CN106442992A - Pharmacokinetic evaluation method of abiraterone derivative - Google Patents
Pharmacokinetic evaluation method of abiraterone derivative Download PDFInfo
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- CN106442992A CN106442992A CN201610630609.6A CN201610630609A CN106442992A CN 106442992 A CN106442992 A CN 106442992A CN 201610630609 A CN201610630609 A CN 201610630609A CN 106442992 A CN106442992 A CN 106442992A
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- abiraterone
- metacortandracin
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- 238000011156 evaluation Methods 0.000 title claims abstract description 12
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- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims abstract description 62
- 229960004103 abiraterone acetate Drugs 0.000 claims abstract description 29
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 claims abstract description 29
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57434—Specifically defined cancers of prostate
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Abstract
The present invention provides a pharmacokinetic evaluation method of an abiraterone derivative. A purpose of the present invention is to obverse the treatment effect of an abiraterone derivative AHS-114 on castrate-resistant prostate cancer by using high AR expressing human prostate cancer cell line LNCaP/AR subcutaneously transplanted CB17SCID tumor bearing mouse models. According to the present invention, after the combination of the 200 mg/kg tested medicine AHS-114 and prednisone, the tumor growth of the castrate-resistant prostate cancer tumor bearing mouse can be significantly inhibited, the significant side effects are not observed, the inhibition effect is equal to the inhibition effect of the combination of the same dose of the 170 mg/kg positive medicine abiraterone acetate and prednisone, but the effective standard of the guidelines for non-clinical research of cytotoxic antitumor drugs.
Description
Technical field
The present invention relates to a kind of pharmcokinetic evaluation method of abiraterone derivative, belong to pharmaceutical research technology neck
Domain.
Background technology
Prostate cancer is one of modal malignant tumour of the male sex, and in global range, prostate-cancer incidence occupy the male sex
In all malignant tumours second, ranked fifth in the related death rate of cancer.The incidence of disease of Asian countries's prostate cancer is gradually
Rise, compared to western countries, in Asian countries's patients with prostate cancer, late period and metastatic prostate cancer patient's proportion are relatively
Greatly.Cut-off China's tumour registration area prostate-cancer incidence in 2012 is 9.92/10 ten thousand, the row male malignancy incidence of disease
6th, have become as the serious big killer threatening our people's health and lives.Endocrine therapy is current late stage prostate
The primary treatments of cancer, Most patients are originally all effective to castration (operation or medicine) or combined androgen blockade treatment,
But after the median time of 14～30 months, most of patient's pathology will gradually develop into castration-resistant prostate cancer
(Castration Resistant Prostate Cancer, CRPC), its median survival interval is less than 20 months.Therefore, develop
The medicine being effective against CRPC is the significant problem involving the interests of the state and the people.
Abiraterone acetate (trade name：ZYTIGA) be CYP17 a kind of (17 α-hydroxylase/C17,20- cracking of inhibitor
Enzyme), in April, 2011, No. 28 are approved by the FDA in the United States listing.ZYTIGA is applied to metacortandracin combination and once accepts previously to contain polyenoid
The treatment [1-2] of castration refractory prostate cancer (CRPC) patient of Paclitaxel Chemotherapy transfer.
Content of the invention
For defect of the prior art, it is an object of the invention to provide a kind of pharmacokinetics of abiraterone derivative
Appraisal procedure.
The present invention is achieved by the following technical solutions：
The present invention provides a kind of pharmcokinetic evaluation method of abiraterone derivative, and it comprises the steps：
Male mice is carried out castration Post operation, inoculates LNCaP/AR cell；
It is divided into Abiraterone acetate -170mg/kg group, Abiraterone acetate joint metacortandracin by equivalent for described male mice
Group, by reagent abiraterone derivative -300mg/kg group, abiraterone derivative -200mg/kg group, abiraterone derive Internet of Things
Close metacortandracin group, solvent control group and totally seven groups of metacortandracin -2mg/kg；
Using oral gastric infusion, all groups of other male mices are administered once a day according to group, successive administration 28
My god, results of regular determination body weight and gross tumor volume, 24 hours after last dose, collect determination of serum PSA (PSA)
Concentration, and take tumour, seminal vesicle and prostate to be weighed, and be calculated relative tumour volume, the Relative tumor rate of increase, swell
Knurl stereomutation percentage, tumor-like hyperplasia and changes of weight percentage.
