CN105982888B - A kind of combination medicine and application thereof containing qinghaosu and taxol - Google Patents
A kind of combination medicine and application thereof containing qinghaosu and taxol Download PDFInfo
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- CN105982888B CN105982888B CN201510098908.5A CN201510098908A CN105982888B CN 105982888 B CN105982888 B CN 105982888B CN 201510098908 A CN201510098908 A CN 201510098908A CN 105982888 B CN105982888 B CN 105982888B
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Abstract
The present invention relates to a kind of combination medicines, contain first active constituent qinghaosu or derivatives thereof and the second active constituent taxol or its officinal salt, hydrate, and optional pharmaceutically acceptable auxiliary material.Qinghaosu or derivatives thereof can be used for treating and/or preventing melanoma with paclitaxel plus application, and the two has synergistic effect well, while greatly reducing the dosage of taxol.
Description
Technical field
The present invention relates to a kind of combination medicine containing qinghaosu and taxol, the combination medicine can be used for treating
And/or prevention melanoma.
Background technique
Melanoma is clinically relatively conventional skin and mucosa and pigmented film malignant tumour, is a kind of extremely dangerous cause
Cutaneum carcinoma is ordered, though disease incidence is low compared with basal-cell carcinoma, squamous cell carcinoma, grade of malignancy is big, and early, death rate height occurs for transfer.
According to comprehensive cancer network (NCCN) guide of US National, first-line treatment recommend Dacarbazine (Dacarbazine,
DTIC) combination therapy based on single medicine, Temozolomide (Temozolomide, TMZ) or the mono- medicine of TMZ/DTIC (such as combination with cisplatin or
Fotemustine)；Newly-increased second line treatment generally recommends Paclitaxel Combined with Carboplatin scheme within 2008.For a long time, Dacarbazine is late
" goldstandard " of phase melanoma medical treatment, single therapy effective percentage are 7.5%~12.2%, other chemotherapeutics exist at present
Not over Dacarbazine in total existence.At this stage, chemotherapy is for Chinese melanoma patients or one important is controlled
Treatment means.Therefore, develop effectively, the lower anti-melanin tumor medicine of toxic side effect it is significant, it is also very urgent.
Qinghaosu is China traditional Chinese medicine worker 1971 from compositae plant artemisia annua (Atemisia annua L.)
A kind of isolated Sesquiterpene lactones compound containing peroxide bridge structure is extracted in leaf, structure and traditional antimalarial are complete
It is complete different, erythrocyte stage plasmodium can be killed rapidly, be the active drug for the world control malaria prevalence that WHO assert, and
China has the drug of security knowledge property right.A variety of derivatives are produced by chemical improvement, such as Artesunate, double hydrogen sweet wormwoods
Element, Artemether etc. are the monomers for treating the high-efficiency low-toxicity of malaria.
With going deep into for research, qinghaosu and its derivative antitumor, immunological regulation, in terms of have one
Fixed curative effect.Especially mainly pass through the production for inducing cell apoptosis, inhibiting free radical in anti-tumor aspect, qinghaosu and its derivative
Life inhibits the effects of angiogenesis to play antitumor action.And artemisinin-based drug effect is not single target spot, it can be effective
Overcome multidrug resistance, with classic chemotherapy medicine without crossing drug resistant, and safety, low toxicity.
Taxol (Taxol) is extraction or semi-synthetic Diterpenes from the bark, trunk or needle of Japanese yew (Chinese yew)
Compound keeps tubulin to stablize, inhibits cell mitogen, clinically by promoting tubulin polymerization to inhibit depolymerization
It is used frequently as the first-line drug for the treatment of breast cancer, oophoroma and lung cancer, is in addition also used for drug combination treatment bladder cancer, oesophagus
Cancer, kidney etc..But allergic reaction caused by taxol, bone marrow suppression, gastrointestinal reaction, cardiac toxic etc. occur when chemotherapy
Rate is higher.
Present inventors have surprisingly found that taxol and qinghaosu and its derivative have it is good cooperate with melanoma to act on,
And drug combination can greatly reduce the dosage of taxol, reduce its toxicity.
Summary of the invention
The first aspect of the present invention provides a kind of combination medicine, contains first active constituent qinghaosu or derivatives thereof,
With the second active constituent taxol or its officinal salt, hydrate, and optional pharmaceutically acceptable auxiliary material.
The second aspect of the present invention provide first aspect present invention described in combination medicine preparation for treat and/or
Prevent the purposes in the drug of melanoma.
