CN102000070B - Manganoporphyrin-lonidamine combined drug for treating tumor - Google Patents
Manganoporphyrin-lonidamine combined drug for treating tumor Download PDFInfo
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Abstract
The invention discloses a manganoporphyrin-lonidamine combined drug for treating tumor, comprising manganoporphyrin, lonidamine and one or more optional pharmacy-acceptable vectors. The inventor of the application carries out a series of experimental researches. Proved by the experiment, after manganoporphyrin without a tumor-resistant function is combined with the lonidamine for pharmacy, the treatment effect for the tumor can be remarkably improved, the toxicity of the medicine can be reduced, the survival time of animals can be prolonged and the unexpected effects can be obtained.
Description
Technical field
The present invention relates to be used to treat the combination medicine of tumor, relate in particular to the combination medicine that is used to treat tumor that includes manganoporphyrin.
Background technology
Annual newly-increased tumor patient 1,600,000-1,700,000 people of China is total about 4,500,000 people in recent years.Its M & M all presents ascendant trend." the Chinese health statistics summary in 2009 " of health ministry issue shows, in the special rates of part cities and counties top ten disease death in 2008, it is the first that malignant tumor occupy, and become the healthy No.1 killer of harm humans.
Although there have been many antitumor drug, and have more chemical compound to come to light to have antitumor action, like DCA and sodium cromoglicate.But; Most of antitumor drug are owing to lack ideal selectivity; In inhibition or killing tumor cell; Human normal tissue cell also had suppress or damaging action, thereby have more side effect, add effect, plus cisplatin in treatment ovarian cancer or the carcinoma of testis inductive neurotoxicity of institute and the nephrotoxicity thereof etc. of bone marrow toxicity due to the cyclophosphamide chemotherapy regimen like cardiac toxicity, the cisplatin of anthracene nucleus class antitumor antibiotic amycin.Therefore, how when keeping and improving the antitumor drug curative effect, reducing its toxic action is the emphasis of antitumor drug research and development.
Metalloporphyrin is one type of superoxide dismutase (SOD) analogies of researching and developing at present, and comprising multiple manganoporphyrin, but catalytic is removed free radical, is used to treat the disease that free radical too much causes.In multiple manganoporphyrin; Manganese (III)-5,10,15; 20-four-[3-[2-(2-methoxyethoxy) ethyoxyl] phenyl]-porphyrin chloride (is disclosed among the Chinese patent CN1450066A; Open day: on October 22nd, 2003), can eliminate oxygen-derived free radicals too much in the body, the disease that prevention and treatment cause owing to the existence that is harmful to peroxide as micromolecule catalytic antioxidant.At present, Shang Weiyou just manganoporphyrin unite the report that is used to treat tumor with antitumor drug.
Summary of the invention
To above-mentioned prior art, the invention provides one type of combination medicine that is used to treat tumor.
A kind of combination medicine that is used to treat tumor comprises manganoporphyrin and sodium cromoglicate and optional can comprise one or more pharmaceutically suitable carrier that wherein the quality proportioning of manganoporphyrin and sodium cromoglicate is good with 1: 1～15.
A kind of combination medicine that is used to treat tumor comprises manganoporphyrin and dichloroacetic acid or its pharmaceutically acceptable salt and optional can comprise one or more pharmaceutically suitable carrier that wherein the quality proportioning of manganoporphyrin and dichloroacetic acid is good with 1: 1～10.
A kind of combination medicine that is used to treat tumor comprises manganoporphyrin and any antitumor drug and optional can comprise one or more pharmaceutically suitable carrier.
Said antitumor drug is any in amycin or its pharmaceutically useful salt, lonidamine or its pharmaceutically useful salt, the platinum series antineoplastic medicament.
Said platinum series antineoplastic medicament is any in carboplatin, bicycloplatin, cisplatin, the oxaliplatin.
Said antitumor drug is the alkylating agent except that oxynitride phosphor lopps medicine.
Said alkylating agent is any or its pharmaceutically useful salt in chlormethine, carmustine, nimustine, procarbazine, uracil mustard, temozolomide, the melphalan.
