CN107049998A - Application of the lycopene cis-isomer in treatment of ovarian cancer medicine is prepared - Google Patents
Application of the lycopene cis-isomer in treatment of ovarian cancer medicine is prepared Download PDFInfo
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- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 title claims abstract description 39
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 title claims abstract description 37
- 235000012661 lycopene Nutrition 0.000 title claims abstract description 37
- 239000001751 lycopene Substances 0.000 title claims abstract description 37
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 title claims abstract description 35
- 229960004999 lycopene Drugs 0.000 title claims abstract description 35
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 title claims abstract description 35
- 206010033128 Ovarian cancer Diseases 0.000 title claims abstract description 13
- 206010061535 Ovarian neoplasm Diseases 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title claims description 67
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 230000006907 apoptotic process Effects 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- OAIJSZIZWZSQBC-UMONDHTKSA-N (6e,8z,10e,12z,14e,16z,18e,20z,22e,24z,26e)-2,6,10,14,19,23,27,31-octamethyldotriaconta-2,6,8,10,12,14,16,18,20,22,24,26,30-tridecaene Chemical compound CC(C)=CCC\C(C)=C\C=C/C(/C)=C/C=C\C(\C)=C\C=C/C=C(\C)/C=C\C=C(/C)\C=C/C=C(\C)CCC=C(C)C OAIJSZIZWZSQBC-UMONDHTKSA-N 0.000 abstract description 9
- 238000002474 experimental method Methods 0.000 abstract description 8
- 206010006187 Breast cancer Diseases 0.000 abstract description 5
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 4
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- 238000006317 isomerization reaction Methods 0.000 abstract description 3
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 abstract description 2
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- 210000004369 blood Anatomy 0.000 abstract description 2
- 239000008280 blood Substances 0.000 abstract description 2
- 230000002596 correlated effect Effects 0.000 abstract description 2
- 208000010570 urinary bladder carcinoma Diseases 0.000 abstract description 2
- 125000000609 carbazolyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 abstract 2
- 239000003560 cancer drug Substances 0.000 abstract 1
- 229940000406 drug candidate Drugs 0.000 abstract 1
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- 239000000243 solution Substances 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
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- OAIJSZIZWZSQBC-UHFFFAOYSA-N (7Z,9Z,7'Z,9'Z)-ψ,ψ-carotene Chemical compound CC(C)=CCCC(C)=CC=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC=C(C)CCC=C(C)C OAIJSZIZWZSQBC-UHFFFAOYSA-N 0.000 description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000010190 G1 phase Effects 0.000 description 2
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 2
- 240000003768 Solanum lycopersicum Species 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
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- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/01—Hydrocarbons
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The Carbazole alkaloids of oophoroma HO 8910 are bred the invention discloses All-cislycopene (Lycopene, Lyp) isomers and apoptosis-induced effect, belong to pharmaceutical technology field.Research shows that the incidence of Lyp concentration and prostate cancer, human primary gastrointestinal cancers, breast cancer, carcinoma of urinary bladder etc. is negatively correlated in blood, but whether plays the role of inhibitory action and cis and trans isomers to oophoroma whether variant there is not been reported.Thus, inventor proposes hypothesis first:By alltrans Lyp can isomerization obtain cis Lyp, and the two is to the Carbazole alkaloids of oophoroma HO 8910 propagation and apoptosis-induced having differences property of effect.In the present invention, inventor confirms above-mentioned hypothesis with cell experiment, and the effect that cis Lyp suppresses the cells of HO 8910 in vitro is more stronger than alltrans Lyp, and the two concentration is in the μ gmL of 10 μ~20‑1When, inhibiting rate and apoptosis rate have significant difference.All-cislycopene can as treatment of ovarian cancer drug candidate.
Description
Technical field
The present invention relates to a kind of new application of isomers of lycopene, and in particular to prepared by lycopene cis-isomer
Application in oophoroma HO-8910 cells propagation and Apoptosis medicine, belongs to pharmaceutical technology field.
