CN107496399A - A kind of combination medicine with antineoplastic effect - Google Patents
A kind of combination medicine with antineoplastic effect Download PDFInfo
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- CN107496399A CN107496399A CN201710719094.1A CN201710719094A CN107496399A CN 107496399 A CN107496399 A CN 107496399A CN 201710719094 A CN201710719094 A CN 201710719094A CN 107496399 A CN107496399 A CN 107496399A
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- medicine
- chlorogenic acid
- combination
- antineoplastic
- dihydrofolate reductase
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
Abstract
The invention provides a kind of combination medicine with antineoplastic effect, and it contains the chlorogenic acid and dihydrofolate reductase inhibitor that are used to be administered simultaneously or respectively of identical or different specification unit formulation, and pharmaceutically acceptable carrier.The effect that can play Synergistic is used in combination with DHFR inhibitor in chlorogenic acid of the present invention, and hematopoiesis function damage and body weight lighten caused by alleviating DHFR inhibitor, effectively reduce the toxic side effect of DHFR inhibitor, the effect of by chlorogenic acid with DHFR inhibitor combination medicines, is excellent, small toxicity, potential applicability in clinical practice are good.
Description
Technical field
The present invention relates to a kind of combination medicine with antineoplastic effect.
Background technology
Dihyrofolate reductase (DHFR) is a kind of enzyme critically important in organism, dihydrofolate reduction in catalysis biological body
Into the reaction of tetrahydrofolic acid, the process for the precursor thymidine of biological synthetic DNA provides one-carbon unit.DHFR
Inhibitor can be combined optionally during growth of tumour cell with DHFR, suppress its catalytic reduction activity, make dihydro leaf
Acid can not be transformed into tetrahydrofolic acid, disturb the synthesis of DNA and protein, ultimately result in cell death, antitumor so as to reach
Purpose.
DHFR inhibitor antitumous effects are obvious, and the treatment frequently as a line and two wires uses, but due to belonging to cell
Toxicity class medicine, it is big to body injury, can not continued therapy.To mitigate the toxic side effect of DHFR inhibitor, clinically generally
By the way of other chemotherapeutics are combined to tumour carry out Intermittent treatment, but due to other chemotherapeutics equally exist it is larger
Toxic side effect, therefore effect and unobvious.Chlorogenic acid is a kind of polyphenol compound, have antibacterial, it is antiviral, increase white blood
Ball, hepatic cholagogic, antitumor, lowering blood pressure and blood fat, the removing bioactivity such as free radical and stimulating central nervous system system.At present
Because toxic side effect is low, antitumous effect is good, it has also become the study hotspot of antineoplastic.
Have no the report by dihydrofolate reductase inhibitors such as pemetrexeds, being used in combination with chlorogenic acid.
The content of the invention
It is an object of the invention to provide a kind of combination medicine with antineoplastic effect, to improve medicine list medicine
While the effect of medication, the toxic side effect of dihydrofolate reductase inhibitor is reduced.
The invention provides a kind of combination medicine with antineoplastic effect, it is characterised in that：It contains identical
Or the chlorogenic acid and dihydrofolate reductase inhibitor that are used to be administered simultaneously or respectively of different size unit formulation, and medicine
Acceptable carrier on.
Wherein, dihydrofolate reductase inhibitor includes but is not limited to pemetrexed, ammonia petrin.
Wherein, the weight of chlorogenic acid and dihydrofolate reductase inhibitor ratio is 1：1—1：5.
The combination medicine of antineoplastic effect of the present invention, the note of the 10mg-240mg containing chlorogenic acid in unit formulation medicine
Penetrate agent or oral formulations；Dosage is 10-40mg/kg chlorogenic acids and dosage 2-40mg/kg combination medicine.
Wherein, when the antineoplastic is pemetrexed, the weight ratio of chlorogenic acid and antineoplastic is 2:5；
When the antineoplastic is ammonia petrin, the weight ratio of chlorogenic acid and antineoplastic is 2:4.