The quality proportioning of above-mentioned manganoporphyrin and amycin is good with 1: 1～6; The quality proportioning of manganoporphyrin and lonidamine is good with 1: 7.5～20; The quality proportioning of manganoporphyrin and carboplatin is good with 1: 2～10; The quality proportioning of manganoporphyrin and cisplatin is good with 1: 1～4, and the quality proportioning of manganoporphyrin and chlormethine is good with 1: 0.5～6, and the quality proportioning of manganoporphyrin and carmustine is good with 1: 1～9; The quality proportioning of manganoporphyrin and procarbazine is good with 1: 5～12, and manganoporphyrin and temozolomide's quality proportioning is good with 1: 22～30.
Said manganoporphyrin is manganese (III)-5,10,15,20-four-[3-[2-(2-methoxyethoxy) ethyoxyl] phenyl]-porphyrin chloride.
The invention also discloses manganoporphyrin in the purposes of preparation in the combination medicine of the treatment tumor of antitumor drug administration.
The dose therapeutically effective of said manganoporphyrin is 0.1～50mg/Kg body weight, preferred 0.01～5mg/Kg body weight.
Said pharmaceutically useful salt comprises the salt of sour addition, such as hydrochloric acid, fumaric acid, maleic acid, citric acid, succinic acid etc.
Said pharmaceutically suitable carrier is conventionally known to one of skill in the art and commonly used, and like filler or the carrier mass in pill, tablet, the capsule etc., these materials are used for this purpose by sanitarian approval and usually as the non-active ingredient of medicament.
Said combination medicine can be processed any dosage form.
Should be appreciated that of the present invention unite to use comprise following dual mode:
The one, manganoporphyrin and the medicine that can unite use are processed independent preparation respectively, the dosage form of two kinds of preparations can be different, and the medicine that can unite use can adopt its existing dosage form.Can these two kinds of medicines successively be used in use, also can take simultaneously.When two kinds of medicines were successively used, the independent preparation of manganoporphyrin can at first be taken.During administration, first kind of component should also do not lost its useful effect in vivo when giving second kind of component successively.
The 2nd, above-mentioned manganoporphyrin and the medicine that can unite use are processed single compound preparation, take simultaneously during use.
When compounding pharmaceutical compositions and use, but need the manganoporphyrin of generation effect and the dosage of combination medicine to change, and finally by medical worker's decision, the factor of being considered comprise patient age and the disease character and the order of severity.
The present inventor has done a series of Related Experimental Study, experiment showed, manganoporphyrin and above-mentioned medication combined medication of uniting use, can improve the oncotherapy effect, and can reduce its toxicity, prolongs the time-to-live of laboratory animal.
Manganoporphyrin itself is antineoplastic action not, but with behind itself and the antitumor drug drug combination, but can strengthen the curative effect of antitumor drug significantly, and reduce its toxic and side effects, has obtained beyond thought effect.
Do detailed explanation through the accompanying drawing and the specific embodiment below.
Description of drawings
Fig. 1 is the pancreatic cancer cell apoptosis rate sketch map that the TUN-EL labelling method is measured in the body (%, 20 *); Wherein, A NS organizes pancreatic cancer cell apoptosis rate (4.7 ± 1.5), B sodium cromoglicate group pancreatic cancer cell apoptosis rate (10.4 ± 1.8), C manganoporphyrin+sodium cromoglicate group pancreatic cancer cell apoptosis rate (22.1 ± 3.4).
Fig. 2 for each group nude rat subcutaneous vaccination people lung cancer A549 cell after diameter of tumor change curve sketch map;
Fig. 3 is manganoporphyrin and the cisplatin combined medicament sketch map that influences to adenocarcinoma of lung mice-transplanted tumor tumor growth.
The specific embodiment
Fill a prescription as follows:
Manganoporphyrin 400mg
Carmustine 3.5g
Polyethylene Glycol 150ml
Water for injection adds to 250ml
Process 50
Preparation technology:
Cillin bottle, plug are slightly washed earlier, and the back is qualified to visible foreign matters with the filterable water for injection fine purifiation of warp 0.45 μ m microporous filter membrane, then dry for standby.
In dosing is irritated, add the manganoporphyrin of recipe quantity, Polyethylene Glycol 50ml dissolves it fully, as solution 1.
In another dosing is irritated, add the carmustine of recipe quantity, Polyethylene Glycol 100ml dissolves it fully, as solution 2.
