CN110974831A - Drug combination for improving fluorouracil sensitivity and application of drug combination - Google Patents
Drug combination for improving fluorouracil sensitivity and application of drug combination Download PDFInfo
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- CN110974831A CN110974831A CN201911000800.2A CN201911000800A CN110974831A CN 110974831 A CN110974831 A CN 110974831A CN 201911000800 A CN201911000800 A CN 201911000800A CN 110974831 A CN110974831 A CN 110974831A
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- fluorouracil
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- hydroxychloroquine
- linolenic acid
- acid ester
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- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229960002949 fluorouracil Drugs 0.000 title claims abstract description 45
- 230000035945 sensitivity Effects 0.000 title claims abstract description 18
- 239000000890 drug combination Substances 0.000 title claims description 6
- 229960004171 hydroxychloroquine Drugs 0.000 claims abstract description 28
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims abstract description 24
- 229960004488 linolenic acid Drugs 0.000 claims abstract description 24
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 16
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 12
- 238000002474 experimental method Methods 0.000 claims abstract description 4
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims 4
- OYHQOLUKZRVURQ-HZJYTTRNSA-M 9-cis,12-cis-Octadecadienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O OYHQOLUKZRVURQ-HZJYTTRNSA-M 0.000 claims 2
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 229940049918 linoleate Drugs 0.000 claims 2
- -1 hydroxychloroquine linolenic acid ester Chemical class 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 10
- 238000002512 chemotherapy Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 210000004027 cell Anatomy 0.000 description 17
- 108010040476 FITC-annexin A5 Proteins 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 230000001640 apoptogenic effect Effects 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
- 235000008207 calcium folinate Nutrition 0.000 description 1
- 239000011687 calcium folinate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
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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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a pharmaceutical composition for improving fluorouracil sensitivity, which is characterized by comprising fluorouracil and hydroxychloroquine linolenic acid ester, wherein the concentration of the fluorouracil is 1.25-10 mu mol/L, the concentration of the hydroxychloroquine linolenic acid ester is 10-160 mu mol/L, fluorouracil monocase group, hydroxychloroquine linolenic acid ester monocase group and fluorouracil combined hydroxychloroquine linolenic acid ester group are arranged, each group of experiments are independently repeated for 3 times, tumor cells are added, and then the tumor cells are respectively cultured on a micro-culture plate for 24 hours, 48 hours and 72 hours, and the data of the tumor cells are observed and recorded. The invention also discloses application of the pharmaceutical composition for improving the sensitivity of fluorouracil in colorectal cancer. Has the advantages that the combined use of the fluorouracil and the hydroxychloroquine linolenic acid ester can improve the sensitivity of fluorouracil chemotherapy and the curative effect, not only can improve the medication compliance of colorectal cancer patients, but also can relieve the pain of the patients.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition for improving fluorouracil sensitivity and application of the pharmaceutical composition.
Background
Colorectal cancer (CRC) is one of the leading causes of cancer death, while the second most common cancer in women and the third most common cancer in men. And in recent years, the incidence of colorectal cancer is increasing in China, 19.1 ten thousand patients die in China only in 2015, and the death rate is ranked fifth in all cancers at present. Clinical treatment the treatment means for CRC is mainly surgical resection of the primary tumor; and when the disease progresses or metastasizes, treatment with a chemotherapeutic regimen. Chemotherapy has been the standard treatment for clinical CRC. According to the National Comprehensive Cancer Network (NCCN) guidelines (2018 edition), first-line treatment of advanced colorectal cancer is based on 5-fluorouracil (5-fluorouracil, 5-Fu) based chemotherapy in combination with other cytotoxic drugs such as calcium folinate, oxaliplatin, etc. Although 5-Fu is the primary drug for CRC first-line therapy and is recommended for combination therapy, it is still limited by the low sensitivity and susceptibility to chemotherapy.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a pharmaceutical composition for improving fluorouracil sensitivity and application of the pharmaceutical composition, and the pharmaceutical composition has the advantages that fluorouracil and hydroxychloroquine linolenic acid ester are used in a combined manner, the fluorouracil sensitivity can be improved, the treatment effect can be improved, the medication compliance of colorectal cancer patients can be improved, and the pain of the patients can be relieved.