Present invention also offers foregoing combination medicine to prepare treatment breast cancer, lung cancer, liver cancer, chorionic epithelium
Cancer, chorioadenoma, treatment MPM, acute leukemia medicine in purposes.
Present invention also offers purposes of the foregoing combination medicine in the medicine for preparing non-multidrug-resistant carcinoma.
Present invention also offers chlorogenic acid and dihydrofolate reductase inhibitor in antitumor combination medicine is prepared
Purposes.
Wherein, the combination medicine is the medicine for treating non-multidrug-resistant carcinoma.
Present invention also offers chlorogenic acid in the medicine for preparing the toxic side effect for reducing dihydrofolate reductase inhibitor
Purposes.
Wherein, the medicine is to weaken dihydrofolate reductase inhibitor to cause the medicine of side effect that body weight lightens.
Wherein, the medicine is the medicine for the side effect that hematopoiesis function caused by repairing dihydrofolate reductase inhibitor damages
Thing.
Chlorogenic acid of the present invention is used in combination with DHFR inhibitor such as pemetrexeds, can play the effect of Synergistic, and
Hematopoiesis function damage and body weight lighten caused by alleviating DHFR inhibitor, effectively reduce the toxic side effect of DHFR inhibitor, will be green
Ortho acid and excellent, small toxicity the effect of DHFR inhibitor combination medicines, potential applicability in clinical practice are good.
The present invention is described in further details below by embodiment, but is not the limit to the present invention
System, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, not departing from, the present invention is above-mentioned
Under the premise of basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Embodiment
The in vitro test of the drug combination of embodiment 1
1st, experiment material
Reagent：Chlorogenic acid, pemetrexed, ammonia petrin.
Cell line：Lung adenocarcinoma A549 cell line, breast cancer cell line MCF-7, hepatoma cell line BEL-7402 strain.
2nd, test method
2.1 cell recovery
Freeze-stored cell strain is taken out from -152 DEG C of ultralow temperature refrigerator-freezers, 40 DEG C of water-baths are thawed, and are centrifuged and are used basal medium
Nutrient solution suspension cell is used after washing, is transferred in Tissue Culture Flask, is statically placed in 37 DEG C of cultures in 5%CO2 cell culture incubators, often
Change liquid within 2~3 days.Cell growth is paved with after cell bottle the cell number needed for 0.25% Trypsin Induced Secondary Culture to experiment
Amount.
2.2 dosing cultures
Take the logarithm growth period cell, 0.25% Trypsin Induced, centrifugation (1000rpm 5min are washed with basal medium
Twice), with nutrient solution suspension cell and cell concentration is adjusted as 6 × 104/ ml, inoculating cell is in 96 orifice plates, per the μ l of hole 50
(cell quantity 3 × 103/ hole), each each concentration of test group is inoculated with 3 multiple holes, by packet dosing is carried out after cell attachment, stands
Culture 48 hours.
2.2.1 half-inhibition concentration
Chlorogenic acid, pemetrexed, ammonia petrin are taken, after being dissolved in water, is diluted with culture medium, is added in vaccinated each multiple holes
50 μ l pharmaceutical culture medium dilutions, the drug concentration being made into such as table 1, each multiple holes of control group add 50 μ l culture medium dilutions.
The drug concentration of table 1
2.2.2 drug combination
Chlorogenic acid, pemetrexed, ammonia petrin are taken, after being dissolved in water, chlorogenic acid+pemetrexed (64 μ are configured to culture medium
G/ml+2 μ g/ml) solution, chlorogenic acid+ammonia petrin (64 μ g/ml+10 μ g/ml) solution, add 50 μ l in vaccinated each multiple holes
Drug solution uses the drug concentration of table 2.
The drug combination drug concentration of table 2
2.3 measure
10 μ l WST are added in above-mentioned each test group hole-1Solution, put 37 DEG C of cell culture incubators and continue after being incubated 4 hours,
The absorption value at different pharmaceutical group and control group 440nm wavelength is determined on μ-Quant microwell plate analyzers.