The third aspect of the present invention provides a kind of method treated and/or prevent melanoma, and this method is living by first
Property ingredient qinghaosu or derivatives thereof and the second active constituent paclitaxel plus be administered in individual in need for the treatment of, or will
Combination medicine described in first aspect present invention is administered in individual in need for the treatment of.Wherein the first active constituent and second is lived
Property ingredient simultaneously, respectively or be successively administered to it is in need for the treatment of individual in.
In the present invention, described qinghaosu or derivatives thereof is selected from qinghaosu, Artesunate, dihydroartemisinine, Artemether
Or its pharmaceutical salt, hydrate, preferably Artesunate, dihydroartemisinine.
In the present invention, the structural formula of dihydroartemisinine is as shown in Equation 1, and the structural formula of Artesunate is as shown in Equation 2, taxol
Structural formula it is as shown in Equation 3.
Combination medicine of the present invention, wherein the molar ratio of the first active constituent and the second active constituent be 1:1~
4:1, preferably 1:1~7:3, more preferably 3:2~7:3, further preferred 7:3.
In a specific embodiment, combination medicine of the present invention, wherein the first active constituent is that double hydrogen are green
Artemisin or its officinal salt, hydrate, the second active constituent are taxol or its officinal salt, hydrate, the first active constituent
Molar ratio with the second active constituent is 3:2~7:3, further preferred 7:3.
In another embodiment, combination medicine of the present invention, wherein the first active constituent is sweet wormwood
Amber ester or its officinal salt, hydrate, the second active constituent are taxol or its officinal salt, hydrate, the first active constituent
Molar ratio with the second active constituent is 1:1~7:3, preferably 3:2~7:3, further preferred 7:3.
Combination medicine of the present invention, wherein the first active constituent and the second active constituent are in same preparation unit
In or the first active constituent and the second active constituent respectively in different specification preparation units.
In application combination medicine of the present invention, wherein the first active constituent and the second active constituent can be same
When, be administered respectively or successively.
Advantageous effect of the invention
The present invention has carried out qinghaosu or derivatives thereof respectively and has inhibited B16 (mouse melanin tumor cell) with paclitaxel plus
The test of proliferation.The results show that qinghaosu of the present invention or derivatives thereof is with paclitaxel plus using the suppression to melanoma cells
Production is greatly reduced the dosage of taxol, and improve curative effect, is being reached identical treatment with there is good synergistic effect
In the case where effect, the toxic side effect of taxol is effectively reduced.
Detailed description of the invention
Fig. 1 is that dihydroartemisinine and paclitaxel plus apply the Fa-CI value curve graph acted on B16 melanoma cells.
Fig. 2 is that Artesunate and paclitaxel plus apply the Fa-CI value curve graph acted on B16 melanoma cells.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
Reagent and method
Cell strain: B16 melanoma cells are purchased from American Type Culture Collecti (American Type Culture
Collection, ATCC), cell number: CX0036.
Drug: dihydroartemisinine (DHA, Wuling Shan Mountain pharmaceutical Co. Ltd, Chongqing Holley, purity 99.1%), injection sweet wormwood
Amber ester (ATS, Guilin south medicine, lot number ZA111202), taxol (Taxol, Shanghai Longxiang Biomedicine Development Co., Ltd., batch
Number 120703).
Drug is prepared: the 1. preparation of 100 μM of Artesunate (ATS) medical fluids: being dissolved with 1mL0.5% sodium bicarbonate solution
60mg Artesunate, drug concentration are 60000 μ g/mL.Take the ATS of 10 μ L60000 μ g/mL to containing 5990 μ L RPMI-1640
In the 10mL graduated centrifuge tube of culture medium (Gibco, article No.: 11875-093, similarly hereinafter), concentration is 100 μ g/mL；Take 3.84mL
Into 6.16mL RPMI-1640 culture medium, it can be made into the ATS mother liquor of 100 μM (38.4 μ g/mL), wherein sodium bicarbonate concentration
It is 0.003%.
2. the preparation of 100 μM of dihydroartemisinine (DHA) medical fluids: DHA0.0100g is weighed with ten a ten thousandth balances, with 200
μ L dimethyl sulfoxide (DMSO) is dissolved, and drug concentration is 50000 μ g/mL.Take the DHA of 10 μ L50000 μ g/mL to containing
In the 10mL graduated centrifuge tube of 4990 μ LRPMI-1640 culture mediums, as 100 μ g/mL.Take 2.84mL to 7.16mL RPMI-
In 1640 culture mediums, it can be made into the DHA mother liquor of 100 μM (28.4 μ g/mL), wherein DMSO concentration is 0.06%.
