CN101336915B - Medicine combination with antitumor activity - Google Patents
Medicine combination with antitumor activity Download PDFInfo
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- CN101336915B CN101336915B CN2008100127562A CN200810012756A CN101336915B CN 101336915 B CN101336915 B CN 101336915B CN 2008100127562 A CN2008100127562 A CN 2008100127562A CN 200810012756 A CN200810012756 A CN 200810012756A CN 101336915 B CN101336915 B CN 101336915B
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Abstract
The invention relates to a pharmaceutical composition, particularly to a pharmaceutical composition with antitumor activity. The pharmaceutical composition with antitumor activity comprises 5,6-dimethylxanthenone-4-acetic acid (DMXAA) or an pharmaceutically acceptable salt or ester thereof and one drug component selected from glycopeptide antibiotics, actinomycins, mitomycins, glucoside antibiotics, Colchicum alkaloid, elemenes, aromatic enzyme inhibitors, LH-RH receptor antagonists, animal antitumor drugs and somatostatin analogues. The synergic composition has better antitumor activity. More specifically, the invention provides an application of the composition in treating tumors.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, particularly relate to a kind of chemical compound 5,6-diformazan xanthone-4-acetic acid (DMXAA) or its pharmaceutically acceptable salt or ester and be selected from any one synergistic combination in the medicine of glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent or somatostatin analogue, they have stronger anti-tumor activity.
Background technology
Growth of tumor relies on the formation of inside tumor blood vessel network, under the vascular endothelial cell growth factor of cancerous cell and associated macrophages release promotes, a large amount of new vesselses form, cancerous cell continues hypertrophy, and oxygen and glucose consume in a large number, and acidic metabolite is piled up, stimulate new vessels to form, neovascularity promotes the rapid expansion of cancer cell population again, moves in circles, and tumor constantly enlarges.Therefore, stoping the formation and the function of blood vessel will be the important channel of oncotherapy.
Angiogenesis inhibitor is that angiogenesis can be destroyed or suppress to a class, stops the medicine of tumor growth and transfer effectively, is a novel targets of present antineoplastic target treatment research, and it opens up a new way for tumor treatment.Be to find out difference between tumor vessel and the normal structure internal blood vessel with tumor vessel as the success or failure key of targeting.Available data shows, compares with the normal structure blood vessel, and the tumor vascular endothelial cell hypertrophy is rapid, and new vessels is many; Responsive more to low-oxygen environment and acidic metabolite.Because close mutually with cancerous cell, cancerous cell may change the characteristic of its vascular endothelial cell again, thereby preparation is that the chemistry and the biological preparation of special target of attack becomes possibility with tumor vessel.
DMXAA is as a kind of novel angiogenesis inhibitor, can inducing tumor cell and the generation of immune factors such as the inner activated macrophage release tumor necrosis factor (TNF-α) of host cell, interferon.After the content of immune factors such as TNF-α and interferon reaches certain level. direct kill cancer cell, suppress propagation, the migration of people's epidermis capillary endothelium and people's capillary endothelial cell, can also cause vascular endothelial cell damage, produce courage and uprightness and coagulation necrosis, make the tumor tissues central necrosis, thereby reach the purpose of oncotherapy.
5,6-dimethyl xanthone-4-acetic acid (DMXAA) is expressed from the next:
Finished at present the I clinical trial phase of DMXAA chemical compound.It is remarkable that clinical trial shows that it irreversibly suppresses the tumor blood flow effect under the human body tolerable dose.As one of first anti-angiogenic medicine, its anti-angiogenic active tumor blood flow effect that suppresses for a long time that produces causes hemorrhagic necrosis zone widely.But, there are some researches show by the fast rapid regeneration of survivaling cell in the abundant dabbling periphery to go out tumor that obviously DMXAA unlikely has the clinical application as single agents or medicine.Therefore, it is even more important to seek the applied in any combination of DMXAA and other antitumor drug.
Summary of the invention
The present invention is exactly in order to solve the problems of the technologies described above, and a kind of pharmaceutical composition with anti-tumor activity is provided, and purpose is to strengthen the DMXAA anti-tumor activity.
The present invention realizes so in order to achieve the above object.
One aspect of the present invention provides a kind of combined method with pharmaceutical composition of anti-tumor activity, described method comprises the mammal to this treatment of needs, comprise the people simultaneously or sequentially the DMXAA that uses effective dose or any one medicine in the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue of its pharmaceutically acceptable salt or ester and effective dose.
On the other hand, the invention provides a kind of DMXAA or its pharmaceutically acceptable salt or ester be used to prepare with the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue simultaneously or sequentially administration with the application of the medicine of treatment cancer.
On the other hand, the invention provides a kind of medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue be used to prepare with DMXAA or its pharmaceutically acceptable salt or ester simultaneously or sequentially administration with the application of the medicine of treatment cancer.