2.4 data processing
(1) GI (growth inhibition ratio)=(1-OD is calculatedMedicine group/ODControl group) × 100%
(2) inhibition rate of tumor cell is mapped with same medicine various concentrations, can obtain dose-effect curve.
(3) according to drug concentration and corresponding inhibition rate of tumor cell, using Logit methods IC50Software for calculation calculates half
Inhibition concentration (IC50Value).
(4) drug combination calculates whether there is synergy with formula.Wherein E (a+b) is the inhibiting rate that two medicines share, that is, is surveyed
Merge effect, Ea and the inhibiting rate that Eb was two prescription used times, for denominator (Ea+Eb-Ea × Eb) it is expected to merge effect, Q is both
Ratio.For Q values at 0.85~1.15, two medicines merge effect to be added (+), and Q values are collaboration (++), Q values ＞ at 1.15~20
20 be obvious collaboration (+++), and Q values are antagonism at 0.05~0.85, and Q values ＜ 0.05 is obvious antagonism.
3rd, experimental result
3.1 half-inhibition concentration
Result of the test such as table 3-1,3-2,3-3：
Table 3-1 chlorogenic acids are to each tumor cell line half-inhibition concentration (μ g/ml)
Table 3-2 pemetrexeds are to each tumor cell line half-inhibition concentration (μ g/ml)
Table 3-3 ammonia petrin is to each tumor cell line half-inhibition concentration (μ g/ml)
By table 3-1,3-2,3-3 can be seen that chlorogenic acid, pemetrexed, aminopterin respectively to lung adenocarcinoma A549 cell line,
The half suppression of breast cancer cell line MCF-7, hepatoma cell line BEL-7402 strain and ALL TCHu147 cell lines
Concentration processed.
Inhibiting rate of 3.2 drug combinations to cell line
Result of the test such as table 4：
Inhibiting rate of the drug combination of table 4 to cell line
As can be seen from Table 4：Chlorogenic acid and pemetrexed drug combination (32 μ g/ml+1 μ g/ml) are thin to adenocarcinoma of lung A549
Born of the same parents' strain, breast cancer cell line MCF-7, hepatoma cell line BEL-7402 strain suppression, ALL TCHu147 cell line systems
For the Q values of effect between 1.15~20, two medical instruments have synergy.
Chlorogenic acid and ammonia petrin drug combination (32 μ g/ml+1 μ g/ml), to lung adenocarcinoma A549 cell line, breast cancer MCF-7
Cell line, hepatoma cell line BEL-7402 strain, the Q values of ALL TCHu147 cell line inhibitory action exist
Between 1.15~20, two medical instruments have synergy.
Experimental result illustrates that chlorogenic acid has synergy with dihydrofolate reductase inhibitor, can improve medicine list medicine
The effect of medication.
The antitumor zoopery of the drug combination of embodiment 2
1st, experiment material
Reagent：Chlorogenic acid, pemetrexed, ammonia petrin, methopterin
Animal：BALB/C-nu mouse (SPF levels, body weight：16-21g, female).
