CN1872049A - Combination of erigeron breviscapus and medication of chemotherapy in platinum class - Google Patents
Combination of erigeron breviscapus and medication of chemotherapy in platinum class Download PDFInfo
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- CN1872049A CN1872049A CN 200610074575 CN200610074575A CN1872049A CN 1872049 A CN1872049 A CN 1872049A CN 200610074575 CN200610074575 CN 200610074575 CN 200610074575 A CN200610074575 A CN 200610074575A CN 1872049 A CN1872049 A CN 1872049A
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Abstract
A compound medicine for treating cancer is prepared from wild-scutellaglucone, the chemicotherapeutic medicine (cisplatin or oxaliplatin) and 5-flurouracil. The useful medicinal composition is also disclosed.
Description
Technical field
The present invention relates to be used for the compositions that antineoplastic is made up of a kind of flavone compound and a kind of platinum-based chemotherapy medicine; The invention still further relates to the purposes of this chemical compound in the medicine of preparation treatment tumor.
Background technology
" chemotherapy " is the abbreviation of " chemotherapy ".The notion of chemotherapy generally is understood that " chemotherapy of tumor " at present, promptly uses antineoplastic chemotherapy medicine, adopts the method for some measure and scheme treatment tumor.Wherein " platinum antineoplastic chemotherapeutics " has mutually similar antitumor action mechanism: the significant feature target spot is positioned at DNA, can be crosslinked in the DNA vessel used to hold grain at the imperial sacrifice by forming, interchain linkage, DNA-protein cross, destroy duplicating and suppressing the growth that cell division etc. is used for suppressing tumor cell of DNA.Common has: and cisplatin (cisplatin CDDP), carboplatin (carboplatin), oxaliplatin (oxaliplatin, JM-216, L-OH), nedaplatin (nedaplatin), network platinum (lobaplatin) etc.They have similar antitumor pharmacology mechanism as similar chemotherapeutics, and similar toxic and side effects is also arranged.
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 of Cancer, 1996, Academic Press, Inc.), two medicines unite action effect when using can pass through " association index " (Combination Index, CI) judge:
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.
Because animal vivo test is difficult to the outer test method of analog, i.e. multiple dose, the drug effect pattern of many concentration.So be difficult to obtain CI numerical value.So those of ordinary skill in the art also has the Q-value that adopts the Jin Shi formula to calculate or statistical procedures after the significant difference that obtains have not (p value) to be used as animal test results judgement (Dai Tijun to drug combination, the Chinese Pharmacological circular, 1998,14 (5): 479-480):
Q＝E(a+b)/Fa+Eb(1-Ea)；
Wherein E is a tumour inhibiting rate, when Q＜0.85 is an antagonism, is addition between Q0.85～1.15, and Q＞1.15 are for collaborative.
Can be as assessment according to the result of cell in vitro test and interior animal experiment to the drug synergism curative effect.
The animal test model that the antitumorigenic substance of establishing in nineteen eighty-three according to national cancer institute screens, be used for having of the interior transplanted tumor strain of mice body: mouse melanin glucagonoma cell strain B16, solid tumor (entity tumor) tumor strains such as mice fibrosarcoma cell strain M5076; Blood such as mouse leukemia cell strain L1210 are the strain of tumor tumor.Those of ordinary skill in the art to adopt and select for use certain tumor tumor strain to be used as animal vivo test model at transplantation tumor: as select for use the mice animal experiment of mouse melanin glucagonoma cell strain B16 to be used as animal vivo test model at entity tumor, heavy or tumor volume suppression ratio is as observation index with tumor; Selecting for use the mice animal experiment of mouse leukemia cell strain L1210 to be used as at blood is the animal vivo test model of tumor, with the increase in life span of tumor animal as observation index.The inside and outside result of the test of coalition judges whether test substance has antitumor action.
Wild-scutellaglucone (having another name called scutellarein, English name Scutellarein) belongs to flavone compound, can extract to obtain from some plants such as Chinese medicine Herba Scutellariae Barbatae.Its molecular weight is 286, molecular formula C
15H
10O
6, structural formula is as follows:
The pharmacological action of relevant wild-scutellaglucone also is not very clear.There is the bibliographical information wild-scutellaglucone that certain antiinflammatory, antioxidation are arranged.
Do not see that so far relevant wild-scutellaglucone and chemotherapeutics have synergistic report on antitumor.
Summary of the invention
Appearance of the present invention partly is based on so unexpected discovery: wild-scutellaglucone and a kind of platinum-based chemotherapy medicine comprise cisplatin and oxaliplatin, and 5-fluorouracil has the synergistic antitumor effect; Unite and use wild-scutellaglucone and a kind of platinum-based chemotherapy medicine such as cisplatin or oxaliplatin, or 5-fluorouracil is used wherein compared with list, and a kind of medicine can produce stronger antitumor action.
The present invention relates to wild-scutellaglucone and comprise that at preparation a kind of and platinum-based chemotherapy medicine cisplatin and oxaliplatin unite with the purposes in the medicine of treatment tumor.
Second aspect of the present invention relates to a kind of synergistic pharmaceutical combination for the treatment of tumor, comprises wild-scutellaglucone and a kind of platinum-based chemotherapy medicine.
The 3rd aspect of the present invention relates to wild-scutellaglucone and unites with the purposes in the medicine of treatment tumor at preparation a kind of and 5-fluorouracil.
The 4th aspect of the present invention relates to a kind of synergistic pharmaceutical combination for the treatment of tumor, comprises wild-scutellaglucone and 5-fluorouracil.
The invention still further relates to the preparation method of aforementioned pharmaceutical compositions.
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 wild-scutellaglucone of the present invention and a kind of platinum-based chemotherapy medicine include but not limited to: cisplatin or oxaliplatin, and 5-fluorouracil can obviously improve both anti-tumor activities successively or during administration simultaneously, has synergism; Thereby can reduce both consumptions, reduce its toxic and side effects.Therefore, wild-scutellaglucone of the present invention and a kind of platinum-based chemotherapy medicine include but not limited to: cisplatin or oxaliplatin, and 5-fluorouracil can be united use with the treatment tumor.
As used herein, term " treatment " are meant that the mammal that gives to treat based on the purpose of curing, alleviating, improving, alleviating, influencing treatment target disease, symptom, disease body constitution (predisposition) is united and use wild-scutellaglucone of the present invention and a kind of platinum-based chemotherapy medicine or 5-fluorouracil.
Term " officinal salt " comprises various inorganic or acylate example hydrochloric acid salt, hydrobromate, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalates: (TRIS is tromethane) with N-methyl-glucamine for various inorganic or organic alkali salts such as sodium hydroxide, Tris.
The technology contents of institute of the present invention incorporated by reference data is incorporated herein by reference in the lump with regard to its integral body.