On the other hand, the invention provides the combination that DMXAA or its pharmaceutically acceptable salt or ester are used to prepare and are selected from the medicine of glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue.
Preferred glycopeptide antibiotics is a Bleomycin A5.
Preferred D actinomycin D class is an actinomycin D.
Preferred mitomycin is an ametycin.
Preferred glucosides antibiotic is a mithramycin.
Preferred Colchicum alkaloid is a colchicine.
Preferred Elemene vinyl is an elemene.
Preferred arimedex is a letrozole.
Preferred LH-RH receptor antagonist is a leuprorelin.
Preferred animal class antineoplastic agent is a norcantharidin.
Preferred somatostatin analogue is a somatostatin.
Therefore, in the present invention, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue can be the medicine that for example is selected from Bleomycin A5, actinomycin D, ametycin, mithramycin, colchicine, elemene, letrozole, leuprorelin, norcantharidin, somatostatin.
In embodiments of the invention, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue can be the medicine that for example is selected from Bleomycin A5, actinomycin D, ametycin, mithramycin, colchicine, letrozole, leuprorelin, norcantharidin, somatostatin.
Advantage of the present invention and effect are as follows:
By a large amount of experiments, we find, order or side by side make up DMXAA or its pharmaceutically acceptable salt or ester and be selected from glycopeptide antibiotics, the D actinomycin D class, mitomycin, glucosides class antibiotic, the Colchicum alkaloid, Elemene vinyl, arimedex, the LH-RH receptor antagonist, animal class antineoplastic agent, in the medicine of somatostatin analogue any one, be preferably selected from Bleomycin A5, actinomycin D, ametycin, mithramycin, colchicine, elemene, letrozole, leuprorelin, in the medicine of norcantharidin or somatostatin any one realized the enhancing of DMXAA anti-tumor activity.
Further the present invention is described in detail below by embodiment and test data.
The specific embodiment
DMXAA or its pharmaceutically acceptable salt or ester and the medicine administration simultaneously or sequentially that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue.
Preferred DMXAA or its pharmaceutically acceptable salt or ester and be selected from the medicine of glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue any one and exist with the potentiation ratio.
Wherein " potentiation ratio " is used to represent DMXAA or its pharmaceutically acceptable salt or ester and is selected from glycopeptide antibiotics, the D actinomycin D class, mitomycin, glucosides class antibiotic, the Colchicum alkaloid, Elemene vinyl, arimedex, the LH-RH receptor antagonist, animal class antineoplastic agent, when the medicine of somatostatin analogue made up, the anti-tumor activity of combination was greater than independent DMXAA or the independent glycopeptide antibiotics that is selected from, the D actinomycin D class, mitomycin, glucosides class antibiotic, the Colchicum alkaloid, Elemene vinyl, arimedex, the LH-RH receptor antagonist, animal class antineoplastic agent, the anti-tumor activity of the medicine of somatostatin analogue.Therefore, if each component exists with the potentiation ratio, their combination generation synergism then.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and glycopeptide antibiotics such as Bleomycin A5 is 100: 1～1: 20 DMXAA: glycopeptide antibiotics, suitable potentiation ratio ranges is 25: 1～1: 10, and preferred proportion is 10: 1～1: 5.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and D actinomycin D class such as actinomycin D is 1000: 1～1: 1 DMXAA: the D actinomycin D class, suitable potentiation ratio ranges is 1000: 1～1: 1, and preferred proportion is 500: 1～1: 1.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and mitomycin such as ametycin is 200: 1～1: 1 DMXAA: mitomycin, and suitable potentiation ratio ranges is 100: 1～1: 1, preferred proportion is 50: 1～5: 1.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and glucosides class antibiotic such as mithramycin is 100: 1～1: 5 DMXAA: glucosides class antibiotic, suitable potentiation ratio ranges is 80: 1～1: 3, and preferred proportion is 50: 1～1: 1.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and Colchicum alkaloid such as colchicine is 20: 1～1: 10 DMXAA: the Colchicum alkaloid, suitable potentiation ratio ranges is 10: 1～1: 5, and preferred proportion is 5: 1～1: 2.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and Elemene vinyl such as elemene is 10: 1～1: 5 DMXAA: Elemene vinyl, and suitable potentiation ratio ranges is 5: 1～1: 3, preferred proportion is 3: 1～1: 2.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and arimedex such as letrozole is 20: 1～1: 10 DMXAA: arimedex, suitable potentiation ratio ranges is 10: 1～1: 5, and preferred proportion is 5: 1～1: 3.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and LH-RH receptor antagonist such as leuprorelin is 10: 1～1: 10 a DMXAA:LH-RH receptor antagonist, suitable potentiation ratio ranges is 5: 1～1: 3, and preferred proportion is 2: 1～1: 2.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and somatostatin analogue such as somatostatin is 200: 1～1: 1 DMXAA: somatostatin analogue, suitable potentiation ratio ranges is 100: 1～1: 1, and preferred proportion is 50: 1～5: 1.