Cell line：The strain of Lewis murine lung cancer cells, the strain of H22 murine hepatocarcinoma cells, EMT-6 mouse mastopathy cell strains
2nd, test method
2.1 method
Take the logarithm the cell in growth period, adding physiological saline after Trypsin Induced to de- wall is made cell suspension, will
The cell suspension prepared is by 0.2ml-1(containing about cell number 1 × 106It is individual), it is inoculated under the left front armpit of mouse, and press body
The random packet of weight, respectively chlorogenic acid group, pemetrexed group, ammonia petrin group, methopterin, chlorogenic acid+pemetrexed joint are used
Medicine group, chlorogenic acid+ammonia petrin, chlorogenic acid+methopterin drug combination group, negative group, every group 6, the second day after inoculation
Intraperitoneal injection, administration capacity are 0.2ml10g-1.Chlorogenic acid group once a day, successive administration 15 times；Pemetrexed, ammonia
Petrin and methopterin group interval are administered once for 5 days, are administered twice altogether；Drug combination group, a chlorogenic acid is given daily, is continuously given
Medicine 15 times, beautiful Qu Sai, ammonia petrin and methopterin are respectively separated 5 days and are administered once, be administered twice altogether, and feminine gender organizes abdomen once a day
Chamber injecting normal saline, successive administration 15 times.Claim mice weights before administration in every 5 days and observe mouse behavior state, treat negative group
Knurl volume is about 0.5cm3When stop experiment, eyeball excise takes hematometry WBC, HBC and HGB content, takes off cervical vertebra and puts to death mouse simultaneously
Weigh, strip tumour and weigh, calculate tumour inhibiting rate.
2.2 data processing
(1) tumour inhibiting rate %=[1- (the average knurl weight of the administration group/average knurl weight of feminine gender group)] × 100%；
(2) two medicines merge Q=E (a+b)/(Ea+Eb-Ea × Eb), and wherein E (a+b) is the inhibiting rate that two medicines share, i.e., real
Survey and merge effect, Ea and the inhibiting rate that Eb was two prescription used times, denominator (Ea+Eb-Ea × Eb) merge effect, Q two for expectation
Person's ratio.For Q values at 0.85~1.15, two medicines merge effect to be added (+), and Q values are collaboration (++), Q values at 1.15~20
＞ 20 is obvious collaboration (+++), and Q values are antagonism at 0.05~0.85, and Q values ＜ 0.05 is obvious antagonism.
3rd, experimental result
The influence of 3.1 drug combination mice-transplanted tumor tumour inhibiting rates
It the results are shown in Table 5-1,5-2,5-3
Influence of the table 5-1 drug combinations to Lewis lung cancer in mice transplantable tumor tumour inhibiting rates
Note：Amount of survival is respectively 4,5 when pemetrexed, ammonia petrin and methopterin test group murine terminator are tested
With 5, another joint
Amount of survival is 4 when the test group murine terminator of medication 3 is tested.
Influence of the table 5-2 drug combinations to H22 liver cancer mouse transplantable tumor tumour inhibiting rates
Note：Amount of survival is respectively 4,4 when pemetrexed, ammonia petrin and methopterin test group murine terminator are tested
With 5, amount of survival is 5 during the experiment of the another test group murine terminator of drug combination 3.
Influence of the table 5-3 drug combinations to EMT-6 breast cancer mouse transplantable tumor tumour inhibiting rates
Note：Amount of survival is respectively 4,3 when pemetrexed, ammonia petrin and methopterin test group murine terminator are tested
With 5, amount of survival is 4 during the experiment of the another test group murine terminator of drug combination 3.
Chlorogenic acid and pemetrexed drug combination (20mg/kg+50mg/kg), right it can be seen from table 5-1,5-2,5-3
The Q values of Lewis lung cancer in mice transplantable tumor tumour inhibiting rates are 1.37, and between 1.15~20, two medical instruments have synergy；To H22 liver cancer
The Q values of mice-transplanted tumor tumour inhibiting rate are 1.37, and between 1.15~20, two medical instruments have synergy；EMT-6 breast cancer mouses are moved
The Q values for planting knurl tumour inhibiting rate are 1.33, and between 1.15~20, two medical instruments have synergy.
Chlorogenic acid and ammonia petrin drug combination (20mg/kg+40mg/kg), to Lewis lung cancer in mice transplantable tumor tumour inhibiting rates
Q values are 1.41, and between 1.15~20, two medical instruments have synergy；Q values to H22 liver cancer mouse transplantable tumor tumour inhibiting rates are 1.43,
Between 1.15~20, two medical instruments have synergy；Q values to EMT-6 breast cancer mouse transplantable tumor tumour inhibiting rates are 1.35,1.15
Between~20, two medical instruments have synergy.