Wild-scutellaglucone of the present invention can extract from plants such as Herba Scutellariae Barbatae and obtain.Wild-scutellaglucone of the present invention also can obtain or common synthetic technology by this area makes or makes by action of microorganisms by commercial sources.Be used to separate or the chemicals of synthetic wild-scutellaglucone 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 wild-scutellaglucone with synthetic.The synthetic chemistry that is used to prepare wild-scutellaglucone 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.GM.Wuts, Protective Groups inOrganic Synthesis, 3
RdEd., John Wiley and Sons (1999), L.Fieser and M.Fieser, Fieser andFieser ' s Reagents for Organic Synthesis, John Wiley and Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and follow-up works thereof.
(wild-scutellaglucone and a kind of platinum-based chemotherapy medicine include but not limited to: cisplatin or oxaliplatin to the present invention relates to use two kinds of compositions; Wild-scutellaglucone and 5-fluorouracil) the Therapeutic Method of compositions.These two kinds of compositions can be simultaneously or administration successively, or wild-scutellaglucone and a kind of platinum-based chemotherapy medicine, wild-scutellaglucone and 5-fluorouracil are made a kind of pharmaceutical composition use in a kind of pharmaceutically suitable carrier.The composition of this pharmaceutical composition can any intestinal easily or the dosage form administration separately or together of parenteral route administration.The intestinal canal administration preparation 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 capsule comprises lactose and dried corn starch.The pharmaceutically suitable carrier that is usually used in tablet comprises lactose and corn starch, also can add lubricants such as magnesium stearate usually.When making oral aqueous suspension agent and/or Emulsion, pharmaceutical composition of the present invention 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.
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, pharmaceutical composition of the present invention can also suck or implant and accumulate or mode administration such as acupuncture by aerosol.
Pharmaceutical composition 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., also may contain solubilizing agents such as soil temperature class or propylene glycol.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 preparation of the present invention too.
Pharmaceutical composition of the present invention can be made into suppository and passes through rectally, method is that pharmaceutical composition of the present invention 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 pharmaceutical composition 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, pharmaceutical composition 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.Pharmaceutical composition 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 pharmaceutical composition 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.
Pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 drug delivery that all can be used for promoting pharmaceutical composition of the present invention through derivant such as hydroxyalkyl cyclodextrin such as 2-and 3-HP-or other soluble derivatives etc. of chemical modification.
The wild-scutellaglucone that pharmaceutical composition of the present invention is contained and a kind of platinum-based chemotherapy medicine include but not limited to: the synergistic effective range (molar concentration rate) of cisplatin or oxaliplatin; Perhaps the synergistic effective range (molar concentration rate) of wild-scutellaglucone and 5-fluorouracil is verified by suitable in vitro tests (in vitro assay).As a kind of tumor chemotherapeutic drug commonly used, the conventional amount used and the route of administration of cisplatin, oxaliplatin and 5-fluorouracil are as follows: cisplatin 15-35 milligram/square metre (body surface area) continuous use a few days also has 70-100 milligram/square metre single medication; Oxaliplatin 85-135 milligram/square metre single medication; 5-fluorouracil 500-1000mg/ day, intravenous drip or arteriovenous perfusion; 5-fluorouracil 200-300mg/ day, oral.The bibliographical information of clinical antitumor dosage of the relevant wild-scutellaglucone of Shang Weijian and suitable route of administration thereof.The accurate consumption of any composition can wait to determine according to the effectiveness of compound used therefor, patient's age, body weight, health and patient's sensitivity in the clinical practice use in the employed compositions.Those of ordinary skill in the art also should know how to pass through the ordinary skill in the art, according to molar concentration rate disclosed by the invention, wild-scutellaglucone and cisplatin, oxaliplatin or 5-fluorouracil are mixed, prepare the synergistic pharmaceutical combination with oncotherapy effect 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.
The synergism that embodiment 1 wild-scutellaglucone combination with cisplatin (CDDP) suppresses in the human tumor cell line growth in vitro
With all kinds of human tumor cell line cell suspensions in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add wild-scutellaglucone (Kunming Fengshanjian Medicine Research Co., Ltd.), and add in the culture fluid than mixing with variable concentrations with cisplatin (Sigma company product).Cultivate and make MTT mensuration after 72 hours.The suppression ratio of on cell proliferation carries out data analysis with CalcuSyn statistical software and drug combination exponential quantity (CI) method during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling wild-scutellaglucone and cisplatin.When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 1-5
All kinds of human tumor cell lines are:
Human hepatoma cell strain HepG2 table 1
Human lung carcinoma cell line A549 table 2
Human stomach cancer cell line MKN28 table 3
Human large intestine cancer cell strain HCT116 table 4