Preferably, described male mice is the male CB17SCID mouse of 6～7 week old.
Preferably, the gross tumor volume of the male mice of inoculation LNCaP/AR cell is 100～250mm3.
Compared with prior art, the present invention has following beneficial effect：
After by reagent abiraterone derivative -200mg/kg joint metacortandracin, little to castration-resistant prostate cancer lotus knurl
Mouse tumour increases more obvious inhibitory action, does not assume obvious toxic-side effects, with the positive drug acetic acid Ah under Isodose
Bit dragon -170mg/kg joint metacortandracin is suitable to the inhibitory action of tumour, but is also not up to《Cell toxicant series antineoplastic medicament is non-
Clinical research technological guidance's principle》Effective standard.
Brief description
The detailed description with reference to the following drawings, non-limiting example made by reading, the further feature of the present invention,
Objects and advantages will become more apparent upon：
Fig. 1 is solvent control group mean relative tumor volume growth tendency；
Fig. 2 is that Abiraterone acetate -170mg/kg organizes mean relative tumor volume growth tendency；
Fig. 3 is Abiraterone acetate joint metacortandracin group mean relative tumor volume growth tendency；
Fig. 4 is that abiraterone derivative -300mg/kg organizes mean relative tumor volume growth tendency；
Fig. 5 is that abiraterone derivative -200mg/kg organizes mean relative tumor volume growth tendency；
Fig. 6 is abiraterone derivative joint metacortandracin group mean relative tumor volume growth tendency；
Fig. 7 is that metacortandracin -2mg/kg organizes mean relative tumor volume growth tendency.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, some deformation can also be made and improve.These broadly fall into the present invention
Protection domain.
Embodiment 1
1.1 test names and numbering
Test name：The pharmacodynamic assessment test of AHS-114
Test number：KP19-2015
1.2 test objective
Using the CB17SCID bearing mouse model of PC-3's LNCaP/AR subcutaneous transplantation of AR overexpression,
Observe the therapeutic action to castration refractory prostate cancer for the abiraterone derivative AHS-114.
The regulation that 1.3 tests are followed
《Drug registration management method》(office of State Food and Drug Administration makes No. 28, on October 01st, 2007)
[3]；
《Cell toxicant series antineoplastic medicament non-clinical study technological guidance's principle》(State Food and Drug Administration's medicine
Evaluate center, in November, 2006) [4]；
《GLP》(office of State Food and Drug Administration makes No. 2,2003 09
The moon 01) [5]；
The enforcement of this test, in addition to scheme specified otherwise, all follows mechanism standard practice instructions (Standard
Operating Procedure:SOP).
2 test materials
2.1 test sample
Title or code name：Abiraterone derivative AHS-114；
Source：Shanghai Mai Bu Pharmaceutical Technology Co., Ltd；
Proterties：White is to off-white powder；
Specification and concentration：99.71%；
Lot number：Mb039-26-3；
Preservation condition：Normal temperature, close drying keeps in Dark Place；
Points for attention：This product easily moisture absorption, guards against damp；
The term of validity：2017.07；
Preserve place：Sichuan Kangcheng Bio-tech Co., Ltd.'s test sample storage chamber；
Compound method：0.9% normal saline [1] containing 0.5% methylcellulose and 0.1% Tween-80；
Identify after preparation：Dated test number, substances title and concentration, dose volume, preservation condition, the term of validity,
Person liable and preparation date etc.；
Condition is kept in after preparation：2～8 DEG C of airtight preservations；
The term of validity after preparation：1 week；
Return and the process of remaining test sample：After administration, remaining test sample unification is collected in waste liquid barrel.Keep sample test sample
Reference《The preservation of test sample》SOP is stored in test sample storage chamber.
