CN1102047C - Reversing agent for multi-medicine resistance of tumor cells - Google Patents
Reversing agent for multi-medicine resistance of tumor cells Download PDFInfo
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Abstract
The present invention discloses a new reversing agent for the multi-medicine resistance of tumor cells, which is an isosteroid alkaloid derivative extracted and separated from traditional Chinese medicine caladium and has a new purpose of being used as a new reversing agent for the multi-medicine resistance of tumor cells. Thereby, the present invention provides a new method and means for clinically treating tumors. The compound and other medicine can act to further increase reversing effect.
Description
The invention belongs to the new purposes of plant compound field.This invention relates to a kind of new multidrug resistance tumor cells inversion agent.They are different steroid alkaloid and derivants thereof that separation and Extraction obtains from plant such as liliaceous plant Bulbus Fritillariae Uninbracteatae.
The chemical anticarcinogenic drug treatment occupies critical role in clinical therapy of tumor, but the tumor cell drug resistance problem but is chemotherapeutical huge obstacle.In a sense, it is all relevant with former of tumor or acquired resistance to die from the case of tumor more than 90%.Begin the seventies with regard to the multidrug resistance problem of noticing tumor cell the influence of clinical Combination chemotherapy greatly (oncology clinical with advances of Basic Research work Atomic Energy Press front page in 1994 such as Sun Yan P.245).Actively develop the research of tumor cell drug resistance inversion agent for this reason both at home and abroad, found the inversion agent that multiple effect is higher in the laboratory at present, as the calcium ion antagonist isoptin, immunosuppressant cyclosporin A or the like.But because problems such as toxic and side effects, still do not have so far generally acknowledge can be at the medicine (Chinese Journal of Hematology 1990 of clinical widespread usage, 3 (2): 161, treatment and prevention of tumour research 1995,1 (22): 61, practical tumor magazine 1995,4 (10): 204). as mentioned above, current clinical this class medicine that presses for.
First purpose of the present invention provides the novel tumor multidrug-resistance inversion agent of a class.
Second purpose of the present invention provides different steroid alkaloid as the purposes of multidrug resistance tumor cells inversion agent in treatment multidrug resistance tumor disease.
A further object of the present invention provides a kind of pharmaceutical composition that has good reverse effect for tumor multidrug-resistance.
Purpose according to the present invention, the tumor multidrug-resistance inversion agent that is provided is different steroid alkaloid and derivant thereof.This chemical compound mainly is from plant, can be from common Chinese medicine such as liliaceous plant Bulbus Fritillariae Uninbracteatae separation and Extraction.It can make tumor multidrug-resistance greatly reduce.This chemical compound has following structure:
Wherein: R
1Can be
Or HR
2Can be
Or=O
R
3, R
4, R
5Can be H, R
6Can be OH
According to the present invention, different steroid alkaloid and derivant thereof can be made into the preparation of intestinal or non-intestinal combination medicine by means known in the art.As tablet, capsule, granule, injection etc.
According to the present invention, different steroid alkaloid and derivant thereof also can with other inversion agent 5 usefulness, reach the purpose that improves reverse effect.As pressing 1: 15 time spent, can improve nearly twenty times of reverse effect with isoptin.
Useful effect: chemical compound of the present invention has potential applicability in clinical practice, because if when giving dose corresponding to Bulbus Fritillariae Uninbracteatae dosage clinically, be unlikely obvious toxic and side effects, and this chemical compound can make tumor multidrug-resistance greatly reduce, can reach about five times.As with isoptin (clinical commonly used drug) 5 usefulness, effect still can greatly improve.The prospect that indicates this compounds clinical practice is better.The drug resistance of tumor problem is chemotherapeutical huge obstacle.The case of dying from tumor is all relevant with tumor constitutional or the living drug resistance of acquisition.So current clinical this class reversing drug treatment resistant tumors disease that presses for.
The following examples will describe the present invention in detail.The extraction of embodiment 1 different steroid alkaloid and derivant thereof and structure are identified:
Chemical compound of the present invention can extract from plant such as liliaceous plant Bulbus Fritillariae Uninbracteatae and obtain.Its concrete preparation route is as follows:
Through identifying:
The chemical compound first is colourless acicular crystal mp 214-215 ℃ .EI--MSm/z:429.3 (M
+), 411.3,384.3,155.1,154.1,112.1 (100%), 98.1,69.1.