People's esophageal cancer cell strain TE2 table 5
HepG2 cell increment suppression ratio when independent medication of table 1 wild-scutellaglucone and combination with cisplatin medication, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 0.1±2.1 | ||
| Wild yellow unit 5 | 5.2±3 | ||
| Wild yellow unit 10 | 35.1±2.5 | ||
| Wild yellow unit 20 | 50.5±3 | ||
| Wild yellow unit 40 | 62.362±2.1 | ||
| Pt1 | 11.1±2 | ||
| Pt2 | 37.64±2.7 | ||
| Pt4 | 45.05±2.5 | ||
| Pt8 | 62.362±3 | ||
| The wild yellow unit 2.5 of Pt1+ | 22.8±2.2 | 0.79 | |
| The wild yellow unit 5 of Pt2+ | 28±2 | 1.3 | |
| The wild yellow unit 10 of Pt4+ | 50±2 | 1.3 | |
| The wild yellow unit 20 of Pt8+ | 90±3.2 | 0.65 | |
| The wild yellow unit 5 of Pt1+ | 33±2 | 0.7 | |
| The wild yellow unit 10 of Pt2+ | 48.83±3.1 | 0.92 | |
| The wild yellow unit 20 of Pt4+ | 78.72±3.5 | 0.835 | |
| The wild yellow unit 40 of Pt8+ | 95±3 | 0.722 | |
| The wild yellow unit 10 of Pt1+ | 45.88±3.5 | 0.742 | |
| The wild yellow unit 20 of Pt2+ | 71.22±2 | 0.847 | |
| The wild yellow unit 40 of Pt4+ | 95±3 | 0.653 |
A549 cell increment suppression ratio when independent medication of table 2 wild-scutellaglucone and combination with cisplatin medication, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 0.1±2 | ||
| Wild yellow unit 5 | 0.7±2 | ||
| Wild yellow unit 10 | 2.2±1 | ||
| Wild yellow unit 20 | 43.5±3 | ||
| Wild yellow unit 40 | 95.3±3 | ||
| Pt1 | 5.5±2 | ||
| Pt2 | 25.22±3.1 | ||
| Pt4 | 46±3.5 | ||
| Pt8 | 67.6±2.7 | ||
| The wild yellow unit 2.5 of Pt1+ | 8.4±3 | 1.1 | |
| The wild yellow unit 5 of Pt2+ | 35.44±2.2 | 0.9 | |
| The wild yellow unit 10 of Pt4+ | 73.5±2.8 | 0.83 | |
| The wild yellow unit 20 of Pt8+ | 93±4.1 | 0.83 | |
| The wild yellow unit 5 of Pt1+ | 5±3 | 1.7 | |
| The wild yellow unit 10 of Pt2+ | 38.11±2.2 | 1.1 | |
| The wild yellow unit 20 of Pt4+ | 74.3±3.5 | 1.1 | |
| The wild yellow unit 40 of Pt8+ | 97.71±2.5 | 0.85 | |
| The wild yellow unit 10 of Pt1+ | 22±2.7 | 1.1 | |
| The wild yellow unit 20 of Pt2+ | 60±3 | 1 | |
| The wild yellow unit 40 of Pt4+ | 95.45±2.5 | 0.957 |
MKN28 cell increment suppression ratio when independent medication of table 3 wild-scutellaglucone and combination with cisplatin medication, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 0.3±2 | ||
| Wild yellow unit 5 | 7.2±2 | ||
| Wild yellow unit 10 | 27.7±3.2 |
| Wild yellow unit 20 | 37.4±2.5 | ||
| Wild yellow unit 40 | 52.4±3.5 | ||
| Pt1 | 3.1±3.2 | ||
| Pt2 | 11.11±2.7 | ||
| Pt4 | 26±3 | ||
| Pt8 | 34.8±3.2 | ||
| Pt16 | 65.7±1.2 | ||
| The wild yellow unit 2.5 of Pt1+ | 1.2±2 | 3.1 | |
| The wild yellow unit 5 of Pt2+ | 22.1±2.2 | 0.83 | |
| The wild yellow unit 10 of Pt4+ | 63.4±2 | 0.55 | |
| The wild yellow unit 20 of Pt8+ | 82.5±3.2 | 0.6 | |
| The wild yellow unit 5 of Pt1+ | 26.1±3.5 | 0.517 | |
| The wild yellow unit 10 of Pt2+ | 45.5±3 | 0.635 | |
| The wild yellow unit 20 of Pt4+ | 68.5±2 | 0.7345 | |
| The wild yellow unit 40 of Pt8+ | 86.04±2 | 0.818 | |
| The wild yellow unit 10 of Pt1+ | 34.5±3 | 0.67 | |
| The wild yellow unit 20 of Pt2+ | 55.5±2.5 | 0.85 | |
| The wild yellow unit 40 of Pt4+ | 86±2.2 | 0.71 | |
| The wild yellow unit 80 of Pt8+ | 95±2.5 | 0.785 |
HCT116 cell increment suppression ratio when independent medication of table 4 wild-scutellaglucone and combination with cisplatin medication, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 0.1±2 | ||
| Wild yellow unit 5 | 11±1.9 | ||
| Wild yellow unit 10 | 14.23±3 | ||
| Wild yellow unit 20 | 64.01±3.2 | ||
| Wild yellow unit 40 | 81.5±3.2 | ||
| Pt1 | 16.5±3.5 |
| Pt2 | 27.1±2.9 | ||
| Pt4 | 33±3.2 | ||
| Pt8 | 45.8±3.2 | ||
| Pt16 | 56.7±2.3 | ||
| The wild yellow unit 2.5 of Pt1+ | 12.4±2.5 | 2.1 | |
| The wild yellow unit 5 of Pt2+ | 37.83±3.2 | 0.746 | |
| The wild yellow unit 10 of Pt4+ | 65.15±2.5 | 0.575 | |
| The wild yellow unit 20 of Pt8+ | 95.2±2.9 | 0.28 | |
| The wild yellow unit 5 of Pt1+ | 23.8±2.2 | 1 | |
| The wild yellow unit 10 of Pt2+ | 43±2 | 0.92 | |
| The wild yellow unit 20 of Pt4+ | 86.13±2.2 | 0.49 | |
| The wild yellow unit 40 of Pt8+ | 98.43±2.5 | 0.318 | |
| The wild yellow unit 10 of Pt1+ | 36.72±3 | 0.923 | |
| The wild yellow unit 20 of Pt2+ | 70±2.8 | 0.79 | |
| The wild yellow unit 40 of Pt4+ | 98.12±2 | 0.346 |
TE2 cell increment suppression ratio when independent medication of table 5 wild-scutellaglucone and combination with cisplatin medication, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 2.3±2 | ||
| Wild yellow unit 5 | 13.4±2.5 | ||
| Wild yellow unit 10 | 47.2±4.3 | ||
| Wild yellow unit 20 | 65.4±2.2 | ||
| Wild yellow unit 40 | 74.01±2.9 | ||
| Pt1 | 28.03±3 | ||
| Pt2 | 29.3±2.7 | ||
| Pt4 | 45±3 | ||
| Pt8 | 57.8±3 | ||
| The wild yellow unit 2.5 of Pt1+ | 23.4±2.7 | 1.459 | |
| The wild yellow unit 5 of Pt2+ | 31.1±2.8 | 1.75 |
| The wild yellow unit 10 of Pt4+ | 57.3±3.2 | 0.99 | |
| The wild yellow unit 20 of Pt8+ | 83.6±2.5 | 0.6 | |
| The wild yellow unit 5 of Pt1+ | 47.5±2.5 | 0.545 | |
| The wild yellow unit 10 of Pt2+ | 63.61±3 | 0.6 | |
| The wild yellow unit 20 of Pt4+ | 76.2±3.2 | 0.765 | |
| The wild yellow unit 40 of Pt8+ | 89±2.9 | 0.815 | |
| The wild yellow unit 10 of Pt1+ | 62.3±2.7 | 0.555 | |
| The wild yellow unit 20 of Pt2+ | 75.13±3.5 | 0.73 | |
| The wild yellow unit 40 of Pt4+ | 85.5±3.5 | 0.956 | |
| The wild yellow unit 80 of Pt8+ | 95±2 | 0.95 |
Annotate: Ye Huangyuan=wild-scutellaglucone; Pt=cisplatin (CDDP)
Suppression ratio %; Mean value SD, n=3
When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Table 1-5 demonstrates at cisplatin with wild-scutellaglucone the molar concentration rate of the IC50 of each cell strain being about (1: 5), and be presented near this concentration ratio the zone (1: 2.5～1: 10) good drug combination index is all arranged, can show significantly that wild-scutellaglucone and cisplatin are to each human tumor cell line: human hepatoma cell strain HepG2, people's large intestine HCT116, human lung carcinoma cell line A549, human stomach cancer cell line MKN45, esophageal cancer cell strain TE2 has good drug combination effect.
