CN1679539A - Synergic medicinal composition for preventing from tumor - Google Patents

Synergic medicinal composition for preventing from tumor Download PDF

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CN1679539A
CN1679539A CNA2005100234679A CN200510023467A CN1679539A CN 1679539 A CN1679539 A CN 1679539A CN A2005100234679 A CNA2005100234679 A CN A2005100234679A CN 200510023467 A CN200510023467 A CN 200510023467A CN 1679539 A CN1679539 A CN 1679539A
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baicaligenin
molar concentration
baicalin
pharmaceutical composition
cisplatin
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吴一心
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Priority to CN2006100065567A priority patent/CN1879615B/en
Priority to PCT/CN2006/000091 priority patent/WO2006076863A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/28—Compounds containing heavy metals
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

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Abstract

An antineoplastic symergistic medicinal composition including a compound and its chemicotherapeutic medicine, such as cisplatin and/or 5-fluracil, and its preparing process are disclosed.

Description

Anti-tumor synergistic pharmaceutical composition
Technical field
The present invention relates to a kind of synergistic antineoplastic pharmaceutical compositions that has, be specifically related to a kind of synergistic antineoplastic pharmaceutical compositions of having of flavone compound and tumor chemotherapeutic drug that contains.The invention still further relates to the preparation method and the pharmaceutical applications of said composition.
Background technology
Chemotherapy is the abbreviation of " chemotherapy ".The notion of chemotherapy generally is understood that " chemotherapy of tumor " at present, promptly uses the antitumor chemicals, adopts the method for some measure and scheme treatment tumor.Yet common chemotherapeutics such as vincristine, cisplatin, methotrexate, cyclophosphamide, 5-fluorouracil (5-Fu) etc. can produce toxic and side effects such as injection site pain, venous thrombosis, bone marrow depression, gastrointestinal reaction, peripheral nervous pathological changes.
For the toxic and side effects that reduces chemotherapeutics, improve curative effect, reduce tumor recurrence and avoid drug-fast generation, selects different chemotherapy drugs in combination uses, become one of important means of chemotherapy of tumors.For example, clinically cisplatin and 5-Fu, bleomycin or epipodophyllotoxin etc. are united the use treatment esophageal carcinoma.
The curative effect sum of the curative effect that " synergism " (Synergistic Effect) produced when being meant two kinds of medication combined use when two prescriptions solely use during greater than same dose.According to middle effect principle (Joseph R.Bertino, Ting-Chao Chou, Chemotherapy:Synergism and Antagonism, Encyclopedia ofCancer, 1996, Academic Press, Inc.), two medicines unite action effect when using can pass through " association index " (Combination Index, CI) judge:
CI = D 1 ( Dx ) 1 + D 2 ( Dx ) 2 + α × D 1 × D 2 ( Dx ) 1 × ( Dx ) 2
Wherein, when D1, D2 are respectively medicine 1 and medicine 2 independent uses, the drug level when cell proliferation inhibition rate reaches x%; (Dx) 1, the concentration of (Dx) 2 mixture Chinese medicine 1 and medicine 2 when reaching the same cell proliferation inhibition rate.
To two kinds of separate medicine α=0; And medicine α=1 independently not mutually.
When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Baikal skullcap root (Scutellaria baicalensis Georgi) head is stated from " Sheng Nong's herbal classic) ", has another name called Huang Wen, no a kind of reed mentioned in ancient books etc.Its pharmacological effect bitter in the mouth, cold in nature, function let out excess-fire, it is damp and hot to remove, and has effects such as antibacterial, heat extraction, detoxifcation, calmness, blood pressure lowering, function of gallbladder promoting.
Baicalin and baicaligenin are main flavone compounds contained in the scutellariae,radix, and both have identical flavone precursor structure:
Baicaligenin is one of main active of Radix Scutellariae, molecular formula C 15H 10O 5, molecular weight 270.25 can be got by the baicalin hydrolysis.Its chemical constitution is: 5,6,7 three hydrogen bases (H) (OH) are replaced by hydroxyl on the flavone precursor structure.
The chemical constitution of baicalin is: 5,6 two hydrogen bases on the flavone precursor structure (H) by hydroxyl (OH) replace, 7 go up hydroxyl (OH) with the glucuronic acid condensation, i.e. baicaligenin-7-O-glucuronic acid, molecular formula C 12H 18O 11, molecular weight 446.37.
Bibliographical information is arranged in recent years, and baicalin and baicaligenin are to the growth of the breast cancer cell of In vitro culture inhibited (So F.V., et al.Cancer Lett., 112:127-133,1997).(CN 03109933.5 also to have patent documentation report baicalin and baicaligenin that esophageal carcinoma and stomach cancer cell are had clearly lethal effect; CN 03109942.4).
Do not see that so far relevant baicaligenin and/or baicalin have synergistic report to tumor chemotherapeutic drug.
Summary of the invention
Appearance part of the present invention is based on such discovery: baicaligenin and/or baicalin have synergism to cisplatin or 5-fluorouracil, can obviously improve the killing activity of the latter to tumor cell; The pharmaceutical composition that contains baicaligenin and/or baicalin and cisplatin and/or 5-fluorouracil has enhanced antitumor action, and more effective than the pharmaceutical composition that only contains single baicaligenin, baicalin, cisplatin or 5-fluorouracil.
One aspect of the present invention relates to a kind of antineoplastic and has synergistic pharmaceutical composition, and said composition comprises the chemical compound of cisplatin and following formula (I), and the molar concentration rate of described cisplatin and formula (I) chemical compound is 1: 2.5 to 1: 10:
Figure A20051002346700062
Wherein, R 1Represent hydrogen or glucal acidic group, R 2, R 3Represent hydrogen separately.
Wherein, described tumor is selected from hepatocarcinoma, colorectal cancer, pulmonary carcinoma, gastric cancer, esophageal carcinoma, breast carcinoma, leukemia, carcinoma of prostate or bladder cancer.Preferred tumor is selected from hepatocarcinoma, colorectal cancer, pulmonary carcinoma, gastric cancer or esophageal carcinoma.
In a preference of the present invention, work as R 1, R 2, R 3When representing hydrogen separately, described chemical compound is a baicaligenin:
When described tumor was hepatocarcinoma, the molar concentration rate of described cisplatin and baicaligenin was 1: 5 to 1: 10;
When described tumor was colorectal cancer, the molar concentration rate of described cisplatin and baicaligenin was 1: 2.5 to 1: 10;
When described tumor was pulmonary carcinoma, the molar concentration rate of described cisplatin and baicaligenin was 1: 2.5 to 1: 10;
When described tumor was gastric cancer, the molar concentration rate of described cisplatin and baicaligenin was 1: 1 to 1: 5;
When described tumor was esophageal carcinoma, the molar concentration rate of described cisplatin and baicaligenin was 1: 5 to 1: 10.
In another preference of the present invention, work as R 1Represent the glucal acidic group, R 2, R 3When representing hydrogen separately, described chemical compound is a baicalin:
When described tumor was hepatocarcinoma, the molar concentration rate of described cisplatin and baicalin was 1: 7.5 to 1: 10;
When described tumor was colorectal cancer, the molar concentration rate of described cisplatin and baicalin was 1: 5 to 1: 10;
When described tumor was pulmonary carcinoma, the molar concentration rate of described cisplatin and baicalin was 1: 7.5 to 1: 10;
When described tumor was gastric cancer, the molar concentration rate of described cisplatin and baicalin was 1: 2.5 to 1: 10;
When described tumor was esophageal carcinoma, the molar concentration rate of described cisplatin and baicalin was 1: 5 to 1: 10.
Another aspect of the present invention relates to a kind of antineoplastic and has synergistic pharmaceutical composition, and said composition comprises the chemical compound of 5-fluorouracil and following formula (I), and the molar concentration rate of described 5-fluorouracil and formula (I) chemical compound is 1: 0.5 to 1: 4:
Figure A20051002346700071
Wherein, R 1Represent hydrogen or glucal acidic group, R 2, R 3Represent hydrogen separately.
Wherein, described tumor is selected from hepatocarcinoma, colorectal cancer, pulmonary carcinoma, gastric cancer, esophageal carcinoma, breast carcinoma, leukemia, carcinoma of prostate or bladder cancer.Preferred tumor is selected from hepatocarcinoma, colorectal cancer, gastric cancer, esophageal carcinoma or breast carcinoma.