2.2 reference substance
Title or code name：Abiraterone acetate；
Source：Shanghai Mai Bu Pharmaceutical Technology Co., Ltd；
Proterties：White is to off-white powder；
Specification and concentration：99.87%；
Lot number：20141101；
Preservation condition：Normal temperature, close drying keeps in Dark Place；
The term of validity：2017.07；
Preserve place：Sichuan Kangcheng Bio-tech Co., Ltd.'s test sample storage chamber；
Compound method：0.9% normal saline containing 0.5% methylcellulose and 0.1% Tween-80；
Identify after preparation：Dated test number, substances title and concentration, dose volume, preservation condition, the term of validity,
Person liable and preparation date etc.；
Condition is kept in after preparation：2～8 DEG C of airtight preservations；
The term of validity after preparation：1 week；
Return and the process of remaining reference substance：After administration, remaining reference substance unification is collected in waste liquid barrel.
Title or code name：Prednisone acetate；
Source：Shanghai Mai Bu Pharmaceutical Technology Co., Ltd；
Proterties：White is to off-white powder；
Specification and concentration：99.5%；
Lot number：100012-201407；
Preservation condition：Normal temperature, close drying keeps in Dark Place；
The term of validity：2017.07；
Preserve place：Sichuan Kangcheng Bio-tech Co., Ltd.'s test sample storage chamber；
Compound method：0.9% normal saline containing 0.5% methylcellulose and 0.1% Tween-80；
Identify after preparation：Dated test number, substances title and concentration, dose volume, preservation condition, the term of validity,
Person liable and preparation date etc.；
Condition is kept in after preparation：2～8 DEG C of airtight preservations；
The term of validity after preparation：1 week；
Return and the process of remaining reference substance：After administration, remaining reference substance unification is collected in waste liquid barrel.
2.3 solvent control product
Title or code name：0.9% physiological saline containing 0.5% methylcellulose and 0.1% Tween-80；
Source：Methylcellulose and Tween-80 come from Sigma, and 0.9% physiological saline comes from Sichuan Cologne medicine company stock
Part Co., Ltd；
Proterties：Colourless clear liquid；
Specification and concentration：0.5% methylcellulose, 0.1% Tween-80,0.9% physiological saline；
Preservation condition：The airtight preservation of room temperature；
Preserve place：Sichuan Kangcheng Bio-tech Co., Ltd.'s test sample storage chamber；
Compound method：Weigh the methylcellulose of required quality, be completely dissolved in appropriate volume 0.9% physiological saline,
Ultrasonically treated 15min, ice bath 10min, are subsequently adding the Tween-80 of required quality, using physiological saline constant volume, fully mix；
Identify after preparation：With white label mark, and indicate test number, substances title and concentration, dose volume,
Preservation condition, the term of validity, person liable and preparation date etc.；
Return and the process of residual solvent reference substance：The solvent control product returned after administration pour sewer into.
2.4 other main agents
Modified form RPMI-1640 culture medium (HyClone Products, specification：500mL, lot number：NZG1385).
Hyclone (Feotal Bovine Serum, Biological Industries Products, specification：
500mL, lot number：1452736).
Trypsase (0.25%Tripsin-EDTA (1 ×), GIBCO Products, specification：100mL, lot number：
1620318).