1HNMR ﹠amp; Ppm (CD
3OD, 400MHz): 0.76 (3H, s, H-19), 1.05 (3H, s, H-21), 1.11 (3H, d, J=7.33Hz, H-27), 3.51 (1H, m, W
1/2=18.6Hz, H-3).
13The CNMR data see the following form. and itself and Peimine (Peimine) standard mixed melting point do not descend its thin layer Rf unanimity.
Chemical compound second is colourless acicular crystal, mp 222-224 ℃.
1HNMR ﹠amp; Ppm (CD
3OD, 400MHz): 0.83 (3H, s, H-19), 1.04 (3H, s, H-21), 1.11 (3H, d, J=6.84Hz, h-27), 3.35 (1H, m, H-6), 3.52 (1H, m, H-3), 3.59 (1H, q).
13The CNMR data see the following form. and by above inferred from input data second is Peiminine (Peiminine)
Chemical compound third is faint yellow sand crystal, mp 246-248 ℃ of .EI-MS m/z:592.2 (M+1)
+, 574.2,458.2,430.2,412.2,394.2,155.1,154.1,112.1 (100%), 98.0,69.0.
1HNMR ﹠amp; Ppm (CD
3OD, 400MHz): 0.86 (3H, s, H-19), 1.13 (3H, d, J=7.6Hz, H-27), 1.16 (3H, s, H-21), 4.39 (1H, d, J=7.62HzH-1 ' H-6).
13The CNMR data see the following form. be (-)-Zhebeinine glycosides (Zhebeininoside) by above inferred from input data third
The chemical compound fourth is the yellowish white powder, mp 246-248 ℃ of .EI-MS m/z:5942 (M+1)
+, 576.2,460.2,432.2,414.2,396.2,155.1,154.1,112.1 (100%), 98.0,69.0.
1HNMR ﹠amp; Ppm (CD
30D, 400MHz): 0.77 (3H, s, H-19), 1.05 (3H, s, H-21), 1.11 (3H, d, J=6.86Hz, H-27), 4.39 (1H, d, J=7.63Hz, H-1 ').
13The CNMR data see the following form.By above inferred from input data fourth is peiminoside (Peiminoside)
The chemical compound first---Ding's
13CNMR chemical displacement value ppm (CD
3OD, 400MHz)
Carbon the first and second the third fourths
1 38.8 39.9 38.0 39.0
2 32.1 32.5 30.6 30.0
3 73.1 73.2 78.8 79.4
4 31.6 33.9 29.7 30.0
5 58.4 54.1 57.4 53.1
6 214.7 71.9 213.8 71.1
7 47.4 42.2 46.6 41.2
8 43.6 40.9 42.7 39.6
9 58.4 59.2 57.5 58.3
10 40.3 37.1 39.6 36.4
11 31.6 31.6 29.9 29.6
12 42.9 43.1 42.0 41.6
13 40.9 40.7 40.0 39.0
14 46.3 46.0 45.4 45.0
15 26.3 26.6 25.5 25.4
16 22.6 22.6 21.8 21.7
17 51.1 51.2 50.2 49.6
18 64.1 64.2 63.2 61.9
19 13.7 14.0 12.9 13.1
20 73.1 73.1 72.3 72.0
21 22.2 22.4 21.4 21.2
22 72.2 71.9 72.2 71.8
23 21.1 21.1 20.2 19.5
24 30.8 31.1 29.1 29.3
25 30.0 30.0 27.5 28.3
26 64.2 64.4 63.2 62.8
27 18.7 18.7 17.8 17.0
1’ 102.3 102.2
2’ 75.1 75.1
3’ 78.1 78.1
4’ 71.7 71.7
5’ 77.9 77.9
6’ 62.8 62.8
Embodiment 2: biological assessment
Mainly sketch the present invention for the reverse effect of tumor multidrug-resistance in the biotic experiment below by above-claimed cpd (being designated hereinafter simply as Compound P M) in vitro tests and bulk testing.
Biotic experiment mainly carries out the expose sb.'s past misdeeds valency of effect for the lethal effect of multiple sensitivity and multidrug resistance tumor cells to it by Compound P M, and utilizes model of nude mice bearing tumor Compound P M to be carried out the evaluation of its reversing effect.One, materials and methods: 1.1 material 1.1.1 cells and zooblast strain:
K562, HL60, MCF-7, the KB cell, the former three cell is provided by Inst. of Hematology, Chinese Academy of Medical Sciences's medicament chamber, and the latter is provided by Radiation Medical Science Inst., Chinese Academy of Military Medical Science (CN.