In a preference of the present invention, work as R 1, R 2, R 3When representing hydrogen separately, described chemical compound is a baicaligenin:
When described tumor was hepatocarcinoma, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 0.5 to 1: 1;
When described tumor was colorectal cancer, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 0.5 to 1: 2;
When described tumor was gastric cancer, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 1 to 1: 2;
When described tumor was esophageal carcinoma, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 1 to 1: 2;
When described tumor was breast carcinoma, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 1 to 1: 2.
In another preference of the present invention, work as R 1Represent the glucal acidic group, R 2, R 3When representing hydrogen separately, described chemical compound is a baicalin:
When described tumor was hepatocarcinoma, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 2 to 1: 4;
When described tumor was colorectal cancer, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 1 to 1: 2;
When described tumor was gastric cancer, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 1 to 1: 2;
When described tumor was esophageal carcinoma, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 1 to 1: 2;
When described tumor was breast carcinoma, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 1 to 1: 2.
The invention still further relates to the method for preparing aforementioned pharmaceutical compositions, this method comprises that the chemical compound with following formula (I) mixes with the tumor chemotherapeutic drug that at least one is selected from the group of being made up of cisplatin and 5-fluorouracil:
Figure A20051002346700081
Wherein, R 1Represent hydrogen or glucal acidic group, R 2, R 3Represent hydrogen separately.
The invention still further relates to the purposes of aforementioned pharmaceutical compositions in the preparation antitumor drug.
Can be used for tumor chemotherapeutic drug of the present invention comprises, but be not limited to: cisplatin (cisplatin), mitomycin (mitomycin C), Irinotecan (Irinotecan), Docetaxel (docetaxel), paclitaxel (paclitaxel), table podophyllin (podophyllotoxin), vincristine (vincristine, VCR), plicamycin (plicamycin), daunorubicin (daunorubicin, DNR), D actinomycin D (dactinomycin, DACT), amycin (doxorubicin, adriamycin, ADM), 5-fluorouracil (5-Fluorouracil), hormone, hormone antagonist and cytokine (as interleukin-2 and β transforming growth factor).
The specific embodiment of the present invention will set forth with the lower part.Other characteristics of the present invention, purpose and advantage will be shown by following elaboration.
The specific embodiment:
The inventor discovers, when the flavone compound of general formula of the present invention (I) and tumor chemotherapeutic drug administration simultaneously, can obviously improve the anti-tumor activity of chemotherapeutics, has synergism.Thereby can reduce the consumption of chemotherapeutics, reduce its toxic and side effects.Therefore, the flavone compound of general formula of the present invention (I) can be used for the preparation tumor chemotherapeutic drug is had synergistic medicine.
Wherein some is that nature exists and can separates from plant and obtain the flavone compound of general formula of the present invention (I).For example, baicaligenin and baicalin can extract from Radix Scutellariae (Scutellaria baicalensis Georgi) root and obtain.Chemical compound of the present invention also can obtain or common synthetic technology by this area makes by commercial sources.Be used to separate or the chemicals of synthetic flavone compound of the present invention comprises solvent, reagent, catalyst, blocking group reagent, removes blocking group reagent.Described separation can also comprise adding or remove suitable blocking group finally to obtain the step of required flavone compound with synthetic.The synthetic chemistry that is used to prepare flavone compound of the present invention transforms and the method for radical protection (going to protect) is known to those skilled in the art, can be referring to R.Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T.W.Green and P.G.M.Wuts, ProtectiveGroups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999), L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wiley and Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and follow-up works thereof.
Can be used for chemotherapeutics of the present invention sets forth in " (summary of the invention) " part.Also can be referring to Isselbacher et al., Harrison ' s Principles of Internal Medicine 13th, McGraw-Hill, 1994..These chemotherapeutics all can obtain or make via the known technology of this area by commercial sources.Select the standard of suitable chemotherapeutics to be based on, for example, tumor type, tumor marker and patient's age and general health situation.
Flavone compound of the present invention can with tumor chemotherapeutic drug administration simultaneously or non-while administration; Can pass through intestinal or parenteral route administration.The intestinal canal administration preparation comprises pill, granule, capsule, suspension or solution.Non-intestinal drug delivery agent comprises injection, cream, unguentum, patch or spray.That the parenterai administration approach comprises is subcutaneous, in the Intradermal, tremulous pulse, vein, muscle, joint, synovial fluid, breastbone, sheath, intralesional, intracranial injection or instillation.Other route of administration can comprise part, rectum, per nasal, through cheek, vagina, Sublingual, mucosa, trachea or urethra.In addition, flavone compound of the present invention can also suck or implant and accumulate or mode administration such as acupuncture by aerosol.
The intestinal canal administration preparation of flavone compound of the present invention includes but not limited to capsule, tablet, Emulsion, aqueous suspension agent, colloidal solution, solution, microcapsule, pill, lozenge, granule, powder.The pharmaceutically suitable carrier that is usually used in tablet comprises lactose and corn starch.Usually also can add lubricants such as magnesium stearate.The pharmaceutically suitable carrier that is usually used in capsule comprises lactose and dried corn starch.When making oral aqueous suspension agent and/or Emulsion, flavone compound can suspend or be dissolved in the oil phase and with emulsifying agent or suspending agent and combine.If desired, also can add some sweeting agents and/or flavouring agent and/or toner.
Flavone compound medicine of the present invention can be made into aseptic injection, as aseptic water or oil phase suspension.This suspension can use suitable dispersant or wetting agent (as Tween 80) and suspending agent etc. to make by the conventional method of this area.But it can also be at the nontoxic diluent of intestinal external administration or aqueous solution or the suspension in the solvent, as the solution in 1,3 butylene glycol.Relevant available support or solvent comprise mannitol, water, ringer's solution, isotonic sodium chloride etc.In addition, aseptic fixedly oil (bland fixed oil) often is used as the media of solvent or suspending agent, thereby comprises that the multiple soft fixedly oil of synthetic glycerine monoesters or diglyceride all is suitable for.Fatty acid can be used for preparing described injection as octadecenic acid and glyceride ester derivatives thereof (as olive oil or Oleum Ricini, particularly its polyoxyethylene radical derivative) etc.Described oil solution or suspension also can comprise a kind of ethanol dilution agent of long-chain or dispersant or carboxymethyl cellulose or similar other dispersants, and this type of material is usually used in preparing pharmaceutical acceptable emulsion and/or suspending agent.Surfactant that some other preparation is commonly used such as Tweens or Spans and/or other similar emulsifying agents or bioavailability promoter etc. can be used for preparing this preparation too.
Flavone compound of the present invention can be made into suppository and passes through rectally, method is that flavone compound is mixed with the non-irritating excipient that suits, the latter is liquid under rectal temperature for solid at room temperature, thereby this suppository is dissolvable in water in the rectum and discharges active ingredient.This type of excipient includes but not limited to: cupu oil, Cera Flava and polyethylene.The local administration preparation of flavone compound of the present invention (as ointment) can be directly used in the affected part.This type of topical formulations contains active ingredient and pharmaceutically suitable carrier, and the latter includes but not limited to mineral oil, liquid petroleum, white oil, propylene glycol, polyoxyethylene or the polyoxy third desaturation compound, emulsifying is cured or water.In addition, flavone compound of the present invention also can be made into lotion or oil preparation.The carrier that is suitable for includes but not limited to: mineral oil, sorbic alcohol monostearate, polysorbate60, spermaceti ester, hexadecanol, 2-octadecanol, benzyl ethanol or water.Flavone compound of the present invention also can be made into enema etc. and is used for the rectum topical.The topical transdermal patch is also within protection scope of the present invention.But flavone compound of the present invention is per nasal spraying or inhalation also, promptly by the conventional method of this area, uses benzyl ethanol or other antiseptic, absorption enhancer, fluorocarbon and/or other solubilizing agents or dispersant to make saline solution.
Flavone compound of the present invention also can pass through drug delivery implant.Adopt the drug delivery implant mode can reach in the administration subject and continue, regularly discharge the effect of flavone compound of the present invention.In addition, drug delivery implant can also be at local organization and organ site-specific delivery of drugs (Negrin et al., Biomaterials 22 (6): 563,2001) regularly release tech also can be used in the administration of flavone compound of the present invention, as delayed release capsule, slow release method and the preparation technique for packing (as polymer and liposome) etc. based on the polymer technology.