3. the preparation of 100 μM of taxol (Taxol) medical fluids: Taxol0.0100g is weighed with ten a ten thousandth balances, with 200
μ LDMSO is dissolved, and drug concentration is 50000 μ g/mL.Take the Taxol of 20 μ L50000 μ g/mL to containing 9980 μ L RPMI-
In the 10mL graduated centrifuge tube of 1640 culture mediums, as 100 μ g/mL are taken in 8.54mL to 1.46mL RPMI-1640 culture medium,
It can be made into the Taxol mother liquor of 100 μM (85.4 μ g/mL), wherein DMSO concentration is 0.17%.
Respectively be made into 100 μM of mother liquors are diluted to when -20 DEG C of preservations, use with fresh RPMI-1640 culture medium
Respective concentration.
Experimental method:
The B16 melanoma cells of logarithmic growth phase are inoculated into 96 orifice plates, and cell-seeding-density is about 1.0 × 105/
ML, every 90 μ L of hole, is placed in 37 DEG C, 5%CO2It is continuously cultivated in incubator 24 hours.Culture plate is then taken out, each medical fluid is diluted
Each hole is added after to working concentration, every hole adds 10 μ L medical fluids.Drug final concentration is specifically shown in Tables 1 and 2, and each concentration sets 3 multiple holes,
And control group (culture solution containing cell) and blank group (blank culture solution) are set, it is placed in 37 DEG C, 5%CO2Incubator continues
Culture 48 hours.
After drug-treated 48 hours, every hole be added Cell Counting Kits-8 (CCK-8, DOJINDO, lot number:
EQ829) 10 μ L of reagent, is placed in 37 DEG C, 5%CO2Incubator is incubated for 4 hours, is 450nm, reference wave in microplate reader Detection wavelength
Absorbance OD value is detected under conditions of a length of 630nm.When calculating growth of tumour cell inhibiting rate (%), calculation formula is as follows:
Inhibiting rate (%)=(control group mean OD value-administration group mean OD value)/control group mean OD value × 100%.
Drug combination analysis method: the merged index theorem (The proposed according to Chou T.C. and Talalay P.
Combination Index Theorem) and mass action in imitate theorem (The Median-Effect Equation As
The Unified Theory) analyzed (bibliography are as follows: Am J Cancer Res 2011；1(7):925-954).
Theorem formula is imitated in drug quality effect are as follows: Dx=Dm[fa/(1-fa)]1/m,
Drug merged index theorem formula are as follows: CI=(D)1/(Dx)1+(D)2/(Dx)2, in which:
CI (Combo index) is combination therapies index, (Dx)1It is first drug (D)1Inhibit when independent role
Rate is the dosage of x%, (Dx)2It is second drug (D)2Inhibiting rate is the dosage of x% when independent role, and (D)1(D)2Respectively
It is the dosage of first drug and second drug when inhibiting rate is also x% when two medicines are used in combination.DmIt is the middle effect of drug
Dose concentration (IC50), m indicates to imitate theorem slope of a curve in mass action, and fa is inhibiting rate.
As CI=1, summation action is indicated；As CI > 1, antagonism is indicated；As CI < 1, synergistic effect is indicated.
Using 1.0 computer software of CompuSyn input each single medicine and its drug combination each dose concentration inhibiting rate (i.e.
Fa value), then it can be with auto computing m, r and DmValue, and fa-CI figure (Chou-Talalay Plot) is simulated, automatically scanning is surveyed
Determine antagonism, addition or the synergistic effect of drug.Wherein r indicates the linearly dependent coefficient that theorem curve is imitated in mass action, and r value is not
Indicate that the parameter of simulation is linearly good less than 0.95.Experiment is repeated 3 times, and each data sheet is stayed alone reason, the mean value tested according to 3 times
The value of ± standard deviation statistics Dm, m and r.
Table 1
Table 2
1 dihydroartemisinine of embodiment (DHA) and inhibition of taxol (Taxol) use in conjunction to B16 melanoma cells
Property test (n=3), experimental result is shown in Table 3.
Table 3
According to the above experimental result, parameter Dm, m and matter can be obtained by carrying out operation to data using 1.0 software of Compusyn
The linearly dependent coefficient r (n=3) that theorem curve is imitated in amount effect, the results are shown in Table 4, and it is medication combined right to simulate DHA and Taxol
The Fa-CI value curve graph of B16 melanoma cells effect, as shown in Fig. 1.
