes the mono-1+D of 1/D and closes the mono-3=12.5/768.09+6.25/25.34=0.26 of 3/D
Embodiment 2
(1) the dilutest with the DMEM high glucose medium containing 10% hyclone, 100kU/L penicillin, 100mg/L streptomycin
Release daidzein and the concentration that 10-hydroxycamptothecine is table 4～6, the daidzein of variable concentrations and the list of 10-hydroxycamptothecine
The experimental result of BGC823 inhibited proliferation is shown in Fig. 3 and table 4-5 by the used time.
Table 4 daidzein BGC823 cell survival Relation Parameters under different dosing dosage calculates
Table 5 10-hydroxycamptothecine BGC823 cell survival Relation Parameters under different dosing dosage calculates
The relational expression of the theoretical dosage and cell survival rate of in like manner deriving daidzein is:
DSingle 1=Dm (fa/fu)1/m=489.1 [(1-fu)/fu)]1/1 . 32
The theoretical dosage of 10-hydroxycamptothecine with the relational expression of cell survival rate is: DSingle 2=Dm (fa/fu)1/m=
10.32[(1-fu)/fu)]1/0 . 74
(2) daidzein promotes the experimental result of BGC-823 cell death with the Synergistic that combines of 10-hydroxycamptothecine
It is shown in Table 6 and Fig. 4.
Table 6 daidzein and 10-hydroxycamptothecine alone with drug combination time BGC823 cell survival rate and CI value
During it can be seen from the results above that daidzein and 10-hydroxycamptothecine are administered simultaneously, CI value at doses and
Can reach between 0.2-0.4 under proportioning, now, Papillary has the most collaborative work to the lethal effect of BGC823 cell
With.If first then presenting the effect of antagonism with adding 10-hydroxycamptothecine effect 24h after daidzein effect 24h again, otherwise then assist
Same-action is smaller, the most also there will be antagonism.So, it should it is best that both are administered simultaneously then curative effect.
Embodiment 3
(1) the dilutest with the DMEM high glucose medium containing 10% hyclone, 100kU/L penicillin, 100mg/L streptomycin
Release daidzein and the concentration that 10-hydroxycamptothecine is table 7～9, the daidzein of variable concentrations and the list of 10-hydroxycamptothecine
The experimental result of HepG2 inhibited proliferation is shown in Fig. 5 and table 7-9 by the used time.
Table 7 daidzein HepG2 cell survival Relation Parameters under different dosing dosage calculates
Table 8 10-hydroxycamptothecine HepG2 cell survival Relation Parameters under different dosing dosage calculates
The relational expression of the theoretical dosage and cell survival rate of in like manner deriving daidzein is:
DSingle 1=Dm (fa/fu)1/m=537.98 [(1-fu)/fu)]1/1.30
The theoretical dosage of 10-hydroxycamptothecine with the relational expression of cell survival rate is:
DSingle 2=Dm (fa/fu)1/m=50.12 [(1-fu)/fu)]1/0.30
(2) with the combination Synergistic of 10-hydroxycamptothecine, daidzein promotes that the experimental result of HepG2 cell death is shown in
Table 9 and Fig. 6.
Table 9 daidzein and 10-hydroxycamptothecine alone with drug combination time HepG2 cell survival rate and CI value
During it can be seen from the results above that daidzein and 10-hydroxycamptothecine are administered simultaneously, CI value at doses and
Can reach between 0.02-0.07 under proportioning, now, the lethal effect of HepG2 cell is had by Papillary the most significantly assists
Same-action.If first then presenting the effect of antagonism with adding 10-hydroxycamptothecine effect 24h after daidzein effect 24h again, otherwise
Then synergism is smaller, the most also there will be antagonism.So, it should it is best that both are administered simultaneously then curative effect.
Embodiment 4
(1) with containing 10% hyclone, 100kU/L penicillin, the DMEM high glucose medium culture medium of 100mg/L streptomycin
Dilution daidzein and 10-hydroxycamptothecine is the concentration of table 10～12 respectively, when the daidzein of variable concentrations is alone pair
The experimental result of Caco2 inhibited proliferation is shown in Fig. 7 and table 10, the variable concentrations HCPT experiment to Caco2 inhibited proliferation
Result is shown in Fig. 7 and table 11.
Table 10 daidzein Caco2 cell survival Relation Parameters under different dosing dosage calculates
Table 11 10-hydroxycamptothecine Caco2 cell survival Relation Parameters under different dosing dosage calculates
The relational expression of the theoretical dosage and cell survival rate of in like manner deriving daidzein is: DSingle 1=Dm (fa/fu
)1/m=6210.17 [(1-fu)/fu)]1/0 . 58
The relational expression of the theoretical dosage and cell survival rate that in like manner can obtain 10-hydroxycamptothecine is: DSingle 2=Dm (fa/
fu)1/m=13.89 [(1-fu)/fu)]1/0 . 84
(2) with the combination Synergistic of 10-hydroxycamptothecine, daidzein promotes that the experimental result of Caco2 cell death is divided
It is not shown in Table 12 and Fig. 8.