Human pancreas cancer MIAPaCa-2 cell suspension is adjusted to every milliliter 5 * 10
6Individual cell, 0.2ml cell suspension (contains 1 * 10
6Individual cell) is inoculated in 30 female Mus pancreas of immune complex defect; Be divided into three groups after 1 week at random; Matched group (NS) tail vein injection saline every day 0.2ml; Sodium cromoglicate group tail vein injection every day sodium cromoglicate 30mg/kg body weight, manganoporphyrin+sodium cromoglicate group tail vein injection every day manganoporphyrin 2mg/kg body weight, sodium cromoglicate 30mg/kg body weight.3 week of injection back execution animal is dissected and extracts tumor continuously, measures gross tumor volume (V=1/6 * π * length * height * wide).Tumor tissues places fixedly 2-4h of 4 ℃ of metaformaldehydes, is embedded in the ornithine amine formyl transferring enzyme complex liquid nitrogen flash freezer ,-80 ℃ of cold preservations.Be cut into the capable CD31 immunohistochemical staining of the thick tissue slice of 5 μ m.
PCNA SABC method is measured pancreatic cancer cell propagation situation: tumor tissue section adopts the strepto-avidin immunohistochemical method of peroxidase labelling with the flushing of PBS liquid.Negative control (with the PBS displacement one anti-negative control of doing) is all established in every batch of dyeing.Observed result under the light microscopic.Observe 5 high power fields for every, the shared percent of statistics positive cell number.PCNA (PCNA) is the granular pattern or the brown positive of diffuse type, is positioned in the cancerous cell nuclear, and endochylema is generally not painted.Part karyokinesis cell shows the positive reaction of whole cell.
TUNE fluorescence spectrometry pancreatic cancer cell apoptosis rate: the tumor specimen of matched group and each experimental group is taken out after cubing, and 10% formalin solution is fixed, the TUNEL marker detection.Apoptotic cell can be the fluorescence positive by the dUTP labelling under the fluorescence microscope.The apoptotic cell in 500 cells of counting under at least 5 representational 100 times of visuals field calculates and respectively organizes apoptosis rate respectively.
Experimental data representes that with mean+SD the multiple comparisons of sample average adopts one factor analysis of variance and LSD-t check between each group of single factor.With SPSS10.0 software analysis result.Experimental result is following:
Gross tumor volume: see table 1.Multiple comparisons between the LSD-t check is organized: each treatment group mean tumour volume all significantly is lower than NS group (P＜0.05), and manganoporphyrin+sodium cromoglicate group mean tumour volume significantly is lower than sodium cromoglicate group (P＜0.05).
Table 1 manganoporphyrin and sodium cromoglicate combination medicine are to the therapeutical effect evaluation (n=10) of mouse pancreas cancer
a: compare P＜0.05 with matched group;
b: compare P＜0.05 with the sodium cromoglicate group.
Pancreatic cancer cell proliferation index: see table 1.Compare variance analysis F=26.47, P=0.000 between the many groups of pancreatic cancer cell proliferation index.Multiple comparisons between the LSD-t check is organized: each treatment group cancerous cell value added index all is starkly lower than NS group (P＜0.05); Manganoporphyrin+sodium cromoglicate group cell proliferation index significantly is lower than NS group and sodium cromoglicate group (P＜0.05).
Pancreatic cancer cell apoptosis rate: see table 1, Fig. 1.Compare variance analysis F:60.22, P=0.000 between the many groups of apoptosis rate.Multiple comparisons between the LSD-t check is organized: each treatment group apoptosis rate is significantly higher than matched group (P＜0.05); Manganoporphyrin+sodium cromoglicate group cell proliferation index is significantly higher than NS group and sodium cromoglicate group (P＜0.05).
Above results suggest, sodium cromoglicate can significantly suppress pancreatic cancer cell propagation in vivo, promote the pancreatic cancer cell apoptosis, thereby suppress pancreatic cancer growth, and the combination medicine of manganoporphyrin and sodium cromoglicate can improve the inhibitory action of sodium cromoglicate to cancer of pancreas.