Background technology
Lycopene (Lycopene, Lyp) has quenching activity oxygen, eliminates human free radical, prevents heart disease, slows down dynamic
The physiological function such as pulse atherosclerosis, prevention kinds cancer, anti-aging, protection skin.Epidemiological study shows, Lyp in blood
The incidence of concentration and prostate cancer, cancer of the esophagus, cancer of pancreas, human primary gastrointestinal cancers, breast cancer, cutaneum carcinoma, carcinoma of urinary bladder etc. is negatively correlated.Perhaps
Many In vitro cell experiments all confirm this point, and Lyp has suppression growth to esophageal carcinoma cell line (Eca9706), before people
Row gland cancer PC-3 cells and breast cancer MDA-MB-231 cells have Inhibit proliferaton and apoptosis-induced effect, thin to cervical cancer Hela cells
Born of the same parents and mice model of forestomach tissue canceration also have certain inhibitory action.But whether Lyp has inhibitory action to the oophoroma for having high incidence
See that there is not been reported before periodical in the present inventor's research paper.
Lyp can reduce the activity of breast cancer cell mitogen, suppress cell cycle arrest in the G1 phases to S phases, Lyp can increase
Strong GJIC (GJIC) function, promotes the interaction between phagocyte, lymphocyte, is lived by secretory cell
Change factors activated cell, be eventually exhibited as the promotion to phagocytic activity and lymphocyte transformation, strengthen immunologic function and then induction
Apoptosis of tumor cells.A research report report that NATUER in 2012 is delivered:Breast cancer genetic analysis show its procarcinogen because
It is similar to oophoroma.
The content of the invention
It is an object of the invention to provide application of the lycopene cis-isomer in treatment of ovarian cancer medicine is prepared.
Lycopene structure formula
Lycopene, molecular formula C40H56, relative molecular mass 536.85 is a kind of important carotenoid in meals, mainly
It is present in tomato products, watermelon, pomegranate, autumn olive and purple grape fruit.The lycopene of natural origin is main with complete
Trans forms are present, and are most stable of structures.In human plasma, lycopene content is 0.2-1.0 μm of ol/L, mainly with suitable
Formula configuration is present, and anti-configuration only accounts for 41%.Foreign study proves that All-cislycopene is easier to be absorbed by the body, it may have
Higher bioactivity.
Both at home and abroad in lycopene and the relation document of cancer, difference between the effects research to cis and trans isomers there is not yet
Report.Thus, inventor proposes hypothesis first:By trans lycopene can the obtained All-cislycopene of isomerization, and the two
To human ovarian cancer cell line HO-8910 Inhibit proliferaton and apoptosis-induced having differences property of effect.In the present invention, demonstrate,proved with cell experiment
Real above-mentioned hypothesis, Preliminary Results prompting suppresses the effect of HO-8910 cells than complete in vitro containing Lyp cis at high proportion
Trans Lyp is more stronger, and the two concentration is in 10 μ gmL-1With 20 μ gmL-1When, inhibiting rate and apoptosis rate relatively have significantly
Sex differernce.
All-cislycopene by all-trans lycopene isomerization using being prepared, with reference to Pierre Lambelet etc. side
Method carries out cisization processing:Weigh the lycopene powder being purchased from appropriate, dissolved, be made with the ethyl acetate solution through membrane filtration
1mg·mL-1Solution, 100 DEG C of water-baths of lucifuge backflow 5h place 12h under the conditions of 4 DEG C, filter, remove crystallization (I medicines, entirely
Trans lycopene), filtrate decompression is evaporated to dryness, and obtains red acicular crystal (II medicines, All-cislycopene powder).
Lycopene cis-isomer is not yet used to prepare medicine at present, and the formulation of health products is capsule and tablet.