Chlorogenic acid and methopterin drug combination (20mg/kg+40mg/kg), to Lewis lung cancer in mice transplantable tumor, H22 livers
Between the Q values equal 0.05~0.85 of cancer mice-transplanted tumor and EMT-6 breast cancer mouse transplantable tumor tumour inhibiting rates, two medical instruments have antagonism work
With.
Chlorogenic acid and pemetrexed drug combination (20mg/kg+50mg/kg) and chlorogenic acid and ammonia petrin drug combination
(20mg/kg+40mg/kg) can improve the survival rate of mouse.Chlorogenic acid and methopterin drug combination (20mg/kg+40mg/
Kg) to the survival rate DeGrain of raising mouse.
The influence of 3.2 drug combination mouse blood routines
It the results are shown in Table 6-1,6-2,6-3
Influence of the table 6-1 drug combinations to Lewis lung cancer in mice blood routines
The * p ＜ 0.05 compared with negative group, * * p ＜ 0.01；The Δ p ＜ compared with positive group (pemetrexed, ammonia petrin)
0.05, Δ Δ p ＜ 0.01
Influence of the table 6-2 drug combinations to H22 liver cancer mouse blood routines
The * p ＜ 0.05 compared with negative group, * * p ＜ 0.01；The Δ p ＜ compared with positive group (pemetrexed, ammonia petrin)
0.05, Δ Δ p ＜ 0.01
Influence of the table 6-3 drug combinations to EMT-6 breast cancer mouse blood routines
The * p ＜ 0.05 compared with negative group, * * p ＜ 0.01；The Δ p ＜ compared with positive group (pemetrexed, ammonia petrin)
0.05, Δ Δ p ＜ 0.01 can be seen that by table 6-1,6-2,6-3：Chlorogenic acid (20mg/kg), can significantly improve Lewis lung cancer
Mouse, H22 liver cancer mouses and EMT-6 breast cancer mouses use WBC, RBC, HGB in pemetrexed (50mg/kg) afterwards blood routine
Reduce phenomenon；In addition, ammonia petrin (40mg/kg) is used to Lewis lung cancer in mice, H22 liver cancer mouses and EMT-6 breast cancer mouses
WBC, RBC, HGB reduce the effect for equally having and being significantly improved in blood routine afterwards；Illustrate that chlorogenic acid is obstructed to folic acid metabolism to lead
The hematopoiesis function damage of cause has repair.
Influence of 3.3 drug combinations to mouse weight
It the results are shown in Table 7-1,7-2,7-3
Influence of the table 7-1 drug combinations to Lewis lung cancer in mice body weight
The * p ＜ 0.05 compared with negative group, * * p ＜ 0.01；The Δ p ＜ compared with positive group (pemetrexed, ammonia petrin)
0.05, Δ Δ p ＜ 0.01
Influence of the table 7-2 drug combinations to H22 liver cancer mouse body weight
The * p ＜ 0.05 compared with negative group, * * p ＜ 0.01；The Δ p ＜ compared with positive group (pemetrexed, ammonia petrin)
0.05, Δ Δ p ＜ 0.01
Influence of the table 7-3 drug combinations to EMT-6 breast cancer mouse body weight
The * p ＜ 0.05 compared with negative group, * * p ＜ 0.01；The Δ p ＜ compared with positive group (pemetrexed, ammonia petrin)
0.05, Δ Δ p ＜ 0.01
It can be seen that by table 7-1,7-2,7-3：Chlorogenic acid (20mg/kg), can significantly improve Lewis lung cancer in mice, H22
Liver cancer mouse and EMT-6 breast cancer mouses using pemetrexed (50mg/kg) Body weight loss afterwards phenomenon；In addition, to Lewis lungs
Body weight loss equally has significantly afterwards using ammonia petrin (40mg/kg) for cancer mouse, H22 liver cancer mouses and EMT-6 breast cancer mouses
Improved effect.Illustrate that chlorogenic acid can alleviate the drug induced weight loss of dihydrofolate reductase inhibitor, improve small
The quality of life of mouse.