Patch is included within protection scope of the present invention equally.It comprises basic unit's (as polymer, cloth, yarn and binder) and pharmaceutical composition of the present invention.One side of basic unit can be provided with a protective layer to prevent the outflow of active ingredient.Described patch also can contain a binding agent that is used for fixing, and the latter can be a kind of natural or synthetic material, can temporarily adhere on the skin when it contacts with the administration subject's skin.Binding agent can be a waterproof.
" pharmaceutically suitable carrier " can not destroy the pharmaceutical active of flavone compound of the present invention, its effective dose simultaneously, and promptly can playing pharmaceutical carrier, to make the consumption of time spent nontoxic to human body." pharmaceutically suitable carrier " includes but not limited to: ion exchange material, aluminium oxide, aluminium stearate, lecithin, self-emulsifying drug delivery system (SEDDS) is as d-alpha-tocopherol cetomacrogol 1000 succinate, the surfactant that pharmaceutical preparatioies such as tween (Tweens) or other similar polymerisation mediums are used, serum albumin such as human serum albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glycerol ester admixture, water, salt, electrolyte such as sulfate protamine, phosphoric acid hydrogen two is received, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium silicate etc.Polyvidon, cellulosic material, polyvinyl alcohol, sodium carboxymethyl cellulose, polypropylene acid esters, ethylene-polyoxyethylene-block polymer and wool grease, cyclodextrin such as α-, β-and gamma-cyclodextrin or its all can be used for promoting the drug delivery of flavone compound of the present invention through hydroxyalkyl cyclodextrin such as the derivant of chemical modification such as 2-and 3-HP-or other soluble derivatives etc.
The synergistic effective range of flavone compound of the present invention and cisplatin or 5-fluorouracil (molar concentration rate) is verified by suitable in vitro tests (in vitro assay).As two kinds of tumor chemotherapeutic drugs commonly used, the conventional amount used and the route of administration of cisplatin and 5-fluorouracil are as follows: cisplatin 20-150mg/ day, intravenous drip or arteriovenous perfusion; 5-fluorouracil 500-1000mg/ day, intravenous drip or arteriovenous perfusion; 5-fluorouracil 200-300mg/ day, oral.The bibliographical information of clinical antitumor dosage of relevant baicaligenin of Shang Weijian and baicalin and suitable route of administration thereof.
Those of ordinary skill in the art should know how to pass through the ordinary skill in the art, according to molar concentration rate disclosed by the invention, baicaligenin and baicalin, cisplatin or 5-fluorouracil are mixed, prepare the synergistic antineoplastic pharmaceutical compositions that has of the present invention.
For the ease of understanding the present invention, the spy enumerates following examples.Its effect should be understood that it is to annotation of the present invention and absolutely not to any type of restriction of the present invention.
Embodiment 1 baicalin and baicaligenin be the synergism on anti-hepatocarcinoma to cisplatin (CDDP) and 5-fluorouracil (5-FU)
Human hepatoma cell strain HepG2 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 1 * 10 3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add baicaligenin or baicalin (existing goods), and mix in the adding culture fluid with different molar concentration rates with CDDP or 5-Fu.Ultimate density baicaligenin: 0.3-200 μ g/ml, baicalin: 0.6-350 μ g/ml, 5-fluorouracil: 0.01-10 μ g/ml, cisplatin: 0.3-3 μ g/ml.Cultivate and make MTT mensuration after 72 hours.To HepG2 inhibition of proliferation rate, carry out data analysis during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling baicaligenin or baicalin and chemotherapeutics with CalcuSyn statistical software and drug combination exponential quantity (CI) method.
HepG2 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 1:
Table 1
Single-dose thing activity (μ m) Combination medicine activity (μ m) Inhibitory rate of cell growth (%) Drug combination coefficient value (CI)
Yellow unit 2.5 ?0.2
Yellow unit 5 ?17.43±1.2
Yellow unit 10 ?40.5±2
Yellow unit 20 ?59.8±3
Yellow unit 40 ?91±2.5
Yellow glycoside 5 ?0.1
Yellow glycoside 10 ?5±0.2
Yellow glycoside 20 ?25.2±2
Yellow glycoside 40 ?75.2±3
Pt1 ?2±0.5
Pt2 ?30±3
Pt4 ?33±3
Pt8 ?77.5±2.5
5-Fu5 ?8±2
5-Fu10 ?20.2±3.5
5-Fu20 ?48±2.78
5-Fu40 ?87.72±1.7
The yellow unit 5 of Pt1+ ?21.2±2 ?0.78
The yellow unit 10 of Pt2+ ?42.9±3 ?0.98
The yellow unit 20 of Pt4+ ?85±2 ?0.98
The yellow unit 10 of Pt1+ ?35±3 ?0.9
The yellow unit 20 of Pt2+ ?73.3±1.2 ?0.98
The yellow unit 40 of Pt4+ ?95.5±2 ?0.88
The yellow unit 5 of 5-Fu10+ ?65±3 ?0.98
The yellow unit 10 of 5-Fu20+ ?31±2 ?1.02
The yellow unit 20 of 5-Fu40+ ?5 ?0.85
The yellow unit 5 of 5-Fu5+ ?18±2 ?0.755
The yellow unit 10 of 5-Fu10+ ?48.2±2 ?0.98
The yellow unit 20 of 5-Fu20+ ?88 ?0.98
The yellow unit 10 of 5-Fu5+ ?35±3 ?0.95
The yellow unit 20 of 5-Fu10+ ?75±3 ?0.98
The yellow unit 40 of 5-Fu20+ ?98±3 ?0.79
The yellow glycoside 7.5 of Pt1+ ?10±1.5 ?1.07
The yellow glycoside 15 of Pt2+ ?59.2±2.5 ?0.875
The yellow glycoside 30 of Pt4+ ?92±3 ?0.85
The yellow glycoside 10 of Pt1+ ?11.2±2 ?1.2
The yellow glycoside 20 of Pt2+ ?65±3 ?0.958
The yellow glycoside 40 of Pt4+ ?95±2 ?0.9
The yellow glycoside 10 of 5-Fu5+ ?12±2.5 ?1.2
The yellow glycoside 20 of 5-Fu10+ ?77±2 ?0.85
The yellow glycoside 40 of 5-Fu20+ ?92.5±3 ?1
5-Fu2.5+ yellow glycoside 10 ?11±1.5 ?0.962
The yellow glycoside 20 of 5-Fu5+ ?57±3 ?0.91
The yellow glycoside 40 of 5-Fu10+ ?91.7±3 ?0.945
Annotate: Huang Yuan=baicaligenin; Yellow glycoside=baicalin; Pt=cisplatin (CDDP); The 5-Fu=5-fluorouracil
Conclusion:
Table 1 show baicaligenin with cisplatin (CDDP) to the HepG2 drug combination time, when the molar concentration rate of cisplatin and baicaligenin presents synergistic action effect during 1: 5 and 1: 10.Baicaligenin is with the 5-fluorouracil drug combination time, when the molar concentration rate of 5-Fu and baicaligenin also presented synergistic action effect at 1: 0.5,1: 1 and 1: 2.
Baicalin is with cisplatin (CDDP) drug combination the time, when the molar concentration rate of cisplatin and baicalin presents synergistic action effect during 2: 15 and 1: 10.Baicalin is with the 5-fluorouracil drug combination time, when the molar concentration rate of 5-fluorouracil and baicalin also presented synergistic action effect at 1: 2 and 1: 4.