People's lung cancer A549 cell suspension is adjusted to every milliliter 15 * 10
6Individual cell is got 0.2ml (3 * 10
6Individual cell) left fore axillary fossa inoculated with subcutaneous injections is in 30 male adult nude rats; Be divided into three groups at random after inoculating for two weeks; Matched group (NS) tail vein injection saline every day 0.2ml, the dichloroacetate sodium group is dissolved in dichloroacetate sodium in the feed water with 0.075g/L, freely absorb every day); Manganoporphyrin+dichloroacetate sodium group except that the feed water that contains dichloroacetate sodium, every day tail vein injection manganoporphyrin 2mg/kg body weight.With around after maximum gauge to the administration of each treated animal tumor of vernier caliper measurement, nude rat is put to death in the back weekly, and the result sees Fig. 2.Can be known that by data the administration group all can suppress growth of tumor significantly gradually, wherein manganoporphyrin+dichloroacetate sodium group suppresses effect and is superior to dichloroacetate sodium group and NS group.
30 of healthy Kunming mouses, body weight 20-24g, male and female dual-purpose.
The 7th day ascites of the oncocyte aseptic extraction lotus H-22 liver cancer mouse of inoculation is with 10 times of normal saline dilutions, in being tried mice right fore axillary fossa subcutaneous injection 0.2ml.
All mices are divided into 3 groups at random, and 10 every group, male and female half and half.Matched group (NS) tail vein injection saline 0.2ml; Amycin group (ADR), tail vein injection high dose amycin 8mg/kg body weight; Manganoporphyrin+ADR group tail vein injection low dosage ADR 4mg/kg body weight, tail vein injection manganoporphyrin 2mg/kg body weight.Each is organized mice and all behind the inoculation oncocyte, began experiment on the 2nd day, and NS group and ADR organize administration weekly 2 times, continuous 2 weeks.1h before manganoporphyrin+ADR group per injection amycin, the tail vein injection manganoporphyrin.Oncocyte inoculation back weighed in the balance heavily with dislocation method execution mice on the 14th day, separated tumor body and function electronic balance again and claimed that tumor is heavy, calculated tumor weight/body weight ratio.Tumour inhibiting rate calculates according to formula (NS group tumor weight-administration group tumor is heavy)/NS group tumor heavy * 100%.Experimental data is seen table 2.Wherein the tumor suppression effect of manganoporphyrin+ADR group is significantly because ADR group and NS group.
Table 2 is respectively organized the average tumor weight of mice, tumor weight/body weight and tumour inhibiting rate (n=10)
a: compare P＜0.05 with the NS group;
b: compare P＜0.05 with the ADR group.
S
180The ascitic type tumor-bearing mice is inoculated back 7 days, extracts milky thickness ascites, and dilution back adjustment oncocyte number is every m12 * 10
7Individual cell.The 0.2ml tumor cell suspension (is contained oncocyte about 4 * 10
6Individual) be inoculated in every Kunming mouse (30, male and female half and half, body weight 18-24g) forelimb oxter subcutaneous tissue.Laboratory animal is divided into 3 groups at random, matched group (NS) tail vein injection saline 0.2ml; The ADR group, tail vein injection high dose ADR 8mg/kg body weight; Manganoporphyrin+ADR group tail vein injection low dosage ADR 4mg/kg body weight, manganoporphyrin 2mg/kg body weight.Behind the inoculation tumor cell suspension 24h, each administration group is according to 1/5 tail vein injection administration of accumulated dose, successive administration 5d, and each administration volume is 0.2ml.Observe survival time of animals after the administration, calculate each administration treated animal increase in life span (%) by following formula:
(administration treated animal on average survive sky-NS treated animal on average survive natural law)/NS treated animal natural law * 100% of on average surviving.
The result sees table 3, and experimental data is represented with mean+SD.
Each treated animal increase in life span of table 3
a: compare P＜0.01 with the NS group;
b: compare P＜0.01 with the ADR group.
Manganoporphyrin+ADR treated animal is on average survived, and natural law significantly is longer than the NS group and ADR organizes.