The potentiation ratio ranges that can successfully suppress the DMXAA of tumor and animal class antineoplastic agent such as norcantharidin is 100: 1～1: 1 DMXAA: animal class antineoplastic agent, suitable potentiation ratio ranges is 50: 1～1: 1, and preferred proportion is 20: 1～2: 1.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is a Bleomycin A5.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is an actinomycin D.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is an ametycin.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is a mithramycin.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is a colchicine.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is an elemene.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is a letrozole.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is a leuprorelin.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is a somatostatin.
In one embodiment, the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue is a norcantharidin.
As anti-tumor agents required DMXAA or its pharmaceutically acceptable salt or ester and the number of combinations that is selected from the medicine of glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue, finally determine its variation according to state of an illness practical situation by the clinician.
DMXAA or its pharmaceutically acceptable salt or ester can any suitable form administrations with the medicine that is selected from glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue.DMXAA can be according to Journal of Medicinal Chemistry 34 (1): 217-22, and in January, 1991, described method was prepared.
Glycopeptide antibiotics, D actinomycin D class, mitomycin, glucosides class antibiotic, Colchicum alkaloid, Elemene vinyl, arimedex, LH-RH receptor antagonist, animal class antineoplastic agent, somatostatin analogue are known drug.
The present invention has comprised above-mentioned suitable and preferred all combinations.
To the present invention be described by following examples below, rather than be used for it is limited.
Embodiment 1The synergistic combination of DMXAA and Bleomycin A5
Material:
Cell strain: people's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell
The preparation of test medication: DMXAA faces the sodium bicarbonate dissolving with preceding usefulness 5%, and being made into the RPMI1640 culture fluid then needs concentration; Bleomycin A5 (PYM) faces uses preceding physiological saline solution, and being made into the RPMI1640 culture fluid then needs concentration.
Cell culture:
People's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell inoculation add an amount of RPMI1640 culture fluid in the aseptic culture bottle, in 37 ℃, 5%CO
2And cultivate in the incubator of saturated humidity.Cell is simple adherent growth, goes down to posterity 1 time in every 2-3 days.With 3g/L trypsinization 1min, make cell suspension when going down to posterity, concentration inoculation on demand with culture fluid piping and druming.
Method:
1, the collaborative people's lung cancer A549 cell that suppresses of DMXAA and Bleomycin A5 (PYM) drug combination
DMXAA and Bleomycin A5 (PYM) form with single medicine and drug combination is divided into: DMXAA organizes (50 μ g/mL), and Bleomycin A5 (PYM) (100,10,1 μ g/mL) is united group (DMXAA:50 μ g/mL and PYM:100,10,1 μ g/mL).Take the logarithm people's lung cancer A549 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add Bleomycin A5 50 μ L/ holes then, at 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, after removing the RPMI1640 culture fluid, every hole adds 20 μ LMTT (5g/L), after continuing to cultivate 4h, every hole adds 150 μ L DMSO dissolving, vibrated 10 minutes, and detected, calculate suppression ratio in microplate reader 492nm place, and be that abscissa, suppression ratio are that vertical coordinate is drawn and suppressed curve with concentration, the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
2, the collaborative people's hepatocarcinoma SMMC-7721 cell that suppresses of DMXAA and Bleomycin A5 (PYM) drug combination
DMXAA and Bleomycin A5 (PYM) form with single medicine and drug combination is divided into: DMXAA organizes (50 μ g/mL), and Bleomycin A5 (PYM) (10,5,2.5 μ g/mL) is united group (DMXAA:50 μ g/mL and PYM:10,5,2.5 μ g/mL).The take the logarithm hepatocarcinoma SMMC-7721 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add cell toxicant kind anti-cancer drugs 50 μ L/ holes then, 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, after removing the RPMI1640 culture fluid, every hole adds 20 μ LMTT (5g/L), after continuing to cultivate 4h, every hole adds the DMSO dissolving of 150 μ L, vibrated 10 minutes, and detected, calculate suppression ratio in microplate reader 492nm place, and be that abscissa, suppression ratio are that vertical coordinate is drawn and suppressed curve with concentration, the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
3, WebbShi mark product method computing formula
(fa)1，2＝1-[1-(fa)1][1-(fa)2]
(fa) 1, (fa) 2 represents the suppression ratio of two medicines respectively
(fa) the theoretical additive effect of 1,2 expression calculating.
If the effect of drug combination is greater than theoretical additive effect, then expression is collaborative.