Matrigel (Matrigel Matrix, CORNING Products, specification：10mL, lot number：4090004)
Human Kallikrein 3/PSA Quantikine ELISA (R＆D Systems Products, specification：96
Hole, lot number：330695)
2.5 key instruments, apparatus
Single Biohazard Safety Equipment (the safe and sound Products in Suzhou, model：BSC-1300IIA2)
CO2gas incubator (THERMO Products, model：THERMO 311)
Inverted microscope (Olympus Products, model：CKX41)
Digimatic calipers (Chengdu Chengliang Tools Group Co., Ltd, model：0-220)
1000 μ L, 200 μ L, 20 μ L micro sample adding appliances (EPPENDRF Products)
Assay balance (METTLER Products, model：ME104)
2.6 cell line
Cell line title：LNCaP/AR PC-3；
Source：Biological therapy state key laboratory of Sichuan University.
3 pilot systems
3.1 experimental animal
Kind：CB17SCID mouse；
Grade：SPF level；
Buy size of animal and sex：80 (male)；
Using size of animal and sex：53 (male)；
Age：5～6 week old；
Body weight：Body weight average 20～24g during castration operation, body weight individual values are in the range of mean ± 20%；
Source：Beijing HFK Bio-Technology Co., Ltd., production licence number：SCXK (capital) 2014-0004.
3.2 feeding and management
3.2.1 environment adapts to
Before test, environment adapts to 6-7 days, selects healthy CB17SCID mouse as animal subject.Laundering period mainly checks knot
Really：
Consistent with the quality index requiring when ordering；
Animal general state is normal；
The weight of animals reaches the weight range of test requirements document；
Underproof abnormal animal does not include this test.
3.2.2 raise place
(animal used as test uses credit number in West China SPF area of Hai Qi Pharmaceutical Technology Co., Ltd (the 3rd)：SYXK (river)
2009-123).
3.2.3 rearing conditions
Stocking density：≤ 5/cage；
Cage tool space displacement frequency：1 times/week.
3.2.4 feeding environment condition
Feeding environment condition standard：People's Republic of China's GB GB14925-2010；
Feeding environment control system：Honeywell company EBI400 automatically controls all-fresh air central air conditioner system；
Temperature：20～26 DEG C of (temperature difference per day<4℃)；
Humidity：Relative humidity 40～70%；
Illumination：Artificial light, 12 hours light and shades replace (07: 30 separate lamp, turns off the light for 19 points for 30 minutes, such as because test needs,
Can illuminate during dark)；
Rate of ventilation：>=15 times/hour, 100% all-fresh air.Non-working time can reduce rate of ventilation, be not below 10 times/
Hour.
3.2.5 feed
Species：Big mouse maintains feed；
Manufacturer：Shanghai Slac Experimental Animal Co., Ltd. provides.Feedstuff Enterprises examine the quality certification：Shanghai
Raise careful (2008) 04002；
Feeding method：Freely absorb (except test has during particular/special requirement)；
Nutrient content detects：(by every batch of offer examining report of supply of forage business) conventional nutrients index：Crude protein, thick
Fat, crude fibre, coarse ash, moisture, calcium and phosphorus；Amino acid index：Threonine, cystine+methionine, valine, different bright ammonia
Acid, leucine, tyrosine+phenylalanine, histidine, lysine, arginine, tryptophan, with reference to country of the People's Republic of China (PRC)
Standard GB14924.3-2010；
The confirmation of food pollution thing content：By every batch of offer examining report of supply of forage business, chemical pollutant index：Arsenic,
Lead, cadmium, mercury, BHC, DDT, AFB1, total plate count, coliform, yeast and mold number, pathogenic bacteria
(salmonella), with reference to National Standard of the People's Republic of China GB14924.2-2001.
3.2.6 drinking-water
Species：Laboratory animal drinking water (reverse osmosis water)；
Method of supplying water：Drinking bottle contains, and freely absorbs；
Total plate count detects：With reference to National Standard of the People's Republic of China GB5749-2006, sampling self-inspection (1 times/week)；
The detection of water quality conventional index：With reference to National Standard of the People's Republic of China GB5749-2006, sampling is sent with phase
The unit closing qualification detects, at least 2 times every year.