In order to achieve the purpose, the invention adopts the technical scheme that: a pharmaceutical composition for improving fluorouracil sensitivity comprises fluorouracil and hydroxychloroquine linolenic acid ester, wherein the concentration of the fluorouracil is 1.25-10 mu mol/L, the concentration of the hydroxychloroquine linolenic acid ester is 10-160 mu mol/L, a fluorouracil single medicine group, a hydroxychloroquine linolenic acid ester single medicine group and a fluorouracil combined hydroxychloroquine linolenic acid ester group are arranged, each group of experiment is independently repeated for 3 times, tumor cells are added, and then the drugs are cultured on a micro-culture plate for 24 hours, 48 hours and 72 hours respectively, and the data of the drugs are observed and recorded.
Preferably, the ratio of the fluorouracil to the hydroxychloroquine linolenic acid ester in the fluorouracil and hydroxychloroquine linolenic acid ester combined group is 1: 8.
Application of a pharmaceutical composition for improving fluorouracil sensitivity in rectal cancer.
The invention has the beneficial effects that:
the result shows that when the ratio of the hydroxychloroquine linolenic acid ester to the fluorouracil is 1:8, the chemotherapy sensitivity of the fluorouracil acting on human colorectal cancer cells HCT116 can be improved, and the treatment effect is improved. The research on the colon cancer resisting effect and mechanism of the combination of hydroxychloroquine linolenic acid ester and fluorouracil as chemotherapeutic drugs is carried out for the first time, and a new choice is provided for the treatment of colon cancer.
Drawings
FIG. 1 shows the inhibition of 5-Fu, AHQ and 5-Fu in combination with AHQ on HCT116 cells for 48h, 72 h;
in fig. 1, c1 and e1 are dose-response curves (n is 3, compared with 5-Fu and AHQ acting alone, P is less than 0.05);
the joint index CI values of d2, f25-Fu and AHQ are below the dotted line and represent synergy;
FIG. 2 is a schematic representation of the apoptosis cycle of 5-Fu, AHQ alone and in combination for 48h on human colon cancer cell HCT 116; wherein (a) representative micrographs of the percentage cell cycle distributions of each group were analyzed by flow cytometry; (b) a flow cytometry determined apoptosis profile; q1(Annexin V-FITC) -/PI +: necrotic cells, Q2(AnnexinV-FITC) +/PI +: late apoptotic cells, Q3(Annexin V-FITC) -/PI-: viable cells, Q4(Annexin V-FITC) +/PI-: early apoptotic cells.
FIG. 3 is a graph of the effect of 5-Fu, AHQ alone and in combination for 72h on the apoptotic cycle of human colon cancer cell HCT 116; wherein (a) representative micrographs of the percentage cell cycle distributions of each group were analyzed by flow cytometry; (b) apoptosis profile as determined by flow cytometry; q1(Annexin V-FITC) -/PI +: necrotic cells, Q2(Annexin V-FITC) +/PI +: late apoptotic cells, Q3(Annexin V-FITC) -/PI-: viable cells, Q4(Annexin V-FITC) +/PI-: early apoptotic cells.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to the accompanying drawings.