The K562/A02 multidrug resistance cell strain is with P
GpAlbumen raises and is main resistance mechanism.Induce and provide by Inst. of Hematology, Chinese Academy of Medical Sciences's medicament chamber.To 40 times of amycin drug resistances, to harringtonine, vincristine, VP16, crossing drug resistants such as daunorubicin.
MCF-7/Adr: the anti-cell strain of multiple medicines, with P
GpProtein expression raises to main resistance mechanism, is drawn from institute of oncology, Beijing by Inst. of Hematology, Chinese Academy of Medical Sciences's medicament chamber, and provides the author to use.To 100 times of amycin drug resistances, to harringtonine, vincristine, VP16, crossing drug resistants such as daunorubicin.
The HL60/Adr multidrug resistance cell strain, expressing rising with multidrug-associated protein (MRP) is main resistance mechanism.Draw from Japan's cell bank and provide the author to use by Inst. of Hematology, Chinese Academy of Medical Sciences's medicament chamber.To 100 times of amycin drug resistances, to homoharringtonine, mitoxantrone, daunorubicin, crossing drug resistants such as methotrexate.
KB
V200Multidrug resistance cell strain is with P
GpProtein expression raises and is main resistance mechanism.Draw from institute of Materia Medica,Chinese Academy of Medical Sciences and provide the author to use by Radiation Medical Science Inst., Chinese Academy of Military Medical Science (CN, to 175 times of vincristine drug resistances, to amycin, paclitaxel, Colchicine crossing drug resistant.Animal: the Balb/C nude mice, in 4-6 week, female, body weight 16 ± 2 grams are available from the military medicine science
Institute's Experimental Animal Center;
Kunming mouse, in 6-8 week, female, male, 20 ± 2 grams are available from Military Medical Science Institute
Experimental Animal Center.1.1.2 reagent
Compound P M solution: after adding a small amount of distilled water among the Compound P M, splash into 1NHCl and make molten (PH～2), add distilled water to 200 μ g/ml again, be mixed with working solution with the RPMI1640 culture fluid again as mother solution.
The amycin standard substance, the ministry of Health of China medicine is identified institute
The vincristine Experimental Pharmaceutical Factory of Beijing Medical Univ
RPMI1640 culture medium U.S. SIGMA company
Calf serum Military Medical Science Institute
MTT (import) magnificent company packing experimental article and instrument:
Culture bottle
Culture plate
CO2 gas incubator
Microplate reader
Chromatograph of liquid 1.2 experimental techniques: the drug resistance multiple of each persister cell to amycin or vincristine measured in 1.2.1 cell killing enhanced sensitivity test (1); (2) measure Compound P M for each cell strain toxicity, select for inhibitory rate of cell growth earlier
Be lower than 10% (IC
50) concentration do enhanced sensitivity test.Compound P M's increases when (3) measuring Compound P M and amycin or vincristine use in conjunction
Quick effect (4) test operation step:
The trophophase liquid culture cell of taking the logarithm is with containing 10% calf serum
The RPMI1640 culture fluid is made into cell suspension, and every hole 180 μ l (cytotoxicity test) or 160 μ l (enhanced sensitivity test) add to 96 hole plastic culture plates, and making every porocyte number is 2 * 10
4Individual, cell adapts to growth 12 hours in culture plate, grouping adds each 20 μ l of experiment medicine, establishes serum-free medium zeroing hole and not dosing cell blank matched group, establishes three parallel holes for every group, every hole final volume is 200 μ l, insufficient section is supplied with drug solvent, puts in the CO2 gas incubator 37 ℃, saturated humidity, 5%CO
2Cultivation is 68 hours under the condition, and every hole adds 5mg/ml MTT liquid 20 μ l, and the same terms was cultivated 4 hours, removed supernatant, and every hole adds dimethyl sulfoxide (DMSO) 150 μ l, the micro oscillator vibration, and abundant dissolved substance, microplate reader detects 540nM wavelength OD value.(5) computational methods
IC
50=suppression ratio is 50% o'clock a drug level