4 test methods
4.1CRPC model is set up
6～7 week old CB17SCID mouse are carried out castration operation, carries out LNCaP/AR cell culture simultaneously.Castration operation 3
After it (mouse state is recovered substantially), mouse shaving inoculates about 1.0*10 in right fore dorsal subcutaneous7Individual/LNCaP/ only
(cell suspension presses 1 with Matrigel to AR cell:1 ratio mixes, and cumulative volume about 100 μ L/ is only), observe weekly mouse after inoculation
State and become knurl situation two to three times.Gross tumor volume reaches 100-250mm3, by mouse according to the equivalent packet of gross tumor volume scope.
4.2 animal packets and mark
4.2.1 animal identification
After environment laundering period and packet：Marked as the identification of animal using tail number and cage card；
The labeling method of cage card：
During environment adapts to：Unification is using white cage card, and indicates test number, animal germline, animal serial number, enters the room
Time, remark information etc.；
After packet：Carry out group differentiation with different colours cage card, test number, animal germline, animal are indicated on cage card
Numbering, process factor, expected test beginning and ending time, remark information etc..
4.2.2 animal packet
Test group design：Solvent control group, Ah acetic acid bit dragon -170mg/kg, Abiraterone acetate joint metacortandracin,
AHS-114-300mg/kg, AHS-114-200mg/kg, AHS-114 joint metacortandracin, metacortandracin -2mg/kg；
Size of animal：Metacortandracin group is 5, other each groups every group 8；
Sex：Male；
Group technology：According to the equivalent packet of CB17SCID mouse tumor size, wherein metacortandracin group is to treat other each components
Group supplements packet with what remaining animal was carried out after finishing.
4.3 dose design and foundation
According to the conversion of people's consumption and with reference to abiraterone derivative AHS-114CB17SCID mouse subacute toxicity test
(KP18-2015) result, and consult with consigner, concrete dose design is shown in Table 1.
Table 1 administration design table
Remarks：It is little that drug combination group need to give this group after first uniformly being mixed two kinds of medicines in portion solvent again
Mouse.
4.4 administration
Method of administration：Oral gavage；
Method of administration selects reason：Consistent with clinical plan route of administration；
Administered volume：10mL/kg；
Administration frequency：Once a day, successive administration 28 days；
Administration：The first administration same day is defined as testing the 1st day.
4.5 Testing index
4.5.1 general state is observed
Observing time and frequency：At least observe 1 time daily；
When overt toxicity symptom in animal, increase observed frequency；
Observation index or content：Including but not limited to mouse appearance sign, general behavior activity, the state of mind, body of gland divide
Secrete, breathing state, fecal character, genitals, dead situations such as and other toxicity performance.
4.5.2 measurement of tumor and evaluation
4.5.2.1 relative tumour volume and Relative tumor appreciation rate
Measurement of tumor frequency：At least measure once before starting administration, administration phase once measures the length of tumour every measurement in 2 days
A () and wide (b), calculates gross tumor volume according to " gross tumor volume (TumorVolume, TV), TV=l/2 × a × b2 ".Count respectively
Calculate relative tumour volume (Relative TumorVolume, RTV, RTV=Vt/V0) and Relative tumor rate of increase T/C (%)
=TRTV/CRTV × 100, wherein V0 are (i.e. first day) the first administration same day to measure gained gross tumor volume, and V t is to survey each time
Gross tumor volume during amount, TRTV is treatment group RTV, and CRTV is negative control group RTV.
The standard of curative effect evaluation：T/C (%) >=40 is invalid；T/C (%)<40, and Analysis of variance and negative control group phase
Compare P<0.05 is effective.
4.5.2.2 gross tumor volume changes percentage
According to gross tumor volume, calculate the last dose same day (the 28th day) gross tumor volume change percentage (Vchange%,
Vchange%=(Vt-V0)/V0× 100), wherein V0Measured gained gross tumor volume, Vt for (i.e. first day) the first administration same day
For gross tumor volume when measuring each time.