Table 4
In investigating test of the composition of DHA and Taxol different ratio to the inhibiting effect of B16 melanoma cells,
The mean value that the linearly dependent coefficient r of theorem curve is imitated in mass action is all larger than 0.95, and expression parameter fitting is good.Independent medication
When, the D of DHA and TaxolmMean value (half-inhibitory concentration) is respectively 11.672 μM and 1.001 μM；DHA and Taxol composition exists
When molar ratio is 3:2 and 7:3, DmMean value (half-inhibitory concentration) is respectively 0.865 μM and 0.472 μM, than DHA or Taxol
D when independent medicationmMean value wants low, and what when the molar ratio of DHA and Taxol is 7:3, Dm mean value was reduced becomes apparent.
By attached Fa-CI curve graph shown in FIG. 1 it can be found that when the molar ratio of DHA and Taxol is 3:2 and 7:3, CI value
Respectively less than 1, show that there is preferable synergistic effect, when wherein the molar ratio of DHA and Taxol is 7:3, two when the two use in conjunction
The synergistic effect of person is the most obvious.
2 Artesunate of embodiment (ATS) is with taxol (Taxol) use in conjunction to the inhibition of B16 melanoma cells
It tests (n=3), experimental result is shown in Table 5.
Table 5
According to the above experimental result, parameter Dm, m and matter can be obtained by carrying out operation to data using 1.0 software of Compusyn
The linearly dependent coefficient r (n=3) that theorem curve is imitated in amount effect, the results are shown in Table 6, and it is medication combined right to simulate ATS and Taxol
The Fa-CI value curve graph of B16 melanoma cells effect, as shown in Fig. 2.
Table 7
In investigating test of the composition of ATS and Taxol different ratio to the inhibiting effect of B16 melanoma cells,
The mean value that the linearly dependent coefficient r of theorem curve is imitated in mass action is all larger than 0.95, and expression parameter fitting is good.Independent medication
When, the D of ATS and TaxolmMean value (half-inhibitory concentration) is respectively 2.573 μM and 0.772 μM；The molar ratio of ATS and Taxol
When for 1:1,3:2 and 7:3, Dm(half-inhibitory concentration) mean value is respectively 0.711 μM, 0.497 μM and 0.359 μM, than ATS or
D when Taxol independent medicationmMean value will be low, and the molar ratio of ATS and Taxol be 7:3 when Dm mean value reduce it is more bright
It is aobvious.
By attached Fa-CI curve graph shown in Fig. 2 it can be found that when the molar ratio of ATS and Taxol is 1:1,3:2 and 7:3,
CI value is respectively less than 1, shows there is preferable synergistic effect when the two use in conjunction, and wherein the molar ratio of ATS and Taxol is 7:3
When, the synergistic effect of the two is the most obvious.
Claims (7)
1. a kind of for treating and/or prevent the combination medicine of melanoma, containing the first active constituent Artesunate or its
Officinal salt, hydrate and the second active constituent taxol or its officinal salt, hydrate, and optionally pharmaceutically acceptable
Auxiliary material, wherein the molar ratio of the first active constituent and the second active constituent be 1:1~4:1.
2. the combination medicine of claim 1, wherein the first active constituent and the second active constituent molar ratio are 1:1~7:3.
3. the combination medicine of claims 1 or 2, wherein the first active constituent and the second active constituent are in same preparation unit
In or the first active constituent and the second active constituent respectively in different specification preparation units.
4. the described in any item combination medicines of claim 1-3 are preparing the drug for treating and/or preventing melanoma
In purposes.
5. combination medicine is preparing the purposes in the drug for treating and/or preventing melanoma, wherein the joint is used
In drug containing the first active constituent dihydroartemisinine or its officinal salt, hydrate and the second active constituent taxol or its
Officinal salt, hydrate, and optional pharmaceutically acceptable auxiliary material, wherein the first active constituent and the second active constituent rub
You are than being 1:1~4:1.
6. purposes described in claim 5, wherein the molar ratio of the first active constituent and the second active constituent is 3:2~7:3.
7. purposes described in claim 5 or 6, wherein the first active constituent and the second active constituent are in same preparation unit
In or the first active constituent and the second active constituent respectively in different specification preparation units.
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| CN101856352A (en) * | 2009-04-10 | 2010-10-13 | 中国科学院上海生命科学研究院 | Synergistic effect of arteannuim and derivative thereof on chemotherapeutic agent |
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| CN101856352A (en) * | 2009-04-10 | 2010-10-13 | 中国科学院上海生命科学研究院 | Synergistic effect of arteannuim and derivative thereof on chemotherapeutic agent |
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| Abstract 470: Artemisinin derivatives synergize with paclitaxel by targeting FOXM1 through Raf/MEK/MAPK signaling pathway in ovarian cancer;Yi Chen等;《Cancer Research》;20141031;第74卷(第19期);第470页 |
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