Embodiment
1 materials and methods
1.1 experiment material
Lycopene powder (purity 90%) (Huabei Pharmaceutic Co., Ltd)
HO-8910 cell lines (Xiangya Hospital, Central-South China Univ.'s cell centre)
Tetrazolium (Sigma companies)
0.4% trypan blue (Gibco companies)
RPM-1640 (Gibco companies)
Newborn calf serum (Hangzhou Chinese holly)
Docetaxel injection (DOC, permanent auspicious medicine)
Dimethyl sulfoxide (DMSO) (DMSO)
Acetonitrile, tetrahydrofuran, ethyl acetate (Chemical Reagent Co., Ltd., Sinopharm Group)
The synthesis of 1.2 All-cislycopenes is with separating
Cisization processing is carried out with reference to Pierre Lambelet etc. method:Weigh the lycopene purchased from North China drugmaker
Appropriate powder, is dissolved with the ethyl acetate solution through membrane filtration, 1mgmL is made-1Solution, 100 DEG C of water-baths of lucifuge backflow 5h,
12h is placed under the conditions of 4 DEG C, is filtered, crystallization (I medicines) is removed, filtrate decompression is evaporated to dryness, and obtains red acicular crystal (II
Number medicine).
The preparation of lycopene oil solution and uv scan:By document[5]Method, weighs I, II medicine and tomato red respectively
Plain each 0.0200g of powder is put in 100mL measuring bottles, and each bottle first adds DMSO0.5ml, adds sunflower oil and is diluted to scale, shakes
It is even, storing solution is made.Precision measures storing solution 1mL plus sunflower oil is settled in 100mL measuring bottles, shakes up, in 200~600nm
Place's scanning ultra-violet absorption spectrum.
I, II medicine oil solution are separated by HPLC:By literature method, I, II medicine oil solution are passed through into HPLC separation detections
Purity, chromatographic condition is chromatographic column:COSMOSIL Cholester posts (4.6mm × 250mm, 5um), mobile phase is tetrahydrofuran
: acetonitrile=15: 85 (v/v), sample size 20uL, flow velocity 1mlmin-1, 15 DEG C of column temperature, Detection wavelength 472nm.With lycopene
Powder and I medicines are as reference substance, and 0.1mgmL containing lycopene is made as test sample in II medicines-1Reference substance and confession
Test sample solution.
1.3HO-8910 the culture and packet of cell
37 DEG C, 5%CO are based on the RPMI1640 cultures containing 10% calf serum2Cultivated under saturated humidity.Cell in culture medium
Adherent growth, growth period cell of taking the logarithm is used to test.Experiment sets 9 group (1) blank control groups:Only contain nutrient solution;(2) solvent
Control group:Nutrient solution containing 0.5%DMSO;(3) II medicines low dose group:The μ gmL of All-cislycopene content about 5-1;(4)II
Number medicine middle dose group:The μ gmL of All-cislycopene content about 10-1;(5) II medicines high dose group:All-cislycopene content is about
20μg·mL-1;(6) I medicines low dose group:The μ gmL of trans lycopene content about 5-1;(7) I medicines middle dose group:It is trans
The μ gmL of lycopene content about 10-1;(8) I medicines high dose group:The μ gmL of trans lycopene content about 20-1;(9) it is positive
Medicine control group:Final concentration of 0.2 μ gmL-1DOC solution.
The measure of 1.4HO-8910 cell growth curves
Collect exponential phase HO-8910 cells 5 × 105/ L is inoculated in 24 well culture plates, per hole 1ml, is then distinguished per hole
1.3 lower each group solution are added, 37 DEG C, 5%CO is put2Cultivated in incubator, and make cell count in 24,48,72,96,120h.
During counting, check cell survival rate more than 95% with 0.4% trypan blue.Every group of 3 multiple holes, take its average value to draw growth bent
Line.