Embodiment 6 manganoporphyrins and lonidamine (LND) combination medicine are to ascitic type tumor treatment evaluation of effect
SPF level C3H/Km mice, 30, age in 12-14 week, body weight 30-35g, left oxter subcutaneous vaccination RIF-1 tumor cell, 2 * 10
5Every in cell is inoculated back about 10 days, treats that gross tumor volume is near 100mm
3, be divided into 3 groups at random, matched group (NS) tail vein injection saline 0.2ml, LND group tail vein injection lonidamine 40mg/kg body weight, manganoporphyrin+LND group tail vein injection lonidamine 40mg/kg body weight, manganoporphyrin 2mg/kg body weight.Use the vernier caliper measurement gross tumor volume, measured once in per 2 days, when gross tumor volume is administration four of volume times.With each group gross tumor volume when growing to administration the natural law difference (comparing) of four times of volumes with the NS group calculate the tumor growth slack time, data are represented with mean+SD.That utilizes loses weight as each treatment group toxicity quantitative target, loses weight to deduct tumor weight calculating through body weight, and tumor weight (mg) is according to (A * B
2) K/2 calculates, wherein A is that length (mm), the B of the tumor longitudinal axis are that wide (mm), the K of tumor vertical axis is transformation ratio, the result is with percent (being benchmark when dividing into groups) expression.Experimental result is seen table 4.Can know that by the gained data tumor suppression effect of manganoporphyrin and LND combination medicine significantly is superior to LND and NS group, and its toxicity is less than LND and NS group.
The tumor growth slack time of each treated animal of table 4
a: compare P＜0.01 with the NS group;
b: compare P＜0.01 with the LND group.
Embodiment 7 manganoporphyrins and procarbazine combination medicine are to the therapeutical effect evaluation of multiple myeloma
Animal: the SCID mice, 30, age in 6-7 week is about body weight 20-25g, male and female half and half
People's multiple myeloma cell line XG7, excitated type gp130mAb that cell strain and antibody: IL-6 relies on
The leak detection of SCID mice: in the blood sampling of SCID mice ELISA rear vein beard, separation of serum detects IgG content in the Mus serum with the ELISA method with capillary tube.
The cultivation of tumor cell: people's multiple myeloma cell line XG7 is incubated among the RMPI-1640 of the IL-6 that contains 3 μ g/ml and 10%FCS, places 37 ℃, 5%C0
2Cell culture incubator in.Transplant the last week, add the excitated type gP130mAb of 5 μ g/ml, in one week of continuous culture, the XG7 cell of the trophophase of taking the logarithm is subsequent use.
The transplanted tumor animal model is set up and administration: get qualified SCID mice, the XG7 cell 0.5ml (1 * 10 for preparing through tail vein injection respectively
7Individual cell), carry out primary vaccination.On the same day of primary vaccination, the excitated type gp130mAb of every injected in mice 100g, subsequently whenever once at a distance from injection in 4 days, each 50g, totally 5 times.To 5 mices that form entity tumor, pluck eyeball and get blood, and win tumor, under aseptic condition, fresh tumor specimen is soaked in the cell culture fluid, remove fat, fiber and slough, shred tumor group then and be made into 3mm
3About, it is subcutaneous to be inoculated in the SCID mice with the trocar.Inoculate back 15 days; Get 30 qualified SCID mices and be divided into three groups at random; Matched group (NS) tail vein injection 0.2ml normal saline; Procarbazine group tail vein injection procarbazine 12mg/kg body weight, manganoporphyrin+procarbazine group tail vein injection procarbazine 12mg/kg body weight, manganoporphyrin 2mg/kg body weight.Put to death mice in 20 days after the administration, take out tumor, measure maximum major diameter (a) of tumor and transverse diameter (d), according to formula V=ab
2/ 2 calculate gross tumor volume.The result sees table 5, and data show that manganoporphyrin can significantly improve the antitumous effect of procarbazine.
Each treated animal multiple myeloma volume (mm of table 5
3)
a: compare P＜0.01 with the NS group;
b: compare P＜0.01 with the procarbazine group.
The trophophase human brain tumour SF763 cell of taking the logarithm, it is 1 * 10 that normal saline is regulated concentration
6/ ml inoculates the BALB/cA mice, and the inoculation volume is 0.025ml, and the inoculation point is the summit of an equilateral triangle, and the base is the line of auris dextra and right eye, and height is about 5mm, and the inoculation degree of depth is about 2mm.With mice with 4.35% trichlorine chloral hydrate anesthesia after, alcohol disinfecting is inoculated with syringe.Inoculate after 7 days, mice is divided into 3 groups respectively at random, 10 every group.Matched group (NS) tail vein injection every day 0.2ml normal saline; The dosage intratumor injection of temozolomide (TMZ) group tail vein injection TMZ 60.0mg/kg body weight every day; Manganoporphyrin+TMZ group tail vein injection TMZ 60.0mg/kg body weight every day, manganoporphyrin 2.0mg/kg body weight was administered once in per two days.Observe and the record death time of animal, compute The average survival time natural law and increase in life span, increase in life span is with the percent calculating divided by matched group The average survival time natural law gained of the difference of administration group The average survival time natural law and matched group The average survival time natural law.Experimental result is seen table 6, and data show that manganoporphyrin can significantly improve temozolomide's antitumous effect.