IC50 concentration when CDDP, 5-FU use separately, each the IC50 concentration of CDDP, 5-FU after associating baicaligenin or the baicalin medication calculates by same software.And calculate drug effect and strengthen ratio.The results are shown in Table 2:
Table 2
Molar concentration rate when reaction medication name or its drug combination IC50 concentration (μ m) IC50 concentration when chemotherapeutics uses separately and the ratio (f2/f1) of the IC50 concentration behind the drug combination
Baicaligenin 15.297??(f1) 1
Baicalin 27.29???(f1) 1
5-fluorouracil 18.9????(f1) 1
Cisplatin 4.5?????(f1) 1
Cisplatin: baicaligenin 1: 5 2???????(f2) 0.44
Cisplatin: baicaligenin 1: 10 1.32????(f2) 0.288
Cisplatin: baicaligenin 1: 7.5 1.88????(f2) 0.4178
Cisplatin: baicalin 1: 10 1.75????(f2) 0.388
5-fluorouracil: baicaligenin 1: 1 9.33????(f2) 0.4937
5-fluorouracil: baicaligenin 1: 2 6.93????(f2) 0.3667
5-fluorouracil: baicalin 1: 2 8.38????(f2) 0.4428
5-fluorouracil: baicalin 1: 4 4.7?????(f2) 0.2487
Conclusion:
Its IC50 is respectively 4.5 μ m and 18.9 μ m during singly with CDDP, 5-FU.After adding baicaligenin, IC50 1 to 5 time drops to 2 μ m when cisplatin and baicaligenin molar concentration rate, and IC50 1 to 10 time drops to 1.32 μ m when cisplatin and baicaligenin molar concentration rate.IC50 drops to 9.3 μ m when 5-fluorouracil is 1 to 1 with the baicaligenin molar concentration rate, and IC50 drops to 6.9 μ m when 5-fluorouracil is 1 to 2 with the baicaligenin molar concentration rate.
After adding baicalin, IC50 1 to 7.5 time drops to 1 when cisplatin and baicalin molar concentration rate.88 μ m drop to 1 as cisplatin and baicalin molar concentration rate IC50 1 to 10 time.75 μ m, IC50 drops to 8.38 μ m when 5-fluorouracil is 1 to 2 with the baicalin molar concentration rate, and IC50 drops to 4.7 μ m when 5-fluorouracil is 1 to 4 with the baicalin molar concentration rate.After the IC50 concentration when using separately by calculating chemotherapeutics and the ratio of the IC50 concentration behind the drug combination can be presented at drug combination with baicaligenin or baicalin, the drug effect of chemotherapeutics had improved 2-4 respectively doubly.
Embodiment 2 baicalins and baicaligenin be the synergism on Chinese People's Anti-Japanese Military and Political College's intestinal cancer to cisplatin (CDDP) and 5-fluorouracil (5-FU)
Human large intestine cancer cell strain HCT116 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 1 * 10 3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add baicalin or baicaligenin, and mix in the adding culture fluid with different molar concentration rates with CDDP or 5-Fu.Ultimate density baicaligenin 0.3-200 μ g/ml, baicalin 0.6-350 μ g/ml, 5-fluorouracil 0.01-10 μ g/ml, cisplatin 0.3-3 μ g/ml.Cultivate and make MTT mensuration after 72 hours.With tetrazolium (MTT) method dyeing and calculate single with and coupling baicaligenin or baicalin and chemotherapeutics to HCT116 inhibition of proliferation rate, carry out data analysis with CalcuSyn statistical software and drug combination coefficient value (CI) method.
HCT116 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 3:
Table 3
Single-dose thing activity (μ m) Combination medicine activity (μ m) Inhibitory rate of cell growth % Drug combination coefficient value (CI)
Yellow unit 5 ?24.43±1.5
Yellow unit 10 ?35.933±3
Yellow unit 20 ?57.02±2
Yellow unit 40 ?72±1
Yellow glycoside 5 ?27.62±2
Yellow glycoside 10 ?33.25±2
Yellow glycoside 20 ?37.65±3
Yellow glycoside 40 ?68.7±3
Pt1 ?5±0.5
Pt2 ?27.33±2
Pt4 ?61.18±3
5-Fu5 ?25.8±2
5-Fu10 ?61.5±3.5
5-Fu20 ?68.5±2.78
The yellow unit 5 of Pt2+ ?47.52±2 ?0.99
The yellow unit 10 of Pt4+ ?83.9±3 ?0.766
The yellow unit 20 of Pt8+ ?97.5±2 ?0.9
The yellow unit 5 of Pt1+ ?29.8±3 ?1.17
The yellow unit 10 of Pt2+ ?60±3 ?0.95
The yellow unit 20 of Pt4+ ?90±3 ?0.658
The yellow unit 10 of Pt1+ ?58.2±1.5 ?0.729
The yellow unit 20 of Pt2 ?75±2 ?0.83
The yellow unit 40 of Pt4+ ?98 ?0.3
5-Fu2.5+ yellow unit 5 ?28.2±3 ?1.31
The yellow unit 10 of 5-Fu5+ ?62.5±2 ?1.02
The yellow unit 20 of 5-Fu10+ ?77.1±2.7 ?0.8
The yellow unit 40 of 5-Fu20+ ?91.2±2.79 ?0.37
5-Fu2.5+ yellow unit 2.5 ?21.2±1.9 ?1.275
The yellow unit 5 of 5-Fu5+ ?49.2±3 ?0.8635
The yellow unit 10 of 5-Fu10+ ?75.2±3 ?0.662
The yellow unit 20 of 5-Fu20+ ?91.2±2.7 ?0.488
The yellow unit 2.5 of 5-Fu5+ ?38±2.2 ?1.0155
The yellow unit 5 of 5-Fu10+ ?63.21±2 ?0.885
The yellow unit 10 of 5-Fu20+ ?82.67±3.2 ?0.7828
The yellow glycoside 5 of Pt1+ ?28.75±2 ?1.1
The yellow glycoside 10 of Pt2+ ?62.9±3.2 ?1
The yellow glycoside 20 of Pt4+ ?88±2 ?0.74
The yellow glycoside 10 of Pt1+ ?44.32±3 ?0.95
The yellow glycoside 20 of Pt2+ ?67.76±1.2 ?0.85
The yellow glycoside 40 of Pt4+ ?95±2 ?0.42
5-Fu2.5+ yellow glycoside 2.5 ?20.5±2.5 ?1.37
The yellow glycoside 5 of 5-Fu5+ ?38.9±2 ?1.1
The yellow glycoside 10 of 5-Fu10+ ?75.2±3 ?0.757
The yellow glycoside 20 of 5-Fu20+ ?87.6±4 ?0.55
5-Fu2.5+ yellow glycoside 5 ?23.7±2 ?1.49
The yellow glycoside 10 of 5-Fu5+ ?52.7±3 ?0.881
The yellow glycoside 20 of 5-Fu10+ ?82.65±3 ?0.45
Annotate: Huang Yuan=baicaligenin; Yellow glycoside=baicalin; Pt=cisplatin (CDDP); The 5-Fu=5-fluorouracil
Conclusion:
Table 3 shows baicaligenin when with chemotherapeutics cisplatin (CDDP) HCT116 being carried out drug combination, when the molar concentration rate of cisplatin and baicaligenin at 1: 2.5, presented synergistic action effect at 1: 5 and 1: 10 o'clock.Baicaligenin and during 5-fluorouracil (5-Fu) drug combination, when the molar concentration rate of 5-Fu and baicaligenin at 2: 1, also presented synergistic action effect in 1: 1 and 1: 2.
Baicalin is with chemotherapeutics cisplatin (CDDP) drug combination the time, when the molar concentration rate of cisplatin and baicalin presents synergistic action effect during 1: 5 and 1: 10.Baicalin and during 5-fluorouracil (5-Fu) drug combination, when the molar concentration rate of 5-Fu and baicalin also presented synergistic action effect at 1: 1 and 1: 2.