The result
1, DMXAA and Bleomycin A5 (PYM) drug combination is to the inhibitory action of people's lung cancer A549 cell
Table 1 is DMXAA, and the individually dosed and drug combination of Bleomycin A5 (PYM) is to the exercising result (OD value and suppression ratio) of people's lung cancer A549 cell.
DMXAA is individually dosed does not as can be seen from the table almost have inhibitory action (suppression ratio≤0.54%) to people's lung cancer A549 cell, and the suppression ratio to people's lung cancer A549 cell behind Bleomycin A5 and the DMXAA drug combination raises.Calculate the effect of drug combination with WebbShi mark product method, the effect of drug combination is greater than theoretical additive effect (that is: actual suppression ratio＞(fa) 1,2), and DMXAA and Bleomycin A5 (PYM) drug combination has cooperative effect.
Table 1.DMXAA, and the individually dosed inhibitory action of people's lung cancer A549 cell being grown with drug combination of Bleomycin A5 (PYM) (x ± s)
2, DMXAA and Bleomycin A5 (PYM) drug combination is to the effect of people's hepatocarcinoma SMMC-7721 cell inhibiting
Table 2 is DMXAA, and the individually dosed and drug combination of Bleomycin A5 (PYM) is to the exercising result (OD value and suppression ratio) of people's hepatocarcinoma SMMC-7721 cell.
DMXAA is individually dosed to people's hepatocarcinoma SMMC-7721 cyto-inhibition very little (suppression ratio≤10%) as can be seen from the table, behind Bleomycin A5 (PYM) and the DMXAA drug combination people's hepatocarcinoma SMMC-7721 cell inhibiting rate is significantly raise, suppression ratio is the highest to increase by 36.82%.Calculate the effect of drug combination with WebbShi mark product method, the effect of drug combination is greater than theoretical additive effect (that is: actual suppression ratio＞(fa) 1,2), and DMXAA and Bleomycin A5 drug combination have cooperative effect.
Table 2.DMXAA, and the individually dosed inhibitory action of people's hepatocarcinoma SMMC-7721 cell being grown with drug combination of Bleomycin A5 (x ± s)
Embodiment 2The synergistic combination of DMXAA and actinomycin D
Material:
Cell strain: people's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell
The preparation of test medication: DMXAA faces the sodium bicarbonate dissolving with preceding usefulness 5%, and being made into the RPMI1640 culture fluid then needs concentration; Actinomycin D faces uses preceding physiological saline solution, and being made into the RPMI1640 culture fluid then needs concentration.
Cell culture:
People's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell inoculation add an amount of RPMI1640 culture fluid in the aseptic culture bottle, in 37 ℃, 5%CO
2And cultivate in the incubator of saturated humidity.Cell is simple adherent growth, goes down to posterity 1 time in every 2-3 days.With 3g/L trypsinization 1min, make cell suspension when going down to posterity, concentration inoculation on demand with culture fluid piping and druming.
Method:
1, the collaborative people's lung cancer A549 cell that suppresses of DMXAA and actinomycin D (AMD) drug combination
DMXAA and actinomycin D (AMD) form with single medicine and drug combination is divided into: DMXAA organizes (50 μ g/mL), and actinomycin D (10,1,0.1 μ g/mL) is united group (DMXAA:50 μ g/mL and AMD:10,1,0.1 μ g/mL).Take the logarithm people's lung cancer A549 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add actinomycin D (AMD) 50 μ L/ holes then, in 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, every hole adds 20 μ LMTT (5g/L) after removing the RPMI1640 culture fluid, after continuing to cultivate 4h, every hole adds 150 μ L DMSO dissolving, vibrates 10 minutes, detect in microplate reader 492nm place, calculate suppression ratio, and be that abscissa, suppression ratio are that vertical coordinate is drawn and suppressed curve with concentration, the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
2, the collaborative people's hepatocarcinoma SMMC-7721 cell that suppresses of DMXAA and actinomycin D (AMD) drug combination
DMXAA and actinomycin D (AMD) are divided into individually dosed and form drug combination: DMXAA organizes (50 μ g/mL), actinomycin D (0.1,0.05,0.025 μ g/mL) is united group (DMXAA:50 μ g/mL and AMD:0.1,0.05,0.025 μ g/mL).The take the logarithm hepatocarcinoma SMMC-7721 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add actinomycin D (AMD) 50 μ L/ holes then, in 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, every hole adds 20 μ L MTT (5g/L) after removing the RPMI1640 culture fluid, after continuing to cultivate 4h, every hole adds 150 μ L DMSO dissolving, vibrates 10 minutes, detect in microplate reader 492nm place, calculate suppression ratio, and be that transverse axis, suppression ratio are that the longitudinal axis is drawn and suppressed curve with concentration, the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
3, WebbShi mark product method computing formula
(fa)1，2＝1-[1-(fa)1][1-(fa)2]
Wherein: (fa) 1, (fa) 2 represent the suppression ratio of two medicines respectively
(fa)) the theoretical additive effect of 1,2 expression calculating.