Example 1:
a drug combination for improving fluorouracil sensitivity is characterized by comprising fluorouracil and hydroxychloroquine linolenic acid ester, wherein the concentration of the fluorouracil is 1.25-10 mu mol/L, the concentration of the hydroxychloroquine linolenic acid ester is 10-160 mu mol/L, a fluorouracil monad group, a hydroxychloroquine linolenic acid ester monad group and a fluorouracil combined hydroxychloroquine linolenic acid ester group are arranged, the ratio of the fluorouracil to the hydroxychloroquine linolenic acid ester in the fluorouracil combined hydroxychloroquine linolenic acid ester group is 1:8, experiments in each group are independently repeated for 3 times, after tumor cells are added, the drugs are respectively cultured on a micro-culture plate for 24 hours, 48 hours and 72 hours, and data of the drugs are observed and recorded.
Example 2:
application of a pharmaceutical composition for improving fluorouracil sensitivity in rectal cancer.
Example 3:
in vitro validation:
the concentration of the 1.5-Fu single medicine group is 1.25-10 mu mol/L; the concentration of the AHQ single medicine group is 10-160 mu mol/L; when the proportion of the 5-Fu and AHQ combined group is 1:8, the action time is 48 and 72 hours, the chemotherapy sensitivity of the 5-Fu on HCT116 cells can be obviously improved, and the anti-tumor activity is improved. See tables 1-3 and FIG. 1.
TABLE 15 inhibition of HCT116 cells by AHQ combined with AHQ (%)
Wherein the calculation formula of each group of average values is (
n-3) administration group compared to control group: p <0.05, P < 0.01; the combination group compared to the 5-Fu group: # P <0.05, # P < 0.01; the combination group compared to the AHQ group: p is less than 0.05 and P is less than 0.01; AHQ group compared to 5-Fu group:&P＜0.05、&&P＜0.01。
TABLE 25 inhibition of 48h of HCT116 cells by AHQ in combination with AHQ (%)
Wherein the average value of each group is calculated by the formula (
n-3) administration group compared to control group: p <0.05, P < 0.01; the combination group compared to the 5-Fu group: # P <0.05, # P < 0.01; the combination group compared to the AHQ group: p is less than 0.05 and P is less than 0.01; AHQ group compared to 5-Fu group:&P＜0.05、&&P＜0.01。
TABLE 35 inhibition of HCT116 cells by AHQ combined with AHQ (%)
Wherein the average value of each group is calculated by the formula (A)
n-3) administration group compared to control group: p <0.05, P < 0.01; the combination group compared to the 5-Fu group: # P <0.05, # P < 0.01; the combination group compared to the AHQ group: p is less than 0.05 and P is less than 0.01; AHQ group compared to 5-Fu group:&P＜0.05、&&P＜0.01。
2. when the drug action ratio is 1:8, when the 5-Fu and the AHQ are combined, the early apoptosis and the late apoptosis of the 5-Fu and AHQ combined group have statistical difference compared with the control group (P is less than 0.01). Suggesting that the mechanism of the combined use is promoting the apoptosis of HCT116 cells.
As shown in FIG. 2, the average value of each group is calculated by the formula
n-3, dosing group compared to control group: p <0.05, P < 0.01; the combination group compared to the 5-Fu group: # P <0.05, # P < 0.01; the combination group compared to the AHQ group: p is less than 0.05 and P is less than 0.01; AHQ group compared to 5-Fu group:&P＜ 0.05、&&P＜0.01。
as shown in FIG. 3, the average value of each group is calculated by the formula
n-3, dosing group compared to control group: p <0.05, P < 0.01; the combination group compared to the 5-Fu group: # P <0.05, # P < 0.01; combination group compared to AHQ group: p is less than 0.05 and P is less than 0.01; AHQ group compared to 5-Fu group:&P＜0.05、&&P ＜0.01)。
in the invention, 5-Fu is short for fluorouracil, AHQ is short for hydroxychloroquine linolenic acid ester, wherein the hydroxychloroquine linolenic acid ester is a medicine disclosed in the invention patent 201310744461.5.
The above-mentioned embodiments only express the specific embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112691107A (en) * | 2021-02-03 | 2021-04-23 | 北京斯利安药业有限公司 | Pharmaceutical composition and application thereof |
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Application publication date: 20200410 |