IC50 concentration when DDP, 5-FU use separately, each the IC50 concentration of CDDP, 5-FU after associating baicaligenin or the baicalin medication calculates by same software.The results are shown in Table 4:
Table 4
Molar concentration rate when reaction medication name or its drug combination IC50 concentration (μ m) IC50 concentration when chemotherapeutics uses separately and the ratio (f2/f1) of the IC50 concentration behind the drug combination
Baicaligenin 15.9????(f1) 1
Baicalin 21.9????(f1) 1
5-fluorouracil 9.535???(f1) 1
Cisplatin 3.2?????(f1) 1
Cisplatin: baicaligenin 1: 2.5 2.1?????(f2) 0.656
Cisplatin: baicaligenin 1: 5 1.536???(f2) 0.48
Cisplatin: baicaligenin 1: 10 ?1???????(f2) 0.3125
Cisplatin: baicalin 1: 5 ?1.5772??(f2) 0.4929
Cisplatin: baicalin 1: 10 ?1.2?????(f2) 0.375
5-fluorouracil: baicaligenin 1: 1 ?5.2318??(f2) 0.5487
5-fluorouracil: baicaligenin 1: 2 ?4.22????(f2) 0.4426
5-fluorouracil: baicaligenin 2: 1 ?6.95????(f2) 0.7289
5-fluorouracil: baicalin 1: 1 ?5.85????(f2) 0.6135
5-fluorouracil: baicalin 1: 2 ?4.59????(f2) 0.481
Conclusion:
Single with CDDP, 5-FU, the time its IC50 be respectively 3.2 μ m and 9.535 μ m.After adding baicaligenin, when cisplatin and baicaligenin drop to 2.1 μ m as cisplatin and baicaligenin molar concentration rate IC50 1 to 2.5 time, IC50 1 to 10 time drops to 1 μ m when cisplatin and baicaligenin molar concentration rate.IC50 drops to 5.23 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 1, IC50 drops to 4.22 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 2, and IC50 drops to 6.95 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 0.5.
After adding baicalin,, cisplatin and baicalin molar concentration rate IC501 1 to 5 time drops to 1.2 μ m as cisplatin and baicaligenin molar concentration rate IC50 1 to 10 time when dropping to 1.5772 μ m.IC50 drops to 5.85 μ m when 5-fluorouracil and baicalin molar concentration rate 1 to 1, and IC50 drops to 4.59 μ m when 5-fluorouracil and baicalin molar concentration rate 1 to 2.
After the IC50 concentration when using separately by calculating chemotherapeutics and the ratio of the IC50 concentration behind the drug combination can be presented at drug combination with baicaligenin or baicalin, the drug effect of chemotherapeutics had improved 1.5-3 respectively doubly.
Embodiment 3 baicalins and baicaligenin be the synergism on anti-pulmonary carcinoma to cisplatin (CDDP) and 5-fluorouracil (5-FU)
Human lung carcinoma cell line A549 cell is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 1 * 10 3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add baicalin or baicaligenin, and mix in the adding culture fluid with different molar concentration rates with CDDP.Ultimate density baicaligenin 0.3-200 μ g/ml, baicalin 0.6-350 μ g/ml, cisplatin 0.3-3 μ g/ml.Cultivate and make MTT mensuration after 72 hours.With tetrazolium (MTT) method dyeing and calculate single with and the coupling baicaligenin or and baicalin and chemotherapeutics to A549 inhibition of proliferation rate, carry out data analysis with CalcuSyn statistical software and drug combination coefficient value (CI) method.
A549 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination coefficient value is seeing Table 5:
Table 5
Single-dose thing activity (μ m) Combination medicine activity (μ m) Inhibitory rate of cell growth % Drug combination coefficient value (CI)
Yellow unit 5 ?1±0.5
Yellow unit 10 ?17.43±3
Yellow unit 20 ?38±2
Yellow unit 40 ?91.2±1
Yellow glycoside 5 ?5±1
Yellow glycoside 10 ?10.3±2
Yellow glycoside 20 ?35.8±2
Yellow glycoside 40 ?62.1±3
Pt1 ?31±2.5
Pt2 ?42.3±3
Pt4 ?49±3
The yellow unit 2.5 of Pt1+ ?15±2 ?5.8
The yellow unit 5 of Pt2+ ?52.5±3 ?0.661
The yellow unit 10 of Pt4+ ?66±3 ?0.677
The yellow unit 5 of Pt1+ ?19±1 ?3.7
The yellow unit 10 of Pt2+ ?59.5±2.5 ?0.69
The yellow unit 20 of Pt4+ ?90.2±2 ?0.515
The yellow unit 10 of Pt1+ ?67±3 ?0.47
The yellow unit 20 of Pt2+ ?85±2 ?0.6
The yellow unit 40 of Pt4+ ?95±2 ?0.79
The yellow glycoside 7.5 of Pt1+ ?26.7±2 ?2
The yellow glycoside 15 of Pt2+ ?55.7±3.1 ?0.7675
The yellow glycoside 30 of Pt4+ ?78±2 ?0.578
The yellow glycoside 10 of Pt1+ ?29.8±2.1 ?1.15
The yellow glycoside 20 of Pt2+ ?61.9±2.1 ?0.7025
The yellow glycoside 40 of Pt4+ ?82.7±3 ?0.6
Annotate: Huang Yuan=baicaligenin; Yellow glycoside=baicalin; The Pt=cisplatin, CDDP; The 5-Fu=5-fluorouracil
Table 5 show baicaligenin with chemotherapeutics cisplatin (CDDP) when A549 is carried out drug combination, when the molar concentration rate of CDDP and baicaligenin presents synergistic action effect during 1: 2.5,1: 5 and 1: 10.
Baicalin is with chemotherapeutics cisplatin (CDDP) drug combination the time, when the molar concentration rate of CDDP and baicalin presents synergistic action effect 1: 7.5 and 1: 10 and during high concentration.
IC50 concentration when CDDP, 5-FU use separately, each the IC50 concentration of DDP, 5-FU after associating baicaligenin or the baicalin medication calculates by same software.The results are shown in Table 6:
Table 6
Molar concentration rate when reaction medication name or its drug combination IC50 concentration (μ m) IC50 concentration when chemotherapeutics uses separately and the ratio (f2/f1) of the IC50 concentration behind the drug combination
Baicaligenin 19.9????(f1) 1
Baicalin 30??????(f1) 1
Cisplatin 4???????(f1) 1
Cisplatin: baicaligenin 1: 2.5 ?2.38?????(f2) 0.595
Cisplatin: baicaligenin 1: 5 ?1.729????(f2) 0.432
Cisplatin: baicaligenin 1: 10 ?0.657????(f2) 0.165
Cisplatin: baicalin 1: 7.5 ?1.8??????(f2) 0.45
Cisplatin: baicalin 1: 10 ?1.59?????(f2) 0.3975
Conclusion:
Its IC50 is 4 μ m during singly with DDP.After adding baicaligenin, IC50 1 to 2.5 time drops to 2.38 μ m when cisplatin and baicaligenin molar concentration rate, and IC50 drops to 1.729 μ m and drops to 0.657 μ m as cisplatin and baicaligenin molar concentration rate IC50 1 to 10 time in the time of 1 to 2.5.
After adding baicalin, IC50 1 to 7.5 time drops to 1.8 μ m when cisplatin and baicaligenin molar concentration rate, and IC50 1 to 10 time drops to 1.59 μ m when cisplatin and baicaligenin molar concentration rate.
After the IC50 concentration when using separately by calculating chemotherapeutics and the ratio of the IC50 concentration behind the drug combination can be presented at drug combination with baicaligenin or baicalin, the drug effect of chemotherapeutics had improved 1.5-5 respectively doubly.
Embodiment 4 baicalins and baicaligenin be the synergism on anti-pulmonary carcinoma to cisplatin (CDDP) and 5-fluorouracil (5-FU)
People's gastric cancer JEG-3 MKN45 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 1 * 10 3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add baicalin or baicaligenin.And mix with different molar concentration rates with CDDP or 5-Fu and to add in the culture fluid.Ultimate density baicaligenin 0.3-200 μ g/ml, baicalin 0.6-350 μ g/ml, 5-fluorouracil 0.01-10 μ g/ml, cisplatin 0.3-3 μ g/ml.Cultivate and make MTT mensuration after 72 hours.With tetrazolium (MTT) method dyeing and calculate single with and coupling baicaligenin or baicalin and chemotherapeutics to MKN45 inhibition of proliferation rate, carry out data analysis with CalcuSyn statistical software and drug combination coefficient value (CI) method.