If the effect of drug combination is greater than theoretical additive effect, then expression is collaborative.
The result
1, DMXAA and actinomycin D (AMD) drug combination is to the inhibition of people's lung cancer A549 cell
Table 3 is DMXAA, and the individually dosed and drug combination of actinomycin D (AMD) is to the exercising result (OD value and suppression ratio) of people's lung cancer A549 cell.
DMXAA is individually dosed does not as can be seen from the table almost have inhibitory action (suppression ratio≤0.54%) to people's lung cancer A549 cell, and the suppression ratio to people's lung cancer A549 cell behind actinomycin D (AMD) and the DMXAA drug combination raises.Calculate the effect of drug combination with WebbShi mark product method, the effect of drug combination is greater than theoretical additive effect (that is: actual suppression ratio＞(fa) 1,2), and DMXAA and actinomycin D (AMD) drug combination has cooperative effect.
Table 3.DMXAA, and the individually dosed inhibitory action of people's lung cancer A549 cell being grown with the drug combination administration of actinomycin D (AMD) (x ± s)
2, DMXAA and actinomycin D (AMD) drug combination is to people's hepatocarcinoma SMMC-7721 cell inhibiting
Table 4 is DMXAA, and the individually dosed and drug combination of actinomycin D (AMD) is to the exercising result (OD value and suppression ratio) of people's hepatocarcinoma SMMC-7721 cell.
DMXAA is individually dosed to people's hepatocarcinoma SMMC-7721 cyto-inhibition very little (suppression ratio≤10%) as can be seen from the table, behind actinomycin D (AMD) and the DMXAA drug combination people's hepatocarcinoma SMMC-7721 cell inhibiting rate is significantly raise, suppression ratio is the highest to increase by 66.21%.Calculate the effect of drug combination with WebbShi mark product method, the effect of drug combination is greater than theoretical additive effect (that is: actual suppression ratio＞(fa) 1,2), and DMXAA and actinomycin D (AMD) drug combination has cooperative effect.
Table 4.DMXAA, and the individually dosed inhibitory action of people's hepatocarcinoma SMMC-7721 cell being grown with the drug combination administration of actinomycin D (AMD) (x ± s)
Embodiment 3The synergistic combination of DMXAA and mitomycin (MMC)
Material:
Cell strain: people's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell
The preparation of test medication: DMXAA faces the sodium bicarbonate dissolving with preceding usefulness 5%, and being made into the RPMI1640 culture fluid then needs concentration; Mitomycin (MMC) faces uses preceding physiological saline solution, and being made into the RPMI1640 culture fluid then needs concentration.
Cell culture:
People's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell inoculation add an amount of RPMI1640 culture fluid in the aseptic culture bottle, in 37 ℃, and 5%CO
2And cultivate in the incubator of saturated humidity.Cell is simple adherent growth, goes down to posterity 1 time in every 2-3 days.With 3g/L trypsinization 1min, make cell suspension when going down to posterity, concentration inoculation on demand with culture fluid piping and druming.
Method:
1, the collaborative people's lung cancer A549 cell that suppresses of DMXAA and mitomycin (MMC) drug combination
DMXAA and mitomycin (MMC) form with independent medicine and drug combination is divided into: DMXAA organizes (50 μ g/mL), and mitomycin (MMC) (2,1,0.5 μ g/mL) is united group (DMXAA:50 μ g/mL and MMC:2,1,0.5 μ g/mL).Take the logarithm people's lung cancer A549 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add mitomycin (MMC) 50 μ L/ holes then, at 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, after removing the RPMI1640 culture fluid, every hole adds 20 μ LMTT (5g/L), after continuing to cultivate 4h, every hole adds 150 μ L DMSO dissolving, vibrated 10 minutes, and detected, calculate suppression ratio in microplate reader 492nm place, and be that abscissa, suppression ratio are that vertical coordinate is drawn and suppressed curve with concentration, the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
2, the collaborative people's hepatocarcinoma SMMC-7721 cell that suppresses of DMXAA and mitomycin (MMC)
DMXAA and mitomycin (MMC) form with single medicine and drug combination is divided into: DMXAA organizes (50 μ g/mL), and mitomycin (MMC) (2,1,0.5 μ g/mL) is united group (DMXAA:50 μ g/mL and MMC:2,1,0.5 μ g/mL).The take the logarithm hepatocarcinoma SMMC-7721 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add mitomycin (MMC) 50 μ L/ holes then, at 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, after removing the RPMI1640 culture fluid, every hole adds 20 μ LMTT (5g/L), after continuing to cultivate 4h, every hole adds 150 μ LDMSO dissolving, vibrated 10 minutes, and detected, calculate suppression ratio in microplate reader 492nm place, and be that abscissa, suppression ratio are that vertical coordinate is drawn and suppressed curve with concentration, the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
3, WebbShi mark product method computing formula
(fa)1，2＝1-[1-(fa)1][1-(fa)2]
Wherein: (fa) 1, (fa) 2 represent the suppression ratio of two medicines respectively
(fa) the theoretical additive effect of 1,2 expression calculating.