4.5.2.3 knurl weight and tumor-like hyperplasia
24 hours after last dose, CB17SCID mouse to be dissected is implemented euthanasia, takes knurl, remove around internal organs as early as possible
Connective tissue, and blood and the body fluid of organ surface is sucked with blotting paper, carried out with one thousandth or more precision electronic balance
Weigh.
Tumor-like hyperplasia (%)=(the average knurl weight of the average knurl weight-administration group of solvent control group) average knurl of/negative control group
Weight × 100%.
The standard of curative effect evaluation：Tumor-like hyperplasia<40% is invalid, >=40%, and it is statistically analyzed P<0.05 is effective.
4.5.3 blood-serum P SA detects
Collection Mouse whole blood before dissecting, room temperature places 0.5h to 1h, and in 4 DEG C, 3000rpm separates blood after being centrifuged 15 minutes
Clearly, save backup in -80 DEG C, according to Human Kallikrein 3/PSA (R＆D after all animals sampling terminates
Systems) Quantikine ELISA kit explanation, carries out each mice serum PSA and measures.
4.5.4 prostate and weight of seminal vesicle
Win the prostate winning each mouse while tumour and seminal vesicle, measure its weight with assay balance.
4.5.5 body weight
Minute：Measure 1 body weight in castration operation consent, and in Post operation, Avoirdupois monitoring is carried out according to mouse state；
Measure 1 time before first administration, measure once within every 1-2 days after starting administration.Percentage is changed according to the body weight that body weight calculates each mouse
Than (Wchange%=(Wt-W0)/W0* 100, wherein W0 are (i.e. first day) the first administration same day to measure gained body weight, Wt is every
Body weight during one-shot measurement).
5 statistical analyses and result judgement
Data acquired carries out data analysis using EXCEL and SPSS.
First homogeneity test of variance is carried out using LEVENE inspection, when variance is neat (P >=0.05), using duplicate measurements variance
The group differences that analysis (Repeated measures ANOVA) changes percentage to relative tumour volume and body weight count
Learn inspection, (P when group differences are statistically significant<0.05), using the Dunnett ' s in one-way analysis of variance (ANOVA)
T inspection (Dunnett method) is compared to the group difference of each time point；Duplicate measurements variance analysis display group difference is no united
When meaning learned by meter (P >=0.05), then statistical analysis terminates.(the P when heterogeneity of variance<0.05), using Kruskal-Wallis H
Rank test (K-W method) carries out statistical analysis.When Kruskal-Wallis H rank test display difference is statistically significant
(P<0.05), then adopt Mann-Whitney U inspection (M-W method) that each time point group difference is compared；Work as Kruskal-
During Wallis H rank test display no significant difference (P >=0.05), statistical analysis terminates.
The group differences of other index means, when variance is neat (P >=0.05), using one-way analysis of variance (ONE-
WAYANOVA) statistical test is carried out to group differences, (P when group differences are statistically significant<0.05), using Dunnett '
S t inspection (Dunnett method) is compared to group difference；When one-way analysis of variance display group difference is not statistically significant
(P >=0.05), then statistical analysis terminates.(the P when heterogeneity of variance<0.05), using Kruskal-Wallis H rank test (K-
W method) carry out statistical analysis.(the P when Kruskal-Wallis H rank test display difference is statistically significant<0.05), then
Using Mann-Whitney U inspection (M-W method), group difference is compared；When Kruskal-Wallis H rank test shows
When showing no significant difference (P >=0.05), statistical analysis terminates.
6 result of the tests
6.1 general states are observed
Each group tumour situation directly perceived is as shown in Figure 1.After entering administration phase, each group Mouse Weight is generally on a declining curve, respectively
Group mouse all has individual mice body to assume thin and weak state.From the point of view of tumour intuitive manner, Abiraterone acetate joint metacortandracin group,
AHS-114 joint metacortandracin group mouse tumor is less relative to other groups, and to post-drug period, each group all has at 1-2 mouse tumor
Necrosis cracking and even festers, as shown in black arrow in Fig. 1 in skin.The each group mouse state of mind is still good.