Embodiment 2 wild-scutellaglucone combination with cisplatin (CDDP) are to the antitumor synergism of transplanted tumor
With the strain of B16 melanoma cell at In vitro culture after two generations, with 2 * 10
6Cell/only the be inoculated in female C57BL/6 of laboratory animal (body weight is about 20 grams) mice oxter is subcutaneous.Inoculate back second day random packet, and begin administration by the 0.1ml/10g body weight.Wild-scutellaglucone (Kunming Fengshanjian Medicine Research Co., Ltd.), and with cisplatin (Sigma company product) with independent medication, the test of different administering mode such as drug combination grouping carrying out antitumor.Every group laboratory animal is 10.Measure the weight of animals before the administration, test and took off neck execution behind the title the weight of animals on 15th, strip tumor block organization and weigh.The mensuration of tumour inhibiting rate is by computing formula; Tumour inhibiting rate=(1-treatment group tumor weight/blank group tumor is heavy) * 100% calculates the heavy suppression ratio of tumor and carries out statistics (t check) and handle.And calculate Q-value according to the Jin Shi formula.
Result of the test sees Table 6
Table 6 separately when medication and combination with cisplatin medication to transplanting the melanomatous animal test results of B16
| Grouping | Dosage mg/kg | The administration schedule | The rate of losing weight % | Heavy (g) the mean value SD of tumor | Tumour inhibiting rate % | Number of animals (only) beginning/end |
| Matched group | - | ＜0 | 2.525±0.15 | 10/10 | ||
| Cisplatin | 2 | 2-4，8-10 | ＜5 | 1.57±0.15 | 37.8 | 10/10 |
| Wild yellow unit | 5 | 2-4，8-10 | ＜5 | 2.39±0.118 | 5.3 | 10/10 |
| Wild yellow unit | 10 | 2-4，8-10 | ＜5 | 2.188±0.07 | 13.34 | 10/10 |
| Wild yellow unit | 20 | 2-4，8-10 | ＜5 | 2.11±0.127 | 16.4 | 10/10 |
| Cisplatin+Ye Huangyuan | 2+5 | 2-4，8-10 | ＜5 | 1.192±0.17 | 52.79 **## | 10/10 |
| Cisplatin+Ye Huangyuan | 2+10 | 2-4，8-10 | ＜5 | 1.115±0.19 | 55.8 **## | 10/10 |
| Cisplatin+Ye Huangyuan | 2+20 | 2-4，8-10 | ＜5 | 1.05±0.15 | 58.4 **## | 10/10 |
Wild yellow unit=wild-scutellaglucone
Administering mode: cisplatin; The abdominal cavity, wild-scutellaglucone; Intraperitoneal administration
*Compare P＜0.01 with single with the cisplatin group
The ##Q value shows synergism
Visible wild-scutellaglucone of result of the test and cisplatin have embodied tangible antitumor potentiation when share.Cisplatin+wild-scutellaglucone 5mg/kg, cisplatin+wild-scutellaglucone 10mg/kg, each group of cisplatin+wild-scutellaglucone 20mg/kg all has significant difference on the statistics with single comparing with the cisplatin group, and Q-value also demonstrates has synergism.Animal test results has been supported the result of in vitro tests significantly, and promptly cisplatin is to having good collaborative medication effect with wild-scutellaglucone, and near the zone 1: 2.5～1: 10 concentration ratio has apparent in view collaborative medication effect.
Change and can see from the weight of animals, each combination group is not seen has any toxicity to strengthen trend.
Comprehensive animal experiment as seen; Wild-scutellaglucone and cisplatin have good synergistic antitumor effect.
The synergism that embodiment 3 wild-scutellaglucones associating 5-fluorouracil (5-FU) suppress in the human tumor cell line growth in vitro
All kinds of human tumor cell line cell suspensions in the cell culture fluid that contains 10% (little) fetal bovine serum, are seeded in 96 porocyte culture plates with 5 * 103/ holes.After cultivating 24 hours, add wild-scutellaglucone (Kunming Fengshanjian Medicine Research Co., Ltd.), and add in the culture fluid than mixing with variable concentrations with 5-Fu (Sigma company product).Cultivate and make MTT mensuration after 72 hours.The suppression ratio of on cell proliferation carries out data analysis with CalcuSyn statistical software and drug combination exponential quantity (CI) method during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling baicaligenin or baicalin and 5-fluorouracil.When CI＜1, be synergism, during CI=1, be summation action CI＞1 o'clock, be antagonism.
Cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 7-12
Each human tumor cell line is:
Human hepatoma cell strain HepG2 table 7
Human stomach cancer cell line MKN28 table 8
Human large intestine cancer cell strain HCT116 table 9
People's esophageal cancer cell strain TE2 table 10
HepG2 cell increment suppression ratio when independent medication of table 7 wild-scutellaglucone and the medication of associating 5-fluorouracil, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 5.5±2.5 | ||
| Wild yellow unit 5 | 7.5±3.2 | ||
| Wild yellow unit 10 | 25.±2.7 | ||
| Wild yellow unit 20 | 60±3.2 | ||
| Wild yellow unit 40 | 82.5±2.5 | ||
| 5-Fu2.5 | 12.8±2.2 | ||
| 5-Fu5 | 30.2±2.8 | ||
| 5-Fu10 | 52.1±2.7 | ||
| 5-Fu20 | 70.61±2.5 | ||
| 5-Fu40 | 82.5±2.5 | ||
| 5-Fu2.5+ wild yellow unit 2.5 | 56.4±2.3 | 0.322 | |
| The wild yellow unit 5 of 5-Fu5+ | 60.4±3 | 0.571 | |
| The wild yellow unit 10 of 5-Fu10+ | 79±2 | 0.6 | |
| The wild yellow unit 20 of 5-Fu20+ | 92±3 | 0.548 | |
| 5-Fu2.5+ wild yellow unit 5 | 51.1±2.8 | 0.518 | |
| The wild yellow unit 10 of 5-Fu5+ | 66.832±2.1 | 0.66 | |
| The wild yellow unit 20 of 5-Fu10+ | 82±3 | 0.76 |
| The wild yellow unit 40 of 5-Fu20+ | 91±2.5 | 0.9 | |
| The wild yellow unit 2.5 of 5-Fu5+ | 61±2.5 | 0.45 | |
| The wild yellow unit 5 of 5-Fu10+ | 75.2.±2.2 | 0.55 | |