If the effect of drug combination is greater than theoretical additive effect, then expression is collaborative.
The result
1, DMXAA and mitomycin (MMC) drug combination is to the inhibition of people's lung cancer A549 cell
Table 5 is DMXAA, and the individually dosed and drug combination of mitomycin (MMC) is to the exercising result (OD value and suppression ratio) of people's lung cancer A549 cell.
DMXAA is individually dosed does not as can be seen from the table almost have inhibitory action (suppression ratio≤0.54%) to people's lung cancer A549 cell, and the suppression ratio to people's lung cancer A549 cell behind mitomycin (MMC) and the DMXAA drug combination raises.Calculate the effect of drug combination with WebbShi mark product method, the effect of drug combination is greater than theoretical additive effect (that is: actual suppression ratio＞(fa) 1,2), and DMXAA and mitomycin (MMC) drug combination has cooperative effect.
Table 5.DMXAA, and the individually dosed inhibitory action of people's lung cancer A549 cell being grown with drug combination of mitomycin (MMC) (x ± s)
2, DMXAA and mitomycin (MMC)) drug combination is to the effect of people's hepatocarcinoma SMMC-7721 cell inhibiting
Table 6 is DMXAA, and the individually dosed and drug combination of mitomycin (MMC) is to the exercising result (OD value and suppression ratio) of people's hepatocarcinoma SMMC-7721 cell.
DMXAA is individually dosed to people's hepatocarcinoma SMMC-7721 cyto-inhibition very little (suppression ratio≤10%) as can be seen from the table, behind mitomycin (MMC) and the DMXAA drug combination people's hepatocarcinoma SMMC-7721 cell inhibiting rate is significantly raise, suppression ratio is the highest to increase by 60.38%.Calculate the effect of drug combination with WebbShi mark product method, the effect of drug combination is greater than theoretical additive effect (that is: actual suppression ratio＞(fa) 1,2), and DMXAA and mitomycin (MMC) drug combination has cooperative effect.
Table 6.DMXAA, and the individually dosed inhibitory action of people's hepatocarcinoma SMMC-7721 cell being grown with drug combination of mitomycin (MMC) (x ± s)
Embodiment 4The synergistic combination of DMXAA and elemene (EE)
Material:
Cell strain: people's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell
The preparation of test medication: DMXAA faces the sodium bicarbonate dissolving with preceding usefulness 5%, and being made into the RPMI1640 culture fluid then needs concentration; Elemene (EE) faces uses preceding physiological saline solution, and being made into the RPMI1640 culture fluid then needs concentration.
Cell culture:
People's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell inoculation add an amount of RPMI1640 culture fluid in the aseptic culture bottle, in 37 ℃, 5%CO
2And cultivate in the incubator of saturated humidity.Cell is simple adherent growth, goes down to posterity 1 time in every 2-3 days.With 3g/L trypsinization 1min, make cell suspension when going down to posterity, concentration inoculation on demand with culture fluid piping and druming.
Method:
1, the collaborative people's lung cancer A549 cell that suppresses of DMXAA and elemene (EE) drug combination
DMXAA and elemene (EE) are divided into individually dosed and form drug combination: DMXAA organizes (50 μ g/mL), and elemene (EE) (80,40,20 μ g/mL) is united group (DMXAA:50 μ g/mL and EE:80,40,20 μ g/mL).Take the logarithm people's lung cancer A549 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add elemene (EE) 50 μ L/ holes then, at 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, after removing the RPMI1640 culture fluid, every hole adds 20 μ LMTT (5g/L), after continuing to cultivate 4h, every hole adds 150 μ L DMSO dissolving, vibrated 10 minutes, and detected, calculate suppression ratio in microplate reader 492nm place, and be that abscissa, suppression ratio are that vertical coordinate is drawn and suppressed curve with concentration, the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
2, the collaborative people's hepatocarcinoma SMMC-7721 cell that suppresses of DMXAA and elemene (EE) drug combination
DMXAA and elemene (EE) form with single medicine and drug combination is divided into: DMXAA organizes (50 μ g/mL), and elemene (EE) (20,10,5 μ g/mL) is united group (DMXAA:50 μ g/mL and EE:20,10,5 μ g/mL).The take the logarithm hepatocarcinoma SMMC-7721 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add elemene (EE) 50 μ L/ holes then, at 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, after removing the RPMI1640 culture fluid, every hole adds 20 μ L MTT (5g/L), after continuing to cultivate 4h, every hole adds 150 μ LDMSO dissolving, vibrated 10 minutes, and detected, calculate suppression ratio in microplate reader 492nm place, and be that abscissa, suppression ratio are that vertical coordinate is drawn and suppressed curve with concentration, the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
3, WebbShi mark product method computing formula
(fa)1，2＝1-[1-(fa)1][1-(fa)2]
Wherein: (fa) 1, (fa) 2 represent the suppression ratio of two medicines respectively
(fa) the theoretical additive effect of 1,2 expression calculating.