MKN45 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination coefficient value is seeing Table 7:
Table 7
Single-dose thing activity (μ m) Combination medicine activity (μ m) Inhibitory rate of cell growth % Drug combination coefficient value (CI)
Yellow unit 1 ?5±0.5
Yellow unit 2 ?17.6±2
Yellow unit 4 ?21.5±2
Yellow unit 8 ?43±3
Yellow unit 16 ?51.25±3
Yellow glycoside 2.5 ?0.01
Yellow glycoside 5 ?23.6±2
Yellow glycoside 10 ?40.25±3
Yellow glycoside 20 ?47.87±3
Yellow glycoside 40 ?82.78±3
Pt1 ?5±0.5
Pt2 ?29.67±3
Pt4 ?43.3±3
Pt8 ?51.5±2.5
?5-Fu5 ?25.2±2
?5-Fu10 ?48.91±3.5
?5-Fu20 ?65.32±2.78
The yellow unit 1 of Pt1+ ?10.02±2 ?1.8
The yellow unit 2 of Pt2+ ?37±3 ?0.769
The yellow unit 4 of Pt4+ ?55±2 ?0.88
The yellow unit 8 of Pt8+ ?77.12±2 ?0.7727
The yellow unit 2.5 of Pt1+ ?19±3 ?1.28
The yellow unit 5 of Pt2+ ?55±2 ?0.628
The yellow unit 10 of Pt4+ ?65±3 ?0.8838
The yellow unit 5 of Pt1+ ?22.2±2 ?1.26
The yellow unit 10 of Pt2+ ?57±2 ?0.89
The yellow unit 20 of Pt4+ ?85±2 ?0.505
5-Fu2.5+ yellow unit 2.5 ?22.5±3 ?1.23
The yellow unit 5 of 5-Fu5+ ?47±3 ?0.92
The yellow unit 10 of 5-Fu10+ ?72±3 ?0.727
The yellow unit 20 of 5-Fu20+ ?87.8±2 ?0.6
5-Fu2.5+ yellow unit 5 ?29±2 ?1
The yellow unit 10 of 5-Fu5+ ?61.5±3 ?0.8442
The yellow unit 20 of 5-Fu10 ?75±3 ?0.749
The yellow glycoside 2.5 of Pt1+ ?10.2±2 ?1.065
The yellow glycoside 5 of Pt2+ ?51.3±3 ?0.605
The yellow glycoside 10 of Pt4+ ?67.2±2 ?0.873
The yellow glycoside 5 of Pt1+ ?23.22±3 ?0.783
The yellow glycoside 10 of Pt2+ ?55.35±1.2 ?0.819
The yellow glycoside 20 of Pt4+ ?85±2 ?0.91
The yellow glycoside 10 of Pt1+ ?45.65±2 ?0.772
The yellow glycoside 20 of Pt2+ ?76.7±3 ?0.4825
The yellow glycoside 40 of Pt4+ ?95±2 ?1.13
5-Fu2.5+ yellow glycoside 2.5 ?17.2±3 ?0.9655
The yellow glycoside 5 of 5-Fu5+ ?37.7±3 ?0.9568
The yellow glycoside 10 of 5-Fu10+ ?71±3 ?0.857
The yellow glycoside 20 of 5-Fu20+ ?89.2±3 ?0.95
5-Fu2.5+ yellow glycoside 5 ?28.2±2.7 ?0.81
The yellow glycoside 10 of 5-Fu5+ ?57.2±3 ?0.85
The yellow glycoside 20 of 5-Fu10+ ?81.5±3 ?0.98
Annotate: Huang Yuan=baicaligenin; Yellow glycoside=baicalin; The Pt=cisplatin, CDDP; The 5-Fu=5-fluorouracil
Table 7 show baicaligenin with chemotherapeutics cisplatin (CDDP) when MKN45 is carried out drug combination, when the molar concentration rate of cisplatin and baicaligenin presents synergistic action effect during 1: 1.1: 2.5 and 1: 5.Baicaligenin and during 5-fluorouracil (5-Fu) drug combination, when the molar concentration rate of 5-Fu and baicaligenin also presented synergistic action effect at 1: 1 and 1: 2.
Baicalin is with chemotherapeutics cisplatin (CDDP) drug combination the time, when the molar concentration rate of cisplatin and baicalin presents synergistic action effect during 1: 2.5,1: 5 and 1: 10.Baicalin and during 5-fluorouracil (5-Fu) drug combination, when the molar concentration rate of 5-Fu and baicalin also presented synergistic action effect at 1: 1 and 1: 2.
IC50 concentration when CDDP, 5-FU use separately, each the IC50 concentration of DDP, 5-FU after associating baicaligenin or the baicalin medication calculates by same software.The results are shown in Table 8:
Table 8
Molar concentration rate when reaction medication name or its drug combination IC50 concentration (μ m) IC50 concentration when chemotherapeutics uses separately and the ratio (f2/f1) of the IC50 concentration behind the drug combination
Baicaligenin 12.46???(f1) 1
Baicalin 18??????(f1) 1
5-fluorouracil 9.535???(f1) 1
Cisplatin 5.8376??(f1) 1
Cisplatin: baicaligenin 1: 1 3.48????(f2) 0.596
Cisplatin: baicaligenin 1: 2.5 2.3?????(f2) 0.4
Cisplatin: baicaligenin 1: 5 1.778???(f2) 0.3
Cisplatin: baicalin 1: 2.5 2.5?????(f2) 0.428
Cisplatin: baicalin 1: 5 1.78????(f2) 0.3
Cisplatin: baicalin 1: 10 1.1?????(f2) 0.188
5-fluorouracil: baicaligenin 1: 1 5.5?????(f2) 0.58
5-fluorouracil: baicaligenin 1: 2 4.255???(f2) 0.446
5-fluorouracil: baicaligenin 2: 1 7.25????(f2) 0.76
5-fluorouracil: baicalin 1: 1 6.21????(f2) 0.65
5-fluorouracil: baicalin 1: 2 4.27????(f2) 0.448
5-fluorouracil: baicalin 2: 1 7.4?????(f2) 0.77
Conclusion:
Its IC50 is respectively 3.2 μ m and 9.535 μ m during singly with CDDP, 5-FU.After adding baicaligenin, when cisplatin and baicaligenin drop to 2.1 μ m as cisplatin and baicaligenin molar concentration rate IC50 1 to 2.5 time, IC50 1 to 10 time drops to 1 μ m when cisplatin and baicaligenin molar concentration rate.IC50 drops to 5.23 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 1, IC50 drops to 4.22 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 2, and IC50 drops to 6.95 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 0.5.
After adding baicalin,, cisplatin and baicalin molar concentration rate IC501 1 to 5 time drops to 1.2 μ m as cisplatin and baicaligenin molar concentration rate IC50 1 to 10 time when dropping to 1.5772 μ m.IC50 drops to 5.85 μ m when 5-fluorouracil and baicalin molar concentration rate 1 to 1, and IC50 drops to 4.59 μ m when 5-fluorouracil and baicalin molar concentration rate 1 to 2
After the IC50 concentration when using separately by calculating chemotherapeutics and the ratio of the IC50 concentration behind the drug combination can be presented at drug combination with baicaligenin or baicalin, the drug effect of chemotherapeutics was divided and you can well imagine 1.3-5 doubly.
Embodiment 5 baicalins and baicaligenin be the synergism on anti-esophageal carcinoma to cisplatin (CDDP) and 5-fluorouracil (5-FU)
People's esophageal carcinoma JEG-3 TE2 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 1 * 10 3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add baicalin or baicaligenin, and mix in the adding culture fluid with different molar concentration rates with CDDP or 5-Fu.Ultimate density baicaligenin 0.3-200 μ g/ml, baicalin 0.6-350 μ g/ml, 5-fluorouracil 0.01-10 μ g/ml, cisplatin 0.3-3 μ g/ml.Cultivate and make MTT mensuration after 72 hours.With tetrazolium (MTT) method dyeing and calculate single with and coupling baicaligenin or baicalin and chemotherapeutics to TE2 inhibition of proliferation rate, carry out data analysis with CalcuSyn statistical software and drug combination coefficient value (CI) method.