| The wild yellow unit 10 of 5-Fu20+ | 87±3 | 0.61 | |
| The wild yellow unit 20 of 5-Fu40+ | 95±3.2 | 0.57 |
MKN28 cell increment suppression ratio when independent medication of table 8 wild-scutellaglucone and the medication of associating 5-fluorouracil, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 11.9±1.8 | ||
| Wild yellow unit 5 | 27.6±2 | ||
| Wild yellow unit 10 | 47.1±3 | ||
| Wild yellow unit 20 | 68±2 | ||
| Wild yellow unit 40 | 89.5±3.5 | ||
| 5-Fu2.5 | 21.8±3 | ||
| 5-Fu5 | 37.8±2.2 | ||
| 5-Fu10 | 52.8±3.2 | ||
| 5-Fu20 | 68.3±3.5 | ||
| 5-Fu40 | 79.1±2.8 | ||
| 5-Fu2.5+ wild yellow unit 2.5 | 34.7±2 | 0.919 | |
| The wild yellow unit 5 of 5-Fu5+ | 55.5±2.7 | 0.8512 | |
| The wild yellow unit 10 of 5-Fu10+ | 75±3 | 0.79 | |
| The wild yellow unit 20 of 5-Fu20+ | 85.52±3.5 | 0.8986 | |
| 5-Fu2.5+ wild yellow unit 5 | 52.5±3.5 | 0.7 | |
| The wild yellow unit 10 of 5-Fu5+ | 66.1±2,3 | 0.88 | |
| The wild yellow unit 20 of 5-Fu10+ | 80.03±2 | 0.99 | |
| The wild yellow unit 40 of 5-Fu20+ | 91.8±2.5 | 0.898 | |
| The wild yellow unit 2.5 of 5-Fu5+ | 66.67±3.2 | 0.41 | |
| The wild yellow unit 5 of 5-Fu10+ | 78.33±2.9 | 0.4777 |
| The wild yellow unit 10 of 5-Fu20+ | 85.7±2.1 | 0.6 | |
| The wild yellow unit 20 of 5-Fu40+ | 95±2 | 0.442 |
HCT116 cell increment suppression ratio when independent medication of table 9 wild-scutellaglucone and the medication of associating 5-fluorouracil, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 3.7±2.1 | ||
| Wild yellow unit 5 | 24.1±2.9 | ||
| Wild yellow unit 10 | 63.8±3.2 | ||
| Wild yellow unit 20 | 91±2 | ||
| Wild yellow unit 40 | 98±1 | ||
| 5-Fu2.5 | 1.28±1.5 | ||
| 5-Fu5 | 35.1±2.2 | ||
| 5-Fu10 | 55.1±3 | ||
| 5-Fu20 | 66.1±3.2 | ||
| 5-Fu40 | 70.3±2.2 | ||
| 5-Fu2.5+ wild yellow unit 2.5 | 55.8±2.1 | 0.42 | |
| The wild yellow unit 5 of 5-Fu5+ | 67.1±3 | 0.68 | |
| The wild yellow unit 10 of 5-Fu10+ | 73.8±2 | 1.17 | |
| The wild yellow unit 20 of 5-Fu20+ | 98±2.7 | 0.66 | |
| 5-Fu2.5+ wild yellow unit 5 | 60.5±2.2 | 0.64 | |
| The wild yellow unit 10 of 5-Fu5+ | 73.3±2 | 0.99 | |
| The wild yellow unit 20 of 5-Fu10+ | 93.1±2.2 | 1 | |
| The wild yellow unit 40 of 5-Fu20+ | 98.9±2.2 | 0.926 | |
| The wild yellow unit 2.5 of 5-Fu5+ | 67.6±3 | 0.446 | |
| The wild yellow unit 5 of 5-Fu10+ | 80±2.8 | 0.65 | |
| The wild yellow unit 10 of 5-Fu20+ | 93±2 | 0.73 | |
| The wild yellow unit 20 of 5-Fu40+ | 98±3 | 0.8 |
TE2 cell increment suppression ratio when independent medication of table 10 wild-scutellaglucone and the medication of associating 5-fluorouracil, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Wild yellow unit 2.5 | 1±2 | ||
| Wild yellow unit 5 | 18.05±2.5 | ||
| Wild yellow unit 10 | 58.72±3.3 | ||
| Wild yellow unit 20 | 82±2 | ||
| Wild yellow unit 40 | 90±2 | ||
| 5-Fu2.5 | 1±1.5 | ||
| 5-Fu5 | 12.5±2.5 | ||
| 5-Fu10 | 31.75±3.3 | ||
| 5-Fu20 | 58±3.2 | ||
| 5-Fu2.5+ wild yellow unit 2.5 | 2.45±2.5 | 1.8 | |
| The wild yellow unit 5 of 5-Fu5+ | 62.42±3 | 0.599 | |
| The wild yellow unit 10 of 5-Fu10+ | 82.77±2.3 | 0.77 | |
| The wild yellow unit 20 of 5-Fu20+ | 95.1±2.7 | 0.85 | |
| 5-Fu2.5+ wild yellow unit 5 | 15.875±3.2 | 1.1 | |
| The wild yellow unit 10 of 5-Fu5+ | 69.42±2.5 | 0.8 | |
| The wild yellow unit 20 of 5-Fu10+ | 90.1±2.2 | 0.92 | |
| The wild yellow unit 40 of 5-Fu20+ | 97±3.2 | 1 | |
| The wild yellow unit 2.5 of 5-Fu5+ | 28±3 | 0.812 | |
| The wild yellow unit 5 of 5-Fu10+ | 82.2±2.8 | 0.56 | |
| The wild yellow unit 10 of 5-Fu20+ | 92.2±2 | 0.75 | |
| The wild yellow unit 20 of 5-Fu40+ | 98±3 | 0.82 |
Annotate: Ye Huangyuan=wild-scutellaglucone; The 5-Fu=5-fluorouracil
Suppression ratio %; Mean value SD, n=3
When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Table 7-10 demonstrates at wild-scutellaglucone and 5Fu and is about (1: 1) at the molar concentration rate to the IC50 of each cell strain, and be presented near this concentration ratio the zone (2: 1～1: 2) good drug combination index is all arranged, can show significantly that wild-scutellaglucone and 5Fu are to each human tumor cell line: human hepatoma cell strain HepG2, people's large intestine HCT116, human stomach cancer cell line MKN45, people's esophageal cancer cell strain TE2 has good drug combination effect.
Embodiment 4 wild-scutellaglucones associating 5-fluorouracil (5-FU) are at the antitumor synergism to transplanted tumor
The strain of B16 melanoma cell is at In vitro culture after two generations, subcutaneous with 2 * 106 cells/only the be inoculated in female C57BL/6 of laboratory animal (body weight is about 20 grams) mice armpit.Inoculate back second day random packet, and begin administration by the 0.1ml/10g body weight.Wild-scutellaglucone (Kunming Fengshanjian Medicine Research Co., Ltd.), with 5-fluorouracil (the general Pharma Inc. in the rising sun East Sea, Shanghai product) with independent medication, the test of different administering mode such as drug combination grouping carrying out antitumor.Every group laboratory animal is 10.Measure the weight of animals before the administration, test and took off neck execution behind the title the weight of animals on 15th, strip tumor block organization and weigh.The mensuration of tumour inhibiting rate is by computing formula; Tumour inhibiting rate=(1-treatment group tumor weight/blank group tumor is heavy) * 100% calculates the heavy suppression ratio of tumor and carries out statistics (t check) and handle.And calculate Q-value according to the Jin Shi formula.