1.2.2 the inoculation of mouse tumor treatment enhanced sensitivity test (1) tumor cell: trophophase multidrug resistance cell strain KB takes the logarithm
V200Cell is outstanding
Liquid 1.5 * 10
7It is subcutaneous that/ml, 0.2ml are inoculated in the nude mice back.(2) inoculation KB
V200Cell after five days (the 6th day) be grouped into matched group, abdominal cavity
Injection vincristine 0.4 μ g/ Mus/sky group, or chemical combination is used in vincristine 0.4 μ g/ Mus/sky 5
Thing PM30 μ g/ Mus/sky group. had a rest two as a course of treatment, continue a course of treatment in 5th.(3) measure the sensitization of Compound P M, treating lives after two courses of treatment immediately kills mice, claims tumor
Body weight is as evaluation index.1.2.3 the pharmacokinetics of Compound P M test (1) Compound P M solution 30 μ g/0.2ml intraperitoneal injection of mice (1.5mg/kg body weight), difference
Time lives and gets blood and liver, spleen, lung and cerebral tissue extremely.(2) Compound P M amount in high effective liquid chromatography for measuring different time blood plasma and the tissue.Two, result 2.1 K562/A02, MCF-7/Adr, HL60/Adr, KB
V200Cell strain drug resistance multiple is measured cell strain amycin IC
50Vincristine IC
50The drug resistance multiple
(μ g/ml) be K562 0.45 ± 0.051K562/A02 17.56 ± 1.823 39MCF-7 0.06 ± 0.007MCF-7/Adr 8.96 ± 0.986 1,40H,L60 0.08 ± 0.009HL60/Adr 8.16 ± 1.027 102KB 6.7 ± 0.7KB (ng/ml)
V2001297.6 the cytotoxic assay of ± 0.33 193 Compound P M: cell line Compound P M IC
50IC
10
(μg/ml) (μg/ml)K562 328.50±36.52 65.35±7.58K562/A02 300.06±33.18 60.63±7.34MCF-7 438.03±38.56 97.20±11.2MCF-7/Adr 412.02±45.40 83.16±9.35HL60 288.27±34.23 66.29±8.10HL60/Adr 256.52±26.15 58.08±6.02KB 104.32±34.96 21.51±10.29KB
V200 130.69±24.56 46.30±12.67
Compound P M kills and wounds the sensitization of drug-resistant tumor cell to amycin. and by inhibitory rate of cell growth is the 50% enhanced sensitivity multiple that calculates: cell line Adr IC
50Adr+PM IC
50The enhanced sensitivity multiple
(μg/ml) (μg/ml)K562 0.45±0.058 0.31±0.041 1.5K562/A02 17.52±1.932 3.07±0.426 5.7MCF-7 0.06±0.008 0.05±0.006 1.2MCF-7/Adr 8.96±0.974 1.53±0.212 5.9HL60 0.04±0.005 0.04±0.006 1.0HL60/Adr 8.16±9.083 1.45±0.197 5.6
*The final concentration of PM is 50 μ g/ml, N=5
Compound P M kills and wounds the sensitization of drug-resistant tumor cell to vincristine (Vin). and by inhibitory rate of cell growth is the 50% enhanced sensitivity multiple that calculates: cell line Vin IC
50Vin+PM IC
50The enhanced sensitivity multiple
(ng/ml) (ng/ml) KB 4.87 ± 1.55 1.69 ± 0.63 2.8KBV200 1661.6 ± 552 233.89 ± 65.0 7.9
*The final concentration of PM is 20 μ g/ml N=3
Repeatedly experimental result shows: Compound P M kills and wounds multidrug resistance tumor cells for amycin or vincristine and has tangible sensitization, and promptly PM has tangible reverse effect really for above-mentioned two kinds of drug-fast tumor cells of medicine.It reverses multiple Yue Keda about 5.For inferring the probability of its clinical practice, use again and kill and wound the IC of this multidrug resistance tumor cells when MCF-7/Adr cell line has been tested Compound P M difference dose
50, and calculate the variation that it reverses multiple.Result such as following table:
PM dosage (μ g/ml) reverses multiple
50 5.6
20 3.46
10 1.54
5 1.24
2.5 1.19
0.5 1.20
*Cell strain is MCF-7/Adr
It is better that the result shows that Compound P M kills and wounds the effect of enhanced sensitivity of mdr cell for amycin when high concentration.Along with the decline of compound concentration, this effect also subtracts mistake rapidly.Identical (the Biochem Pharmacology1995 of the trend that this dose-effect relationship changes and other inversion agent such as isoptin, 50 (8): 1245-55), and the latter's still unsure its actual application value in clinical verification, obstacle just is that effect is arranged when drug level is high, but can't reach this level (Chinese Journal of Hematology 1988 in the human body, 9 (6): 340-3) and drug level when low, the cause that effect is too low again.Therefore the effect in the time of if can improving Compound P M low concentration just may have the meaning of practical application.The present invention adopts low dose compounds PM and low dosage isoptin (Ver) 5 usefulness, and to improve the effect of PM to the MCF-7/Adr cell, the result is as follows:
Group reverses multiple
PM(0.5μg/ml) 1.151
Ver(0.5μg/ml) 1.199
PM+Ver 1.540
(0.5μg+0.5μg)
This explanation isoptin can make the PM effect improve.And this result as with preceding table (reversing effect of various dose PM) reference mutually, can roughly estimate the effect when it is equivalent to PM10 μ g/ml, promptly quite PM has improved the effect of twenty times of dosage; Because the dosage of isoptin is very low, this dosage is that human body can tolerate fully.Compound P M 5 usefulness isoptins may have the meaning of practical clinical under this condition.2.2 Compound P M is for the reverse effect in the tumor-bearing mice bulk testing
Experiment is used the Balb/C nude mice, the about 16 ± 2g of body weight, 4-6 week in age.
Subcutaneous vaccination 1.5 * 10
7/ ml KB
V200Grouping on the five behind the cell 0.2ml.Be matched group, vincristine i.p 4 μ g/ Mus/sky group, vincristine i.p 4 μ g/ Mus/skies add PM i.p30 μ g/ Mus/sky group.The medicine injection was a course of treatment in 5 days, had a rest two days.Medication is promptly lived after one course of treatment and is claimed tumor heavy extremely again.The result is as showing:
Group tumor heavy (g)
Contrast 0.846 ± 0.237
Vincristine 0.731 ± 0.400
Vincristine+PM 0.618 ± 0.407
*N＝5
PRELIMINARY RESULTS shows that vincristine can make the tumor bulk-growth slower than matched group person, and vincristine adds PM person's better effects if.2.3 the pharmacokinetics of Compound P M test
Utilize behind the reversed phase liquid chromatography quantitative analysis mice i.p PM 30 μ g/ Mus content of Compound P M in the different time blood plasma and liver, spleen, lung and cerebral tissue.Blood plasma Chinese medicine concentration change sees Table:
Get blood time PM concentration (μ g/ml)
(after the injection) (M ± SD)
5 minutes 0.78 ± 0.190
10 minutes 0.96 ± 0.140
20 minutes 0.79 ± 0.087
30 minutes 0.53 ± 0.008
60 minutes 0.43 ± 0.072
2 hours 0.25 ± 0.035
4 hours 0.11 ± 0.020
8 hours 0.034 ± 0.008
12 hours 0.00
*N＝4
Behind the mouse peritoneal injection Compound P M pharmacokinetic parameter T (1/2) C (Max) T (Peak) AUC CL/F (S) V/F (C) (h) (μ g/ml) (h) after (μ g/ml) h μ g/kg/h (μ g/ml) (μ g/kg/ μ g/ml) 0.84 0.87 0.15 1.60 1265.9 1535.9 each internal organs Chinese medicine concentration change trend but peak value similar substantially to the blood plasma person moves, content is higher in spleen and the lymph node.Discuss:
Along with the mechanism of multidrug resistance problem generation and the further investigation of inversion agent, recognize various kinds of cell component such as P gradually
GpAlbumen, multidrug-associated protein (MRP), lung drug-resistant protein (LRP), glutathione s transferase (GST), the expression of topoisomerase-II (Top-II) etc. or the variation of function all can cause chemical sproof variation, and (Science 1983,221:1285-88, Cancer Res.1989,49:6634, Cancer Res.1991,51:6592, Cancer 1992,70:764, Anticancer Res.1996,16 (2): 709-14). and inversion agent known today general do also more single, as isoptin, cyclosporin A etc. for expressing P
GpMultidrug resistance cell effect obviously (Molecular Pharmacology 1995,47:51-56, Anticancer Res.1992,12 (6B): 2127-32).Therefore, the searching effect is more extensive or act on other machine-processed inversion agent and just seem very for important.The inversion agent of finding the new chemical structure will increase this probability.Different steroid alkaloid of the present invention is to belong to the newtype chemical constitution as inversion agent, and can act on the different multidrug resistance cell strain of two kinds of mechanism (as MCF-7/Adr and HL