TE2 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination coefficient value is seeing Table 9:
Table 9
Single-dose thing activity (μ m) Combination medicine activity (μ m) Inhibitory rate of cell growth % Drug combination coefficient value (CI)
Yellow unit 5 0.9
Yellow unit 10 16.8±1.7
Yellow unit 20 49±2
Yellow unit 40 91.3±3
Yellow glycoside 5 1
Yellow glycoside 10 9±1
Yellow glycoside 20 45.2±3
Yellow glycoside 40 71.2±3
Pt1 8.8±0.5
Pt2 31.99±3
Pt4 44.42±3
Pt8 75±2.5
5-Fu5 7.2±2
5-Fu10 13.9±3.5
5-Fu20 39.08±2.78
5-Fu40 44.2±1.7
The yellow unit 5 of Pt1+ 22±2 ?0.95
The yellow unit 10 of Pt2+ 52±2 ?0.988
The yellow unit 20 of Pt4+ 86±3 ?0.91
The yellow unit 10 of Pt1+ 38±3 ?0.95
The yellow unit 20 of Pt2+ 71±3 ?0.99
The yellow unit 40 of Pt4+ 95±4.2 ?0.932
The yellow unit 5 of 5-Fu5+ 12.5±2 ?1.1
The yellow unit 10 of 5-Fu10+ 42.2±3 ?0.9
The yellow unit 20 of 5-Fu20+ 74.2±3 ?0.97
The yellow unit 10 of 5-Fu5+ 22.5±2 ?1.12
The yellow unit 20 of 5-Fu10+ ?67±3 ?0.98
The yellow unit 40 of 5-Fu20+ ?95±3 ?0.9
The yellow glycoside 5 of Pt1+ ?11±1 ?1.39
The yellow glycoside 10 of Pt2+ ?49.5±3 ?0.9
The yellow glycoside 20 of Pt4+ ?82.35±3 ?0.82
The yellow glycoside 10 of Pt1+ ?32.5±2.5 ?0.926
The yellow glycoside 20 of Pt2+ ?69.8±3 ?0.876
The yellow glycoside 40 of Pt4+ ?95±2 ?0.69
The yellow glycoside 5 of 5-Fu5+ ?11.2±1.5 ?1.13
The yellow glycoside 10 of 5-Fu10+ ?40.7±2 ?0.8
The yellow glycoside 20 of 5-Fu20+ ?75.5±3 ?0.722
The yellow glycoside 10 of 5-Fu5+ ?21.2±2 ?1.025
The yellow glycoside 20 of 5-Fu10+ ?65.8±3 ?0.772
The yellow glycoside 40 of 5-Fu20+ ?95±2 ?0.58
Annotate: Huang Yuan=baicaligenin; Yellow glycoside=baicalin; The Pt=cisplatin, CDDP; The 5-Fu=5-fluorouracil
Conclusion:
Table 9 show baicaligenin with chemotherapeutics cisplatin (CDDP) when TE1 is carried out drug combination, when the molar concentration rate of cisplatin and baicaligenin presents synergistic action effect during 1: 5 and 1: 10.Baicaligenin and during 5-fluorouracil (5-Fu) drug combination, when the molar concentration rate of 5-Fu and baicaligenin also presented synergistic action effect at 1: 1 and 1: 2.
Baicalin is with chemotherapeutics cisplatin (CDDP) drug combination the time, when the molar concentration rate of cisplatin and baicalin presents synergistic action effect during 1: 5 and 1: 10.Baicalin and during 5-fluorouracil (5-Fu) drug combination, when the molar concentration rate of 5-Fu and baicalin also presented synergistic action effect at 1: 1 and 1: 2.
IC50 concentration when CDDP, 5-FU use separately, each the IC50 concentration of CDDP, 5-FU after associating baicaligenin or the baicalin medication calculates by same software.The results are shown in Table 10:
Table 10
Molar concentration rate when reaction medication name or its drug combination IC50 concentration (μ m) IC50 concentration when chemotherapeutics uses separately and the ratio (f2/f1) of the IC50 concentration behind the drug combination
Baicaligenin 19.9???(f1) 1
Baicalin 25.17??(f1) 1
Cisplatin 4.03???(f1) 1
5-fluorouracil 40?????(f1) 1
Cisplatin: baicaligenin 1: 5 1.82???(f2) 0.452
Cisplatin: baicaligenin 1: 10 1.23???(f2) 0.305
Cisplatin: baicalin 1: 5 2.15???(f2) 0.533
Cisplatin: baicalin 1: 10 1.36???(f2) 0.337
5-fluorouracil: baicaligenin 1: 1 12?????(f2) 0.3
5-fluorouracil: baicaligenin 1: 2 ?7.66???(f2) 0.19
5-fluorouracil: baicalin 1: 1 ?12?????(f2) 0.3
5-fluorouracil: baicalin 1: 2 ?7.8????(f2) 0.195
Conclusion:
Single with CDDP, 5-FU, the time its IC50 be respectively 4.03 μ m and 40 μ m.After adding baicaligenin, IC50 1 to 5 time drops to 1.82 μ m when cisplatin and baicaligenin molar concentration rate, and IC50 1 to 10 time drops to 1.23 μ m when cisplatin and baicaligenin molar concentration rate.IC50 drops to 12 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 1, and IC50 drops to 7.66 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 2.
After adding baicalin,, cisplatin and baicaligenin molar concentration rate IC50 1 to 5 time drops to 1.36 μ m as cisplatin and baicaligenin molar concentration rate IC50 1 to 10 time when dropping to 2.15 μ m.IC50 drops to 12 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 1, and IC50 drops to 7.8 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 2.
After the IC50 concentration when using separately by calculating chemotherapeutics and the ratio of the IC50 concentration behind the drug combination can be presented at drug combination with baicaligenin or baicalin, the drug effect of chemotherapeutics was divided and you can well imagine 2-5 doubly.
Embodiment 6 baicalins and baicaligenin be the synergism on anti-breast cancer to cisplatin (CDDP) and 5-fluorouracil (5-FU)
Human breast JEG-3 MCF-7 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, is seeded in 96 porocyte culture plates with 1 * 103/ hole.After cultivating 24 hours, add baicalin or baicaligenin, and mix in the adding culture fluid with different molar concentration rates with 5-Fu.Ultimate density baicaligenin 0.3-200 μ g/ml, baicalin 0.6-350 μ g/ml, 5-fluorouracil 0.01-10 μ g/ml.Cultivate and make MTT mensuration after 72 hours.With tetrazolium (MTT) method dyeing and calculate single with and coupling baicaligenin or baicalin and chemotherapeutics to MCF-7 inhibition of proliferation rate, carry out data analysis with CalcuSyn statistical software and drug combination coefficient value (CI) method.
MCF-7 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination coefficient value is seeing Table 11:
Table 11
Single-dose thing activity (μ m) Combination medicine activity (μ m) Inhibitory rate of cell growth % Drug combination coefficient value (CI)
Yellow unit 2.5 1±0.5
Yellow unit 5 17.43±3
Yellow unit 10 38±2
Yellow unit 20 91.2±1
Yellow glycoside 5 5±1
Yellow glycoside 10 21.5±2
Yellow glycoside 40 85.2±3
5-Fu5 8±2
5-Fu10 20.2±3.5
?5-Fu20 ?48±2.8
?5-Fu40 ?87.7±1.8
The yellow unit 5 of 5-Fu5+ ?25±3 ?1.42
The yellow unit 10 of 5-Fu10+ ?67.8±2 ?0.9359
5-Fu20+ Huang 20 ?90.2±2 ?0.81
The yellow unit 10 of 5-Fu5+ ?36.5±4 ?1.3
The yellow unit 20 of 5-Fu10+ ?82±2 ?0.93
The yellow unit 40 of 5-Fu20+ ?95 ?0.769
The yellow glycoside 5 of 5-Fu5+ ?22.5±2.5 ?1.5
The yellow glycoside 10 of 5-Fu10+ ?65.2±2 ?0.825
The yellow glycoside 20 of 5-Fu20+ ?87.2±3 ?0.84
The yellow glycoside 10 of 5-Fu5+ ?35.2±2 ?1.36
The yellow glycoside 20 of 5-Fu10+ ?79.8±3 ?0.88
The yellow glycoside 40 of 5-Fu20+ ?95 ?0.77
Annotate: Huang Yuan=baicaligenin; Yellow glycoside=baicalin; The Pt=cisplatin, CDDP; 5-Fu=5-fluorouracil conclusion:
Table 11 show baicaligenin at chemotherapeutics 5-fluorouracil (5-Fu) when MCF-7 is carried out drug combination, when the molar concentration rate of 5-Fu and baicaligenin presents synergistic action effect during 1: 1 and 1: 2.
Baicalin is with chemotherapeutics 5-fluorouracil (5-Fu) drug combination the time, when the molar concentration rate of 5-Fu and baicalin also presented synergistic action effect at 1: 1 and 1: 2.