Result of the test sees Table 11
Table 11 separately when medication and the medication of associating 5-fluorouracil to transplanting the melanomatous animal test results of B16
| Grouping | Dosage mg/kg | The administration schedule | The rate of losing weight % | Heavy (g) the mean value SD of tumor, | Tumour inhibiting rate % | Number of animals (only) beginning/end |
| Matched group | - | ＜0 | 2.525±0.15 | 10/10 | ||
| 5Fu | 10 | Subcutaneous 1-10 | ＜5 | 1.55±0.16 | 38.6 | 10/10 |
| Wild yellow unit | 2.5 | Abdominal cavity 1-10 | ＜5 | 2.45±0.147 | 3 | 10/10 |
| Wild yellow unit | 5 | Abdominal cavity 1-10 | ＜5 | 2.38±0.10 | 5.7 | 10/10 |
| Wild yellow unit | 10 | Abdominal cavity 1-10 | ＜5 | 2.22±0.10 | 12.08 | 10/10 |
| The wild yellow unit of 5Fu+ | 10+2.5 | 1-10 | ＜5 | 1.352±0.09 | 46.45 **## | 10/10 |
| The wild yellow unit of 5Fu+ | 10+5 | 1-10 | ＜5 | 1.21±0.10 | 52 **## | 10/10 |
| The wild yellow unit of 5Fu+ | 10+10 | 1-10 | ＜5 | 0.82±0.10 | 67.5 **## | 10/10 |
Wild yellow unit=wild-scutellaglucone; The 5Fu=5-fluorouracil
Administering mode: 5-fluorouracil; Subcutaneous administration, wild-scutellaglucone; Intraperitoneal administration
*Compare P＜0.01 with single with the 5-fluorouracil group
The ##Q value shows synergism
Visible wild-scutellaglucone of result of the test and 5-fluorouracil have embodied tangible antitumor potentiation when share.5-fluorouracil+wild-scutellaglucone 2.5mg/kg, 5-fluorouracil+wild-scutellaglucone 5mg/kg, each group of cisplatin+wild-scutellaglucone 10mg/kg all has significant difference on the statistics with single comparing with the 5-fluorouracil group, and Q-value also demonstrates has synergism.Animal test results has been supported the result of in vitro tests significantly, and promptly 5-fluorouracil is to having good synergistic antitumor effect with wild-scutellaglucone, and near the zone 1: 2～2: 1 concentration ratios has apparent in view collaborative medication effect.
Change and can see from the weight of animals, each combination group is not seen has any toxicity to strengthen trend.
Comprehensive animal experiment as seen; Wild-scutellaglucone and 5-fluorouracil have good synergistic antitumor effect.
The synergism of embodiment 5 wild-scutellaglucones associating oxaliplatin on tumor cell line
With various human cancer cell strain cell suspensions in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add wild-scutellaglucone (Kunming Fengshanjian Medicine Research Co., Ltd.), and add in the culture fluid than mixing with variable concentrations with oxaliplatin (Sigma company product).Cultivate and make MTT mensuration after 72 hours.The suppression ratio of on cell proliferation carries out data analysis with CalcuSyn statistical software and drug combination exponential quantity (CI) method during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling wild-scutellaglucone and oxaliplatin.When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Each human tumor cell line is:
Human hepatoma cell strain HepG2 table 12
People's large intestine HCT116 table 13
Human lung carcinoma cell line A549 table 14
Human stomach cancer cell line MKN45 table 15
Cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 12-15
HepG2 cell increment suppression ratio when independent medication of table 12 wild-scutellaglucone and the medication of associating oxaliplatin, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination index CI |
| Wild yellow unit 2.5 | 1±3 | ||
| Wild yellow unit 5 | 5.5±3 | ||
| Wild yellow unit 10 | 32.7±3.2 | ||
| Wild yellow unit 20 | 51.2±5.2 |
| Oxaliplatin 1 | 25.2±3.5 | ||
| Oxaliplatin 2 | 37.8±4.5 | ||
| Oxaliplatin 4 | 55.8±3.9 | ||
| Oxaliplatin 8 | 63.5±4.7 | ||
| Wild yellow first 0.5+ platinum 2.5 difficult to understand | 15±3 | 1.47 | |
| Wild yellow first 1+ platinum 5 difficult to understand | 27±4.2 | 1.388 | |
| Wild yellow first 2+ platinum 10 difficult to understand | 55±5.2 | 0.97 | |
| Wild yellow first 4+ platinum 20 difficult to understand | 92±5.2 | 0.4657 | |
| Wild yellow first 1+ platinum 10 difficult to understand | 43.1±3.2 | 1 | |
| Wild yellow first 2+ platinum 20 difficult to understand | 72.2±3.9 | 0.95 | |
| Wild yellow first 4+ platinum 40 difficult to understand | 95.8±3 | 0.63 | |
| Wild yellow first 0.5+ platinum 7.5 difficult to understand | 25.2±3 | 1.22 | |
| Wild yellow first 1+ platinum 15 difficult to understand | 57.7±3.2 | 0.96 | |
| Wild yellow first 2+ platinum 30 difficult to understand | 92.2±3 | 0.635 |
HCT116 cell increment suppression ratio when independent medication of table 13 wild-scutellaglucone and the medication of associating oxaliplatin, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination index CI |
| Wild yellow unit 2.5 | 1±5.5 | ||
| Wild yellow unit 5 | 12±6.5 | ||
| Wild yellow unit 10 | 22.5±3.2 | ||
| Wild yellow unit 20 | 65.1±5.2 | ||
| Wild yellow unit 40 | 82±7 | ||
| Oxaliplatin 1 | 21±5.7 | ||
| Oxaliplatin 2 | 42.81±3.8 | ||
| Oxaliplatin 4 | 58.2±5.5 | ||
| Oxaliplatin 8 | 65.2±6.2 | ||
| Wild yellow first 0.5+ platinum 2.5 difficult to understand | 12±5.5 | 1.62 |
| Wild yellow first 1+ platinum 5 difficult to understand | 32±6.7 | 1 | |
| Wild yellow first 2+ platinum 10 difficult to understand | 59±5.7 | 0.9 | |