1.5MTT method
Growth period HO-8910 cell of taking the logarithm is made 1 × 105Individual/L single cell suspension, is inoculated in 96 well culture plates, treats thin
1.3 lower each group solution are separately added into after born of the same parents are adherent per hole, cumulative volume is, per hole 200ul, 4 multiple holes to be set per dose, in 48h
Afterwards, 5mg/mlMTT20 μ l are added per hole to continue to be incubated 4h, discard nutrient solution, dimethyl sulfoxide (DMSO) (DMSO) 100 μ l are added per hole,
Fully mix, ELIASA (EX-800) surveys absorbance (A) value at 570nm, and experiment is repeated 3 times.Calculate average A-value and suppression
Rate:Inhibiting rate (inhibitory, IR)=[(solvent control group A values-experimental group A values)/solvent control group A values] × 100%.
1.6 flow cytometer PI methods detect that suitable, anteiso- structure lycopene sunflower oil solution is thin to human ovarian cancer HO-8910
Born of the same parents' apoptosis rate difference growth period HO-8910 cell of taking the logarithm is made 1 × 106Individual/L single cell suspension, is inoculated in 6 well culture plates
In, it is separately added into per hole after 1.3 lower each group solution, culture 48h, collects cell, PBS washings is made single cell suspension, used
The 70% fixed 12h of 4 DEG C of ice ethanol, 30min, FACSort fluidic cells are contaminated with qiagen rnase enzyme and the dye liquor of propidium iodide
Instrument carries out cycle analysis, is apoptotic cell less than G1 phase DNA contents cell.
1.7 statistical analysis
Data withRepresent, taken statistics analysis with SPSS11.0 softwares, two sample averages compare to be examined using t, with P < 0.05
There is significant for difference.
2 results
The Qualitive test of 2.1I, II medicine:By the contrast of ultraviolet spectrogram, I medicines can be assert with lycopene powder
For all-trans lycopene, the cis peak at 362nm reported in the literature is occurred in that in II medicines.
The purity testing of 2.2I, II medicine:By HPLC method separation detection purity, calculated using quantified by external standard method, with kind
Lycopene powder is as reference substance, and it is 95.82% to try to achieve alltrans Lyp contents in I medicines;Using I medicines as reference substance, try to achieve
Cis Lyp contents are 79.53% in II medicines.
2.3 is suitable, anteiso- structure lycopene sunflower oil solution is to the ratio of human ovarian cancer cell line HO-8910 growth inhibition curve
Compared with
Blank control group is consistent with solvent control group cell growth, shows 0.5%DMSO on the growth of cell without influence;I medicines
Substantially it is suppressed compared with blank control group with the cell growth of each dosage group of II medicines and positive drug control group;Each experiment
Group is in set concentration range, and with the increase of dosage, its inhibitory action strengthens;Growth inhibition of two high dose groups to cell
Effect is remarkably reinforced compared with positive drug control group;I medicines low dose group to the growth inhibition effect of cell and II medicine phases ratio without
Notable difference, but middle and high dosage I medicines group is weak compared with II medicines group suppression cell growth effect.See Fig. 1.
2.4 is suitable, anteiso- structure lycopene sunflower oil solution compares human ovarian cancer cell line HO-8910 proliferation inhibition rate
Solvent control group no significant difference (P > 0.05) compared with the absorbance of blank control group, illustrates 0.5%DMSO to thin
Intracellular growth is without influence.Each experimental group of lycopene and the positive drug control group difference compared with blank control group have pole conspicuousness (P <
0.01).II medicines with the middle and high dosage group of I medicines is corresponding respectively compares, as a result with significant difference (P < 0.05).It is two high
Dosage group is with there were significant differences compared with positive drug control group (P < 0.05).The basic, normal, high dosage group of II medicines is thin to HO-8910
Born of the same parents' proliferation inhibition rate is respectively 17.25%, 24.13%, 62.03%;The basic, normal, high dosage group of I medicines increases to HO-8910 cells
It is respectively 16.86%, 17.57%, 54.05% to grow inhibiting rate;Positive drug control group is to HO-8910 cell proliferation inhibition rates
44.5%.It is shown in Table 1.
The inhibitory action that table 1 is suitable, anteiso- structure lycopene grows to human ovarian cancer cell line HO-8910
Note:Compared with blank control group,aP < 0.01;Compared with I medicine middle dose groups,bP < 0.05;With I medicine high dose groups
Compare,cP < 0.05;With the μ gmL of DOC 0.2-1Group compares,dP < 0.05.