The therapeutical effect of the table 6 pair cerebral tumor
a: compare P＜0.01 with the NS group;
b: compare P＜0.01 with the TMZ group.
The antitumor action of embodiment 9 manganoporphyrins and carboplatin combination medicine
30 of BABIMc nu/nu nude mouses, SPF level, age in male and female half and half, 6 week, body weight 17-25g.The subcutaneous stomach organization SGC-7901 that goes down to posterity of nude mouse puts to death mice with tumor during plantation, skin degerming, is won tumor tissues at complete separation, immerses in the normal saline, shreds to plant to 30 nude mice backs subcutaneous respectively for the tumor fragment of about 2mm diameter.In inoculation second week of back, animal is divided into three groups at random, matched group (NS) tail vein injection saline 0.2ml; Carboplatin group tail vein injection carboplatin 6mg/kg body weight, manganoporphyrin+carboplatin group tail vein injection carboplatin 6mg/kg body weight, manganoporphyrin 3mg/kg body weight; Be administered twice weekly, treat disconnected neck execution at the 6th weekend mice, get complete tumor tissues; Measure the maximum major diameter (a) and transverse diameter (b) of Subcutaneous tumor, according to formula V=ab
2/ 2 calculate gross tumor volume, and calculate tumour inhibiting rate, and tumour inhibiting rate=(treatment group gross tumor volume-NS organizes gross tumor volume)/NS organizes gross tumor volume * 100%, and data represent that with mean+SD experimental result is seen table 7.Manganoporphyrin can significantly improve the antitumous effect of carboplatin.
The growth inhibited effect of table 7 couple nude mouse subcutaneous vaccination people gastric cancer SGC-7901
a: compare P＜0.05 with the NS group;
b: compare P＜0.05 with the TMZ group
The antitumor action of embodiment 10 manganoporphyrins and cisplatin combined medicament
30 of 4-5 T739 male mices in age in week, the SPF level is about 20g; 2 of LA795 adenocarcinoma of lung mice with tumor.Put to death mice with tumor, peel off the tumor piece under the aseptic condition, add the 4ml normal saline by the 1g tumor tissues and put into surface plate, shred tumor; Grind to form homogenate, cross 360 order steel meshes, process the tumor cell suspension; Pour centrifuge tube into, add normal saline, it is 2 * 10 that microscopically is regulated cell density
6/ ml, every mice right rear leg root outside subcutaneous injection 0.2ml tumor cell suspension is set up the high metastatic tumo(u)r model of mice.
Inoculate and after 4 days 30 experiment mices are divided into 3 groups at random, 10 every group.Every tail vein injection saline 0.2ml of matched group (NS), once a day; The cisplatin group, cisplatin 2mg/ (kgd) is dissolved in normal saline 0.2ml tail vein injection, in inoculating back the 4th, 11,18 day respectively once; Manganoporphyrin+cisplatin group, cisplatin are pressed the medication of cisplatin group dosage, manganoporphyrin dosage every day 2mg/kg body weight, and administration time is with the cisplatin group.
During the medication per 2 days with maximum major diameter (a) of vernier caliper measurement mice Subcutaneous tumor and transverse diameter (b), according to formula V=ab
2/ 2 calculate gross tumor volumes, and the result is as shown in Figure 3, behind the tumor inoculation 1-4 days; Growth of xenografted speed is basic identical, and tumor formation rate is 100%, and each volume of organizing the subcutaneous transplantation tumor increases gradually; The matched group growth of xenografted is obviously faster than the administration group, and manganoporphyrin+cisplatin group tumor growth is the slowest.The prompting manganoporphyrin can improve the inhibitory action of cisplatin to tumor.