| Wild yellow first 4+ platinum 20 difficult to understand | 88.9±6 | 0.57 | |
| Wild yellow first 0.5+ platinum 5 difficult to understand | 17±5.5 | 1.4 | |
| Wild yellow first 1+ platinum 10 difficult to understand | 43.9±6.1 | 1 | |
| Wild yellow first 2+ platinum 20 difficult to understand | 75.2±5.2 | 0.78 | |
| Wild yellow first 4+ platinum 40 difficult to understand | 95±3.7 | 0.6 | |
| Wild yellow first 0.5+ platinum 7.5 difficult to understand | 45±5.3 | 0.67 | |
| Wild yellow first 1+ platinum 15 difficult to understand | 71±6.2 | 0.69 | |
| Wild yellow first 2+ platinum 30 difficult to understand | 95±6 | 0.47 |
A549 cell increment suppression ratio when independent medication of table 14 wild-scutellaglucone and the medication of associating oxaliplatin, and drug combination index
| Single-dose thing activity | The combination medicine activity | Inhibitory rate of cell growth (%) | Drug combination index CI |
| Wild yellow unit 2.5 | 1±5.1 | ||
| Wild yellow unit 5 | 5.8±4.2 | ||
| Wild yellow unit 10 | 15±5.2 | ||
| Wild yellow unit 20 | 55.18±5 | ||
| Wild yellow unit 40 | 81±6 | ||
| Oxaliplatin 1 | 29±5.7 | ||
| Oxaliplatin 2 | 41±3.9 | ||
| Oxaliplatin 4 | 52.2±4.2 | ||
| Oxaliplatin 8 | 62.3±6.2 | ||
| Wild yellow first 0.5+ platinum 2.5 difficult to understand | 12.2±5.5 | 2.87 | |
| Wild yellow first 1+ platinum 5 difficult to understand | 31.5±5.7 | 1.2 | |
| Wild yellow first 2+ platinum 10 difficult to understand | 59.8±6.6 | 0.7 | |
| Wild yellow first 4+ platinum 20 difficult to understand | 87±5.9 | 0.5 | |
| Wild yellow first 0.5+ platinum 5 difficult to understand | 15.9±5.8 | 2.2 |
| Wild yellow first 1+ platinum 10 difficult to understand | 42±5.2 | 1 | |
| Wild yellow first 2+ platinum 20 difficult to understand | 75.8±5.2 | 0.7 | |
| Wild yellow first 4+ platinum 40 difficult to understand | 95.29±2.1 | 0.5 | |
| Wild yellow first 0.5+ platinum 7.5 difficult to understand | 47±7.2 | 0.9 | |
| Wild yellow first 1+ platinum 15 difficult to understand | 72±7.2 | 0.6 | |
| Wild yellow first 2+ platinum 30 difficult to understand | 92.8±2 | 0.5 |
MKN45 cell increment suppression ratio when independent medication of table 15 wild-scutellaglucone and associating sand difficult to understand utilize medicine, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination index CI |
| Wild yellow unit 2.5 | 1±6 | ||
| Wild yellow unit 5 | 18.2±5.5 | ||
| Wild yellow unit 10 | 57.8±6.2 | ||
| Wild yellow unit 20 | 90±7 | ||
| Oxaliplatin 1 | 30.2±5.7 | ||
| Oxaliplatin 2 | 42±5.5 | ||
| Oxaliplatin 4 | 48±7.5 | ||
| Oxaliplatin 8 | 59±7 | ||
| Wild yellow first 0.5+ platinum 2.5 difficult to understand | 17.9±6 | 2.2 | |
| Wild yellow first 1+ platinum 5 difficult to understand | 32.5±3 | 1.45 | |
| Wild yellow first 2+ platinum 10 difficult to understand | 63±7 | 0.8 | |
| Wild yellow first 4+ platinum 20 difficult to understand | 88±6 | 0.7 | |
| Wild yellow first 0.5+ platinum 5 difficult to understand | 19.7±5 | 2.2 | |
| Wild yellow first 1+ platinum 10 difficult to understand | 49.7±5.2 | 1 | |
| Wild yellow first 2+ platinum 20 difficult to understand | 82±6.2 | 0.88 | |
| Wild yellow first 4+ platinum 40 difficult to understand | 95.9±7 | 0.88 | |
| Wild yellow first 0.5+ platinum 7.5 difficult to understand | 42.8±3.5 | 0.9 | |
| Wild yellow first 1+ platinum 15 difficult to understand | 72±7.2 | 0.8 |
| Wild yellow first 2+ platinum 30 difficult to understand | 92.5±5 | 0.8 |
Wild yellow unit=wild-scutellaglucone (μ m)
Platinum=oxaliplatin (μ m) difficult to understand
The % suppression ratio; Mean value SD, n=3
When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Table 12-15 demonstrates at oxaliplatin and wild-scutellaglucone at the molar concentration rate (1: 10) to the IC50 of each cell strain, and near the zone (1: 5～1: 15) this concentration ratio good drug combination index is arranged all, can show significantly that baicaligenin and oxaliplatin all have good drug combination effect to human hepatoma cell strain HepG2, people's large intestine HCT116, human lung carcinoma cell line A549, human stomach cancer cell line MKN45.
Embodiment 6 wild-scutellaglucones associating oxaliplatin is to the antitumor synergism of transplanted tumor
The strain of B16 melanoma cell is at In vitro culture after two generations, subcutaneous with 2 * 106 cells/only the be inoculated in female C57BL/6 of laboratory animal (body weight is about 20 grams) mice oxter.Inoculate back second day random packet, and begin administration by the 0.1ml/10g body weight.Wild-scutellaglucone (Kunming Fengshanjian Medicine Research Co., Ltd.), and with oxaliplatin (Sigma company product) with independent medication, the test of different administering mode such as drug combination grouping carrying out antitumor.Every group laboratory animal is 10.Measure the weight of animals before the administration, test and took off neck execution behind the title the weight of animals on 15th, strip tumor block organization and weigh.The mensuration of tumour inhibiting rate is by computing formula; Tumour inhibiting rate=(1-treatment group tumor weight/blank group tumor is heavy) * 100% calculates the heavy suppression ratio of tumor and carries out statistics (t check) and handle.And calculate Q-value according to the Jin Shi formula.