IC50 concentration when DDP, 5-FU use separately, each the IC50 concentration of DDP, 5-FU after associating baicaligenin or the baicalin medication is by going out with computed in software.The results are shown in Table 12:
Table 12
Molar concentration rate when reaction medication name or its drug combination IC50 concentration (μ m) IC50 concentration when chemotherapeutics uses separately and the ratio (f2/f1) of the IC50 concentration behind the drug combination
Baicaligenin 15.2???(f1) 1
Baicalin 18.15??(f1) 1
5-fluorouracil 12.5???(f1) 1
5-fluorouracil: baicaligenin 1: 1 7.712??(f2) 0.617
5-fluorouracil: baicaligenin 1: 2 6??????(f2) 0.48
5-fluorouracil: baicalin 1: 1 8.25???(f2) 0.66
5-fluorouracil: baicalin 1: 2 6.175??(f2) 0.49
Conclusion:
Single with 5-FU, the time its IC50 be respectively 12.5 μ m.After adding baicaligenin, IC50 drops to 7.712 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 1, and IC50 drops to 6 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 2.
After adding baicalin, IC50 drops to 8.25 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 1, and IC50 drops to 6.175 μ m when 5-fluorouracil and baicaligenin molar concentration rate 1 to 2.
After the IC50 concentration when using separately by calculating chemotherapeutics and the ratio of the IC50 concentration behind the drug combination can be presented at drug combination with baicaligenin or baicalin, the drug effect of chemotherapeutics had improved 1.5-2 respectively doubly.
Each above listed pertinent literature is all introduced the application as a reference with a full piece of writing.Many aspects involved in the present invention have been done as above and have been set forth.Yet, it should be understood that under the prerequisite of spirit that does not depart from the present invention and scope, any modification of foregoing description is all allowed.Equally, similarly situation is also included within the claim.

Claims (35)

1. antineoplastic has synergistic pharmaceutical composition, and said composition comprises the chemical compound of cisplatin and following formula (I), it is characterized in that, the molar concentration rate of described cisplatin and formula (I) chemical compound is 1: 2.5 to 1: 10:
Wherein, R 1Represent hydrogen or glucal acidic group, R 2, R 3Represent hydrogen separately.
2. the pharmaceutical composition of claim 1, wherein said tumor is selected from hepatocarcinoma, colorectal cancer, pulmonary carcinoma, gastric cancer, esophageal carcinoma, breast carcinoma, leukemia, carcinoma of prostate or bladder cancer.
3. the pharmaceutical composition of claim 2, wherein said tumor is selected from hepatocarcinoma, colorectal cancer, pulmonary carcinoma, gastric cancer or esophageal carcinoma.
4. the pharmaceutical composition of claim 3 is wherein worked as R 1, R 2, R 3When representing hydrogen separately, described chemical compound is a baicaligenin.
5. the pharmaceutical composition of claim 4, wherein when described tumor was hepatocarcinoma, the molar concentration rate of described cisplatin and baicaligenin was 1: 5 to 1: 10.
6. the pharmaceutical composition of claim 4, wherein when described tumor was colorectal cancer, the molar concentration rate of described cisplatin and baicaligenin was 1: 2.5 to 1: 10.
7. the pharmaceutical composition of claim 4, wherein when described tumor was pulmonary carcinoma, the molar concentration rate of described cisplatin and baicaligenin was 1: 2.5 to 1: 10.
8. the pharmaceutical composition of claim 4, wherein when described tumor was gastric cancer, the molar concentration rate of described cisplatin and baicaligenin was 1: 1 to 1: 5.
9. the pharmaceutical composition of claim 4, wherein when described tumor was esophageal carcinoma, the molar concentration rate of described cisplatin and baicaligenin was 1: 5 to 1: 10.
10. the pharmaceutical composition of claim 3 is wherein worked as R 1Represent the glucal acidic group, R 2, R 3When representing hydrogen separately, described chemical compound is a baicalin.
11. the pharmaceutical composition of claim 10, wherein when described tumor was hepatocarcinoma, the molar concentration rate of described cisplatin and baicalin was 1: 7.5 to 1: 10.
12. the pharmaceutical composition of claim 10, wherein when described tumor was colorectal cancer, the molar concentration rate of described cisplatin and baicalin was 1: 5 to 1: 10.
13. the pharmaceutical composition of claim 10, wherein when described tumor was pulmonary carcinoma, the molar concentration rate of described cisplatin and baicalin was 1: 7.5 to 1: 10.
14. the pharmaceutical composition of claim 10, wherein when described tumor was gastric cancer, the molar concentration rate of described cisplatin and baicalin was 1: 2.5 to 1: 10.
15. the pharmaceutical composition of claim 10, wherein when described tumor was esophageal carcinoma, the molar concentration rate of described cisplatin and baicalin was 1: 5 to 1: 10.
16. antineoplastic has synergistic pharmaceutical composition, said composition comprises the chemical compound of 5-fluorouracil and following formula (I), it is characterized in that, the molar concentration rate of described 5-fluorouracil and formula (I) chemical compound is 1: 0.5 to 1: 4:
Figure A2005100234670003C1
Wherein, R 1Represent hydrogen or glucal acidic group, R 2, R 3Represent hydrogen separately.
17. the pharmaceutical composition of claim 16, wherein said tumor is selected from hepatocarcinoma, colorectal cancer, pulmonary carcinoma, gastric cancer, esophageal carcinoma, breast carcinoma, leukemia, carcinoma of prostate or bladder cancer.
18. the pharmaceutical composition of claim 17, wherein said tumor is selected from hepatocarcinoma, colorectal cancer, gastric cancer, esophageal carcinoma or breast carcinoma.
19. the pharmaceutical composition of claim 18 is wherein worked as R 1, R 2, R 3When representing hydrogen separately, described chemical compound is a baicaligenin.
20. the pharmaceutical composition of claim 19, wherein when described tumor was hepatocarcinoma, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 0.5 to 1: 1.
21. the pharmaceutical composition of claim 19, wherein when described tumor was colorectal cancer, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 0.5 to 1: 2.
22. the pharmaceutical composition of claim 19, wherein when described tumor was gastric cancer, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 1 to 1: 2.
23. the pharmaceutical composition of claim 19, wherein when described tumor was esophageal carcinoma, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 1 to 1: 2.
24. the pharmaceutical composition of claim 19, wherein when described tumor was breast carcinoma, the molar concentration rate of described 5-fluorouracil and baicaligenin was 1: 1 to 1: 2.
25. the pharmaceutical composition of claim 18 is wherein worked as R 1Represent the glucal acidic group, R 2, R 3When representing hydrogen separately, described chemical compound is a baicalin.
26. the pharmaceutical composition of claim 25, wherein when described tumor was hepatocarcinoma, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 2 to 1: 4.
27. the pharmaceutical composition of claim 25, wherein when described tumor was colorectal cancer, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 1 to 1: 2.
28. the pharmaceutical composition of claim 25, wherein when described tumor was gastric cancer, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 1 to 1: 2.
29. the pharmaceutical composition of claim 25, wherein when described tumor was esophageal carcinoma, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 1 to 1: 2.
30. the pharmaceutical composition of claim 25, wherein when described tumor was breast carcinoma, the molar concentration rate of described 5-fluorouracil and baicalin was 1: 1 to 1: 2.
31. the method for arbitrary pharmaceutical composition of preparation claim 1～30, this method comprises that the chemical compound with following formula (I) mixes with the tumor chemotherapeutic drug that at least one is selected from the group of being made up of cisplatin and 5-fluorouracil:
Wherein, R 1Represent hydrogen or glucal acidic group, R 2, R 3Represent hydrogen separately.
32. the method for claim 31 is wherein worked as R 1, R 2, R 3When representing hydrogen separately, described chemical compound is a baicaligenin.
33. the method for claim 31 is wherein worked as R 1Represent the glucal acidic group, R 2, R 3When representing hydrogen separately, described chemical compound is a baicalin.
34. arbitrary method of claim 31-33, this method comprise that also adding pharmaceutically acceptable additive is mixed with suitable dosage form with described mixture.
35. the purposes of arbitrary pharmaceutical composition of claim 1～30 in the preparation antitumor drug.
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CN112661739A (en) * 2020-12-30 2021-04-16 福建省中科生物股份有限公司 Terpene phenol compound and application of terpene phenol compound and cisplatin in antitumor medicine
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