If the effect of drug combination is greater than theoretical additive effect, then expression is collaborative.
The result
1, DMXAA and elemene (EE) drug combination is to the inhibition of people's lung cancer A549 cell
Table is for DMXAA, and the individually dosed and drug combination of elemene (EE) is to the exercising result (OD value and suppression ratio) of people's lung cancer A549 cell.
DMXAA is individually dosed does not as can be seen from the table almost have inhibitory action (suppression ratio≤0.54%) to people's lung cancer A549 cell, and the suppression ratio to people's lung cancer A549 cell behind elemene (EE) and the DMXAA drug combination raises.Calculate the effect of drug combination with WebbShi mark product method, (that is: actual suppression ratio＞(fa) 1,2, and DMXAA and elemene (EE) drug combination has cooperative effect greater than theoretical additive effect for the effect of drug combination.
Table 7.DMXAA, and the individually dosed inhibitory action of people's lung cancer A549 cell being grown with drug combination of elemene (EE) (x ± s)
2, DMXAA and elemene (EE)) drug combination is to people's hepatocarcinoma SMMC-7721 cell inhibiting
Table 8 is DMXAA, and the individually dosed and drug combination of elemene (EE) is to the exercising result (OD value and suppression ratio) of people's hepatocarcinoma SMMC-7721 cell.
DMXAA is individually dosed to people's hepatocarcinoma SMMC-7721 cyto-inhibition very little (suppression ratio≤10%) as can be seen from the table, behind elemene (EE) and the DMXAA drug combination people's hepatocarcinoma SMMC-7721 cell inhibiting rate is significantly raise, suppression ratio is the highest to increase by 40%.Calculate the effect of drug combination with WebbShi mark product method, the effect of drug combination is greater than theoretical additive effect (that is: actual suppression ratio＞(fa) 1,2), and DMXAA and elemene (EE) drug combination has cooperative effect.
Table 8.DMXAA, and the individually dosed inhibitory action of people's hepatocarcinoma SMMC-7721 cell being grown with drug combination of elemene (EE) (x ± s).
Embodiment 5The synergistic combination of DMXAA and norcantharidin
Material:
Cell strain: people's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell
The preparation of test medication: DMXAA faces the sodium bicarbonate dissolving with preceding usefulness 5%, and being made into the RPMI1640 culture fluid then needs concentration; Norcantharidin faces uses preceding physiological saline solution, and being made into the RPMI1640 culture fluid then needs concentration.
Cell culture:
People's lung cancer A549 cell and hepatocarcinoma SMMC-7721 cell inoculation add an amount of RPMI1640 culture fluid in the aseptic culture bottle, in 37 ℃, 5%CO
2And cultivate in the incubator of saturated humidity.Cell is simple adherent growth, goes down to posterity 1 time in every 2-3 days.With 3g/L trypsinization 1min, make cell suspension when going down to posterity, concentration inoculation on demand with culture fluid piping and druming.