Result of the test sees Table 16
Table 16 separately when medication and the medication of associating oxaliplatin to transplanting the melanomatous animal test results of B16
| Grouping | Dosage mg/kg | The administration schedule | The rate of losing weight % | Heavy (g) the mean value SD of tumor | Tumour inhibiting rate % | Number of animals (only) beginning/end |
| Matched group | - | ＜0 | 2.525±0.15 | 10/10 | ||
| Platinum difficult to understand | 2 | 2-4，8-10 | ＜5 | 1.62±0.125 | 35.8 | 10/10 |
| Wild yellow unit | 5 | 2-4，8-10 | ＜5 | 2.39±0.118 | 5.3 | 10/10 |
| Wild yellow unit | 10 | 2-4，8-10 | ＜5 | 2.188±0.07 | 13.34 | 10/10 |
| Wild yellow unit | 20 | 2-4，8-10 | ＜5 | 2.11±0.127 | 16.4 | 10/10 |
| Platinum+Ye Huangyuan difficult to understand | 2+10 | 2-4，8-10 | ＜5 | 1.22±0.108 | 51.6 ** | 10/10 |
| Platinum+Ye Huangyuan difficult to understand | 2+20 | 2-4，8-10 | ＜5 | 1.125±0.12 | 55 ** | 10/10 |
| Platinum+Ye Huangyuan difficult to understand | 2+30 | 2-4，8-10 | ＜5 | 1.052±0.125 | 58 ** | 10/10 |
Platinum=oxaliplatin difficult to understand, Ye Huangyuan=wild-scutellaglucone
Administering mode: oxaliplatin; The abdominal cavity, baicaligenin; Intraperitoneal administration
*Compare P＜0.01 with single with the cisplatin group
The ##Q value shows synergism
Visible wild-scutellaglucone of result of the test and oxaliplatin have embodied tangible antitumor potentiation when share.Oxaliplatin+wild-scutellaglucone 5mg/kg, oxaliplatin+wild-scutellaglucone 10mg/kg, each group of oxaliplatin+wild-scutellaglucone 20mg/kg all has significant difference on the statistics with single comparing with the oxaliplatin group, and Q-value also demonstrates has synergism.Animal test results has been supported the result of in vitro tests significantly, and promptly oxaliplatin is to having good collaborative medication effect with wild-scutellaglucone, and near the zone 1: 2.5～1: 10 concentration ratio has apparent in view collaborative medication effect.
Change and can see from the weight of animals, each combination group is not seen has any toxicity to strengthen trend.
Comprehensive animal experiment as seen; Wild-scutellaglucone and oxaliplatin have good synergistic antitumor effect.
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 before not departing from spirit of the present invention to put that those skilled in the art can carry out equivalents and modification to it.Their scope is also included within the appended claim.
Claims (21)
1. wild-scutellaglucone is a kind of medication combined with the purposes in the medicine of treatment tumor with platinum-based chemotherapy in preparation.
2. the purposes of claim 1, wherein said platinum-based chemotherapy medicine is selected from cisplatin and oxaliplatin.
3. the purposes of claim 2, wherein when described platinum-based chemotherapy medicine was cisplatin, described tumor was selected from melanoma, hepatocarcinoma, colorectal cancer, pulmonary carcinoma, gastric cancer, esophageal carcinoma and other solid tumors.
4. the purposes of claim 2, wherein when described platinum-based chemotherapy medicine was oxaliplatin, described tumor was selected from melanoma, hepatocarcinoma, colorectal cancer, pulmonary carcinoma, gastric cancer and other solid tumors.
5. a synergistic pharmaceutical combination for the treatment of tumor comprises wild-scutellaglucone and a kind of platinum-based chemotherapy medicine.
6. the synergistic pharmaceutical combination of claim 5, wherein said platinum-based chemotherapy medicine is selected from cisplatin and oxaliplatin.
7. the synergistic pharmaceutical combination of claim 6, wherein when described platinum-based chemotherapy medicine was cisplatin, the molar concentration rate of described cisplatin and wild-scutellaglucone was 1: 2.5 to 1: 10.
8. the synergistic pharmaceutical combination of claim 7, wherein said tumor is a solid tumor.
9. the synergistic pharmaceutical combination of claim 7, wherein said tumor is a melanoma.
10. the synergistic pharmaceutical combination of claim 6, wherein when described platinum-based chemotherapy medicine was oxaliplatin, the molar concentration rate of described oxaliplatin and wild-scutellaglucone was 1: 2.5 to 1: 10.
11. the synergistic pharmaceutical combination of claim 10, wherein said tumor are solid tumor.
12. the synergistic pharmaceutical combination of claim 10, wherein said tumor are melanoma.
13. the preparation method of arbitrary synergistic pharmaceutical combination of claim 5～12, this method comprise a kind of platinum-like compounds is mixed with the wild-scutellaglucone of claim 1.
14. the method for claim 13, wherein said platinum-like compounds is selected from cisplatin and oxaliplatin.
15. wild-scutellaglucone is united with the purposes in the medicine of treatment tumor at preparation a kind of and 5-fluorouracil.
16. the purposes of claim 15, wherein said tumor are selected from melanoma, hepatocarcinoma, colorectal cancer, gastric cancer, esophageal cancer cell and other solid tumors.
17. a synergistic pharmaceutical combination for the treatment of tumor comprises wild-scutellaglucone and 5-fluorouracil.
18. the synergistic pharmaceutical combination of claim 17, the molar concentration rate of wherein said 5-fluorouracil and wild-scutellaglucone are 1: 2 to 2: 1.
19. the synergistic pharmaceutical combination of claim 18, wherein said tumor are solid tumor.
20. the synergistic pharmaceutical combination of claim 18, wherein said tumor are melanoma.
21. the preparation method of arbitrary synergistic pharmaceutical combination of claim 17～20, this method comprise 5-fluorouracil is mixed with wild-scutellaglucone.
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| CN 200610074575 CN1872049A (en) | 2005-04-21 | 2006-04-20 | Combination of erigeron breviscapus and medication of chemotherapy in platinum class |
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| CN 200610074575 CN1872049A (en) | 2005-04-21 | 2006-04-20 | Combination of erigeron breviscapus and medication of chemotherapy in platinum class |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309493A (en) * | 2010-07-11 | 2012-01-11 | 山东新时代药业有限公司 | Anti-cancer medicinal composition |
| CN103494838A (en) * | 2013-09-30 | 2014-01-08 | 武汉大学 | Chemotherapy medicine composition |
| WO2021170001A1 (en) * | 2020-02-25 | 2021-09-02 | 华东理工大学 | Oxaliplatin-flavonoid drug eutectic crystal, preparation method therefor and use thereof |
-
2006
- 2006-04-20 CN CN 200610074575 patent/CN1872049A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309493A (en) * | 2010-07-11 | 2012-01-11 | 山东新时代药业有限公司 | Anti-cancer medicinal composition |
| CN102309493B (en) * | 2010-07-11 | 2013-05-29 | 山东新时代药业有限公司 | Anti-cancer medicinal composition |
| CN103494838A (en) * | 2013-09-30 | 2014-01-08 | 武汉大学 | Chemotherapy medicine composition |
| WO2021170001A1 (en) * | 2020-02-25 | 2021-09-02 | 华东理工大学 | Oxaliplatin-flavonoid drug eutectic crystal, preparation method therefor and use thereof |
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