2.5 is suitable, comparison of the anteiso- structure lycopene sunflower oil solution to human ovarian cancer cell line HO-8910 Apoptosis
Solvent control group no significant difference (P > 0.05) compared with the apoptosis rate of blank control group.Each reality of lycopene
Testing group and the positive drug control group difference compared with blank control group has pole conspicuousness (P < 0.01).II medicines and I medicines are middle and high
Dosage group is corresponded to respectively to be compared, as a result with significant difference (P < 0.05) (P < 0.05).High dose group apoptosis rate is high
In positive drug control group, difference has conspicuousness (P < 0.05).The basic, normal, high dosage group apoptosis rate of II medicines is respectively
11.5%th, 29.9%, 39.7%;The basic, normal, high dosage group apoptosis rate of I medicines is respectively 11.8%, 23.1%, 32.4%;
Positive drug control group apoptosis rate is 24.6%.See Fig. 2.PI detection apoptotic cell scatter diagrams are shown in Fig. 3.
Recent study find, Lyp molecules from anti-configuration be changed into cis-configuration when, lighter, fusing point reduction, absorb
Peak shifts, and heat treatment can dramatically increase the cis-Lyp in tomato juice.This experiment isomate process is consistent with document.This is thin
Born of the same parents' experimental result shows that the effect for suppressing HO-8910 cells in vitro containing cis Lyp at high proportion is more stronger than alltrans Lyp, and
The two concentration is in 10 μ gmL-1With 20 μ gmL-1When, inhibiting rate and apoptosis rate relatively have significant difference.
Suitable, anteiso- structure lycopene sunflower oil solution is to human ovarian cancer cell line HO-8910 growth inhibition curve and Apoptosis
Relatively see Figure of description.Fig. 1 is the growth curve chart that suitable, anteiso- structure lycopene suppresses HO-8910 cells, Fig. 2 be it is suitable,
The figure that anteiso- structure lycopene influences on human ovarian cancer cell line HO-8910 apoptosis rate, packet situation is:1. blank control group, 2.
Solvent control group, 3.II medicine low dose groups, 4.II medicine middle dose groups, 5.II medicine high doses, 6.I medicine low dose groups,
7.I medicine middle dose groups, 8.I medicine high dose groups, the μ gmL of 9.DOC 0.2-1Group.Com-parison and analysis situation is:With blank control
Group compares,aP < 0.01;Compared with I medicine middle dose groups,bP < 0.05;With I medicines;High dose group compares,cP < 0.05;With
DOC 0.2μg·mL-1Group compares,dP < 0.05.Fig. 3 is apoptotic cell scatter diagram, and packet situation is:1. blank control group, 2.
Solvent control group, 3.II medicine low dose groups, 4.II medicine middle dose groups, 5.II medicine high doses, 6.I medicine low dose groups,
7.I medicine middle dose groups, 8.I medicine high dose groups, the μ gmL of 9.DOC 0.2-1Group.
Claims (2)
1. application of the lycopene cis-isomer in treatment of ovarian cancer medicine is prepared.
2. apply according to claim 1, lycopene cis-isomer or its pharmaceutically acceptable salt or contain them
Middle any pharmaceutical composition is preparing the application for the treatment of oophoroma.
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CN111603458A (en) * | 2020-06-24 | 2020-09-01 | 南华大学附属第二医院 | A composition for treating ovarian cancer |
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CN1612728A (en) * | 2001-11-12 | 2005-05-04 | 利库德天然产品工业有限公司 | Method and pharmaceutical preparations for reducing the activity of cells |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111603458A (en) * | 2020-06-24 | 2020-09-01 | 南华大学附属第二医院 | A composition for treating ovarian cancer |
CN111603458B (en) * | 2020-06-24 | 2022-12-16 | 南华大学附属第二医院 | A composition for treating ovarian cancer |
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