Method:
1, the collaborative people's lung cancer A549 cell that suppresses of DMXAA and norcantharidin (NCTD) drug combination
DMXAA and norcantharidin (NCTD) form with single medicine and drug combination is divided into: DMXAA organizes (50 μ g/mL), norcantharidin (NCTD) (10,5,2.5 μ g/mL) is united group (DMXAA:50 μ g/mL and NCTD:10,5,2.5 μ g/mL).Take the logarithm people's lung cancer A549 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add norcantharidin (NCTD) 50 μ L/ holes then, at 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with RPMI1640 culture fluid 100 μ L, every hole adds 20 μ L MTT (5g/L) after removing the RPMI1640 culture fluid, and after continuing to cultivate 4h, every hole adds 150 μ L DMSO dissolving, vibrated 10 minutes, detect in microplate reader 492nm place, calculate suppression ratio, and be abscissa with concentration, suppression ratio is that vertical coordinate is drawn the inhibition curve, and the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
2, the collaborative people's hepatocarcinoma SMMC-7721 cell that suppresses of DMXAA and norcantharidin (NCTD) drug combination
DMXAA and norcantharidin (NCTD) form with single medicine and drug combination is divided into: DMXAA organizes (50 μ g/mL), norcantharidin (NCTD) (0.1,0.05,0.025 μ g/mL) is united group (DMXAA:50 μ g/mL and NCTD:20,10,5 μ g/mL).The take the logarithm hepatocarcinoma SMMC-7721 cell of trophophase is with 5 * 10
3Individual/hole is inoculated in two 96 well culture plates, and every pore volume 100 μ L cultivate and abandon stock solution after 16 hours, and by adding DMXAA and fresh medium 50 μ L/ holes shown in the top grouping, matched group adds 50 μ L fresh mediums, establishes 4 multiple holes for every group.Continue to cultivate 4 hours, add cell toxicant kind anti-cancer drugs 50 μ L/ holes then, 37 ℃, 5%CO
2Supernatant discarded behind the cultivation 24h under the condition, clean cell with 100 μ L 1640, remove every hole, 1640 backs and add 20 μ L MTT (5g/L), after continuing to cultivate 4h, every hole adds 150 μ L DMSO dissolving, vibrated 10 minutes, detect in microplate reader 492nm place, calculate suppression ratio, and be transverse axis with concentration, suppression ratio is that the longitudinal axis is drawn the inhibition curve, and the effect of its drug combination adopts WebbShi mark product method to calculate.
Suppression ratio (%)=[A
492(contrast)-A
492(administration group)]/[A
492(contrast)-A
492(blank)] * 100%
3, WebbShi mark product method computing formula
(fa)1，2＝1-[1-(fa)1][1-(fa)2]
Wherein: (fa) 1, (fa) 2 represent the suppression ratio of two medicines respectively
(fa) the theoretical additive effect of 1,2 expression calculating.
If the effect of drug combination is greater than theoretical additive effect, then expression is collaborative.
The result
DMXAA and norcantharidin (NCTD) drug combination is to the inhibition of people's lung cancer A549 cell
Table 9 is DMXAA, and the individually dosed and drug combination of norcantharidin (NCTD) is to the exercising result (OD value and suppression ratio) of people's lung cancer A549 cell.
DMXAA is individually dosed does not as can be seen from the table almost have inhibitory action (suppression ratio≤0.54%) to people's lung cancer A549 cell, and the suppression ratio to people's lung cancer A549 cell behind norcantharidin (NCTD) and the DMXAA drug combination raises.Calculate the effect of drug combination with WebbShi mark product method, the effect of drug combination is greater than theoretical additive effect (that is: actual suppression ratio＞(fa) 1,2), and DMXAA and norcantharidin (NCTD) drug combination has cooperative effect.
Table 9.DMXAA, and the individually dosed inhibitory action of people's lung cancer A549 cell being grown with drug combination of norcantharidin (NCTD) (x ± s)
2, DMXAA and norcantharidin (NCTD)) drug combination is to people's hepatocarcinoma SMMC-7721 cell inhibiting
Table 10 is DMXAA, and the individually dosed and drug combination of norcantharidin (NCTD) is to the exercising result (OD value and suppression ratio) of people's hepatocarcinoma SMMC-7721 cell.
DMXAA is individually dosed to people's hepatocarcinoma SMMC-7721 cyto-inhibition very little (suppression ratio≤10%) as can be seen from the table, behind norcantharidin (NCTD) and the DMXAA drug combination people's hepatocarcinoma SMMC-7721 cell inhibiting rate is significantly raise, suppression ratio is the highest to increase by 37.12%.Calculate the effect of drug combination with WebbShi mark product method, (that is: actual suppression ratio＞(fa) 1,2, and DMXAA and norcantharidin (NCTD) drug combination has cooperative effect greater than theoretical additive effect for the effect of drug combination.
Table 10.DMXAA, and the individually dosed inhibitory action of people's hepatocarcinoma SMMC-7721 cell being grown with drug combination of norcantharidin (NCTD) (x ± s)
Claims (3)
1. the pharmaceutical composition with anti-tumor activity is characterized in that it is by 5, and 6-dimethyl xanthone-4-acetic acid and Bleomycin A5 are formed, 5, and the potentiation ratio ranges of 6-dimethyl xanthone-4-acetic acid and Bleomycin A5 is 100: 1～1: 20.
2. the pharmaceutical composition with anti-tumor activity according to claim 1 is characterized in that describedly 5, and the potentiation ratio ranges of 6-dimethyl xanthone-4-acetic acid and Bleomycin A5 is 25: 1～1: 10.
3. the pharmaceutical composition with anti-tumor activity according to claim 1 is characterized in that describedly 5, and the potentiation ratio ranges of 6-dimethyl xanthone-4-acetic acid and Bleomycin A5 is 10: 1～1: 5.
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