60/ Adr), thus be the multidrug-resistance reversal agent that belongs to new class from its chemical constitution and functional characteristics, thereby its potential applicability in clinical practice or may be different with the comparatively single inversion agent of effect.The greatest difficulty that runs into when inversion agent carries out the transition to clinical practice at present is that patient can only tolerate smaller dose, and the haemoconcentration level is very low, and the valid density when testing with isolated cells relatively, and is mutually far short of what is expected.Therefore,, find low concentration still to have the medicine of effect, just be easy to be connected mutually with clinical as in test cell line.The present invention considers that the mechanism of action of Compound P M and other inversion agent such as isoptin is different.So 5 usefulness, to increase effect.This data shows that Compound P M0.5 μ g/ml (is equivalent to IC as a result
101/100) 5 usefulness isoptins, 0.5 μ g/ml (clinical safety consumption) effect is obvious.Because more easily reach this with medicament requirement in clinical patient, thereby actual application prospect is comparatively optimistic.Conclusion:
Compound P M when isolated test for multidrug resistance tumor cells strain K562/A02, MCF-7/Adr, HL
60/ Adr and KB
V200Reverse effect is all arranged, (～IC when big with concentration
10), reversing coefficient and can reach about 5 times, reduction drug level then effect descends rapidly.But PM0.5 μ g/ml (IC
101/100 concentration) act on increase with isoptin 0.5 μ g/ml (clinical safety consumption) 5 times spent, effect during suitable approximately PM10 μ g/ml.At lotus KB
V200The preliminary test of cell nude mice shows that mice two all posterior tuberosities of vincristine 0.4 μ g/ Mus i.p treatment heavily are 87% of contrast, and vincristine 0.4 μ g/ Mus to add Compound P M 30 μ g/ Mus i.p therapists be 73%. Compound P M to the toxicity of mice is: oral LD
5011.4mg/kg, lumbar injection LD
506.67mg/kg. 10 minutes plasma concentration promptly reach the peak behind the lumbar injection 1.5mg/kg.T
1/2Be 0.84h, C (Max) 0.87 μ g/ml, T (peak) 0.15h, the growth and decline trend of AUC 1.60 μ g/ml.h tissue concentrations and blood plasma person are identical, and content is higher in spleen and the lymph node.
Claims (5)
1. the different steroid alkaloid that has following structure, or the application of salt in preparation tumor multidrug-resistance inversion agent medicine that form of itself and acid
Wherein: R
1Can be
Or H
R
2Can be
Or=0R
3, R
4, R
5Can be H, R
6Can be OH
2. the described application of claim 1, wherein said inversion agent also contain and are useful on the antitumor drug that preparation is worked by reversal of multidrug resistance of tumor cells, and pharmaceutical excipient or carrier.
3. application according to claim 2, wherein said medicine can be made into tablet, capsule, injection or granule dosage form.
4. application according to claim 1 is characterized in that described medicine can also contain other inversion agent.
5. application according to claim 1, its described acid can comprise hydrochloric acid, bromine hydracid, nitric acid, maleic acid, Palmic acid, succinic acid.
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|---|---|---|---|
| CN98117402A CN1102047C (en) | 1998-08-19 | 1998-08-19 | Reversing agent for multi-medicine resistance of tumor cells |
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| CN102327571B (en) * | 2011-09-30 | 2016-04-27 | 四川大学 | Bulbus Fritillariae Cirrhosae total alkaloids and contained compound are preparing the novelty teabag in cancer therapy drug |
| CN102600142B (en) * | 2012-02-21 | 2014-08-20 | 新疆维吾尔自治区药物研究所 | New application of peiminine in manufacturing gastric cancer multidrug resistance reversing medicaments |
| CN106474125A (en) * | 2016-12-29 | 2017-03-08 | 新疆维吾尔自治区药物研究所 | Peiminine improves the application of the sensitive drug to chemotherapeutics for the tumor cell as preparation |
| CN110672742B (en) * | 2019-10-09 | 2022-07-15 | 浙江省食品药品检验研究院 | Thunberg fritillary bulb identification method |
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| Title |
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| 湖南中医学院学报 1998-06-01 刘静等 * |
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