Experimental result illustrates that the DHFR such as chlorogenic acid and pemetrexed inhibitor has synergy, it is possible to increase individually uses
The effect of medicine, and the toxic side effect that hematopoiesis function damages and body weight lightens caused by can alleviating DHFR inhibitor.
To sum up, the work that can play Synergistic is used in combination in the DHFR inhibitor such as chlorogenic acid of the present invention and pemetrexed
With, and hematopoiesis function damage and body weight lighten caused by alleviating DHFR inhibitor, effectively reduce the toxic side effect of DHFR inhibitor,
Chlorogenic acid and excellent, small toxicity the effect of DHFR inhibitor combination medicines, potential applicability in clinical practice is good.
Claims (11)
- A kind of 1. combination medicine with antineoplastic effect, it is characterised in that：It contains identical or different specification unit The chlorogenic acid and dihydrofolate reductase inhibitor that are used to be administered simultaneously or respectively of preparation, and pharmaceutically acceptable load Body.
- 2. combination medicine according to claim 1, it is characterised in that：Dihydrofolate reductase inhibitor is U.S. bent for training Plug, ammonia petrin.
- 3. combination medicine according to claim 1 or 2, it is characterised in that：Chlorogenic acid and dihyrofolate reductase suppress The weight ratio of agent is 1：1—1：5.
- 4. combination medicine according to claim 3, it is characterised in that：When the antineoplastic is pemetrexed, the weight ratio of chlorogenic acid and antineoplastic is 2:5；When the antineoplastic is ammonia petrin, the weight ratio of chlorogenic acid and antineoplastic is 2:4.
- 5. the combination medicine described in Claims 1 to 4 any one is on preparation treatment breast cancer, lung cancer, liver cancer, chorion Skin cancer, chorioadenoma, treatment MPM, acute leukemia medicine in purposes.
- 6. use of the combination medicine in the medicine for preparing non-multidrug-resistant carcinoma described in Claims 1 to 4 any one On the way.
- 7. the purposes of chlorogenic acid and dihydrofolate reductase inhibitor in antitumor combination medicine is prepared.
- 8. purposes according to claim 7, it is characterised in that：The combination medicine is the non-multidrug-resistant carcinoma for the treatment of Medicine.
- 9. purposes of the chlorogenic acid in the medicine for preparing the toxic side effect for reducing dihydrofolate reductase inhibitor.
- 10. purposes according to claim 9, it is characterised in that：The medicine is to weaken dihydrofolate reductase inhibitor Cause the medicine for the side effect that body weight lightens.
- 11. purposes according to claim 9, it is characterised in that：The medicine is to repair dihydrofolate reductase inhibitor The medicine of the side effect of caused hematopoiesis function damage.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758277A (en) * | 2015-03-06 | 2015-07-08 | 刘晓梅 | Uses of chlorogenic acid in preparation of drugs treating multidrug resistance of cancer |
| CN106999596A (en) * | 2014-11-25 | 2017-08-01 | 阿波卡-阿格里科拉共同股份公司 | Cynara scolymus titration extract and application thereof |
-
2017
- 2017-08-21 CN CN201710719094.1A patent/CN107496399B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106999596A (en) * | 2014-11-25 | 2017-08-01 | 阿波卡-阿格里科拉共同股份公司 | Cynara scolymus titration extract and application thereof |
| CN104758277A (en) * | 2015-03-06 | 2015-07-08 | 刘晓梅 | Uses of chlorogenic acid in preparation of drugs treating multidrug resistance of cancer |
Non-Patent Citations (1)
| Title |
|---|
| KAZUMI YAGASAKI ET AL.: "Inhibitory effects of chlorogenic acid and its related compounds on the invasion of hepatoma cells in culture", 《CYTOTECHNOLOGY》 * |
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