Table 12 daidzein and 10-hydroxycamptothecine alone with drug combination time Caco2 cell survival rate and CI value
A: represent and add 10-hydroxycamptothecine effect 24h again after first adding daidzein effect 24h
B: represent that daidzein acts on 48h after 10-hydroxycamptothecine dosing simultaneously
C: represent and add daidzein effect 24h again after first adding 10-hydroxycamptothecine effect 24h
During it can be seen from the results above that daidzein and 10-hydroxycamptothecine are administered simultaneously, CI value at doses and
Can reach between 0.2-0.6 under proportioning, now, the lethal effect of Caco2 cell is had by Papillary the most significantly works in coordination with
Effect.If first then present the effect of antagonism with adding 10-hydroxycamptothecine effect 24h after daidzein effect 24h again, otherwise also
There is synergism, but synergism is less than synergism when being administered simultaneously, so both should be administered simultaneously then that curative effect is
Good.
Embodiment 5
(1) with containing 10% hyclone, 100kU/L penicillin, the DMEM high glucose medium culture medium of 100mg/L streptomycin
Dilution puerarin and the concentration that 10-hydroxycamptothecine is table 13～14, increase MCF7 when the puerarin of variable concentrations is alone respectively
The experimental result growing inhibitory action is shown in Fig. 9 and table 13, and the experimental result of MCF7 inhibited proliferation is shown in Fig. 1 by variable concentrations HCPT
And table 2.
Table 13 puerarin MCF7 cell survival Relation Parameters under different dosing dosage calculates
The relational expression of the theoretical dosage and cell survival rate of in like manner deriving puerarin is: DSingle 1=Dm (fa/fu)1/m
=719.69 [(1-fu)/fu)]1/0 . 77
The relational expression of the theoretical dosage and cell survival rate that in like manner can obtain 10-hydroxycamptothecine is: DSingle 2=Dm (fa/
fu)1/m=16.91 [(1-fu)/fu)]1/0.92
(2) puerarin promotes the experimental result of MCF7 cell death respectively with the combination Synergistic of 10-hydroxycamptothecine
It is shown in Table 14 and Figure 10.
Table 14 puerarin and 10-hydroxycamptothecine alone with drug combination time MCF7 cell survival rate and CI value
A: represent and add 10-hydroxycamptothecine effect 24h again after first adding puerarin effect 24h
B: represent that puerarin acts on 48h after 10-hydroxycamptothecine dosing simultaneously
C: represent and add puerarin effect 24h again after first adding 10-hydroxycamptothecine effect 24h
It can be seen from the results above that puerarin and 10-hydroxycamptothecine are either administered simultaneously, or by different order
It is administered, all shows antagonism.And puerarin and daidzein belong to isoflavone, there is common parent nucleus 3-phenyl chromone
Structure, but puerarin does not show and has synergism with HCPT, and shows when daidzein acts on HCPT simultaneously
The strongest synergism.
Claims (7)
1. an antineoplastic pharmaceutical compositions, it is characterised in that containing 10-hydroxycamptothecine and daidzein.
Antineoplastic pharmaceutical compositions the most according to claim 1, it is characterised in that described 10-hydroxycamptothecine and Semen sojae atricolor
The mol ratio of aglycon is 0.03～2:1.
Antineoplastic pharmaceutical compositions the most according to claim 1, it is characterised in that described 10-hydroxycamptothecine and Semen sojae atricolor
The concentration of aglycon is respectively 0.3～25 μM and 5～20 μMs.
Antineoplastic pharmaceutical compositions the most according to claim 1, it is characterised in that described daidzein is liked with 10-hydroxyl
Tree alkali adds simultaneously.
Antineoplastic pharmaceutical compositions the most according to claim 4, it is characterised in that described daidzein is liked with 10-hydroxyl
Tree alkali acts on 30～50h after adding simultaneously.
Antineoplastic pharmaceutical compositions the most according to claim 1, it is characterised in that described 10-hydroxycamptothecine and Semen sojae atricolor
The retarder thinner of aglycon is dimethyl sulfoxide or ethanol.
7. in claim 1-6 antineoplastic pharmaceutical compositions described in any one at preparation treatment pulmonary carcinoma, cancer of pancreas, colon
Application in the medicine of cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111317732A (en) * | 2020-02-04 | 2020-06-23 | 牡丹江医学院 | Pharmaceutical composition for preventing nephropathy of CT contrast agent and preparation method thereof |
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