The antitumor action of embodiment 11 manganoporphyrins and carmustine combination medicine
The C6 glioma cell is inoculated in the RPMI-1640 that contains 15% hyclone, and 37 ℃, 5%CO
2The conventional cultivation in the incubator.The trophophase cell of taking the logarithm is by every Mus inoculation 1 * 10
6The amount of cell is with subsequent use in its dilution and the 15 μ l cell culture fluids.30 Wistar rats, body weight 200-250g, 5cm under the dura mater is vertically inserted with microsyringe in anesthesia boring back, and 15 μ l cell suspension are slowly injected (10min), goes out bone wax sealing bone hole behind the pin, skin suture.
Inoculate back 5 days, rat is divided into three groups at random, every tail vein injection saline 0.2ml of matched group (NS), once a day; The carmustine group is dissolved in 0.2ml normal saline tail vein injection once a day by carmustine 2mg/kg; Manganoporphyrin+carmustine group, carmustine is by suitable carmustine group dosage medication, manganoporphyrin dosage every day 2mg/kg body weight.Each treated animal time-to-live of record after the administration.
Death in 14-18 days lives forever and lived 23 days most after the NS winding kind, on average survives 17 days; The shortest survival of carmustine group 26 days, most of above 30 days, 2 survivals surpass 80 days, live forever most and live 127 days, on average survive 62 days; The shortest survival of manganoporphyrin+carmustine group 42 days, 5 survivals surpass 80 days, have survived 150 days for 2, do not occur nervous symptoms yet.It is thus clear that manganoporphyrin can significantly improve the inhibitory action of carmustine to the Mus glioma.
The HL-60 cell is placed the RPMI-1640 cultivating system that contains 10% hyclone, at 37 ℃, the CO of 5% volume fraction
2, cultivate under the saturated humidity, 48-72h goes down to posterity 1 time.
Take the logarithm trophophase h1-60 cell inoculation in 96 orifice plates, and every hole inoculates about 1.5 * 10
3Individual cell.Experiment divides 3 groups: matched group (only adding culture fluid), chlormethine group (the final concentration 0.80mg/l of chlormethine), manganoporphyrin+chlormethine group (final concentration of manganoporphyrin is 1.5mg/l, and the final concentration of chlormethine is with the chlormethine group).Establish 3 multiple holes for every group, 24,48, detect behind the 72h.4h adds 5mg/ml MTT 20 μ l before detecting, and after continuing to cultivate 4h, level is centrifugal, blots supernatant, adds DMSO 150 μ l concussion 5min, and 490nm measures absorbance (OD value).Repeat 3 times.Calculate inhibitory rate of cell growth, absorbance representes that with mean+SD the result sees table 8.
Table 8 manganoporphyrin and chlormethine combination medicine are to HL-60 leukaemia's inhibition effect
*: compare P＜0.05 with the chlormethine group
Claims (1)
1. manganoporphyrin-lonidamine combination medicine that is used to treat the ascitic type tumor is characterized in that: comprise manganoporphyrin and lonidamine and optional can comprise one or more pharmaceutically suitable carrier.
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| CN1549712A (en) * | 2001-08-31 | 2004-11-24 | ǰ����� | Antitumor agents and process for producing the same |
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Patent Citations (2)
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|---|---|---|---|---|
| CN1549712A (en) * | 2001-08-31 | 2004-11-24 | ǰ����� | Antitumor agents and process for producing the same |
| CN101160354A (en) * | 2005-04-18 | 2008-04-09 | 前田浩 | Polymeric pharmaceutical agent for treatment of cancer and process for production of the same |
Non-Patent Citations (4)
| Title |
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| Benjamin J 等.《A manganese porphyrin superoxide dismutase mimetic enhances tumor radioresponsiveness》.《International Journal of Radiation Oncology Biology Physics》.2005,第63卷(第2期),摘要. |
| Benjamin J 等.《A manganese porphyrin superoxide dismutase mimetic enhances tumor radioresponsiveness》.《International Journal of Radiation Oncology Biology Physics》.2005,第63卷(第2期),摘要. * |
| 曹正国 等.《锰卟啉光动力学疗法对人膀胱癌BIU-87细胞Bcl-2表达的影响》.《中国肿瘤》.2008,第17卷(第3期),第239-242页. |
| 曹正国 等.《锰卟啉光动力学疗法对人膀胱癌BIU-87细胞Bcl-2表达的影响》.《中国肿瘤》.2008,第17卷(第3期),第239-242页. * |
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| CN102000070A (en) | 2011-04-06 |
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