6.2 measurement of tumor and evaluation
6.2.1.1 relative tumour volume
As shown in table 2 and Fig. 2, solvent control group mean relative tumor volume presents steady-state growth trend, in administration phase
(the 28th day) last day was 3.92 ± 0.5, and metacortandracin -2mg/kg group tumour growth situation is similar with solvent control group, is giving
Medicine last day is 4.14 ± 0.71.Abiraterone acetate -170mg/kg group, AHS-114-300mg/kg and AHS-114-
200mg/kg group administration last day mean relative tumor volume be respectively 3.87 ± 0.5,3.93 ± 0.37 and 3.20 ±
0.55, also suitable with solvent control group.Two drug combination group Abiraterone acetate joint metacortandracins, AHS-114 combine bold and vigorous Buddhist nun
Pine group effect is relatively preferable, and administration last day mean relative tumor volume is respectively 1.62 ± 0.29,2.16 ± 0.30.
Compared with solvent control group, Abiraterone acetate joint metacortandracin group is administered the 4th day relative tumour volume conspicuousness
Reduce (P<0.05), administration reduces (P to off-test relative tumour volume all pole conspicuousnesses on the 7th day<0.01)；AHS-114 joins
Close metacortandracin group to be administered the 10th day, reduce (P within the 19th day to the equal conspicuousness of off-test relative tumour volume<0.05)；Other are each
Group there are no significant compared with solvent control group difference (P >=0.05).
Compared with alone group of prednisone acetate, Abiraterone acetate joint metacortandracin group self administration of medication the 4th day to off-test,
Relative tumour volume all pole conspicuousnesses reduce (P<0.01)；AHS-114-300mg/kg group be administered the 10th day relative swollen with the 16th day
Knurl volume conspicuousness reduces (P<0.05)；AHS-114-200mg/kg group is administered the 10th day, the 13rd day and the 16th day Relative tumor
Volume conspicuousness reduces (P<0.05)；AHS-114 joint metacortandracin group is in administration the 7th day, the 19th day and the 28th day Relative tumor
Volume conspicuousness reduces (P<0.05), administration the 10th day to 16 days, the 22nd day and the 25th day relative tumour volume pole conspicuousness fall
Low (P<0.01).
Two drug combination groups are compared, relative tumour volume there are no significant difference (P >=0.05).
Each group relative tumour volume initial data and chart are as shown in annex.
Table 2 each group mean relative tumor volume (Mean ± SEM)
Remarks：*P<0.05, * * P<0.01vs. solvent control group；▲P<0.05,▲▲P<0.01vs. metacortandracin group；#P<
0.05,##P<0.01 Abiraterone acetate joint metacortandracin group vs.AHS-114 joint metacortandracin group.
6.2.1.2 Relative tumor appreciation rate
Each group Relative tumor appreciation rate (T/C (%)) as shown in table 3 and Fig. 3, statistical test result and Relative tumor body
Long-pending identical, therefore not to repeat here.As seen from Figure 3, two drug combination groups T/C (%) with administration time growth be in continue under
Fall trend, in administration last day, Abiraterone acetate joint metacortandracin group T/C (%) is that 41.39 ± 7.46, AHS-114 joins
Closing metacortandracin group T/C (%) is 55.03 ± 7.60, all conspicuousness can suppress tumour growth, but be the failure to reach《Cell toxicant class resists
Tumour medicine non-clinical study technological guidance's principle》The effective standard of medicine in effective standard (T/C (%)≤40).
Table 3 each group Relative tumor appreciation rate (%) (Mean ± SEM)
Remarks：*P<0.05, * * P<0.01vs. solvent control group；▲P<0.05,▲▲P<0.01vs. metacortandracin group；#P<
0.05,##P<0.01 Abiraterone acetate joint metacortandracin group vs.AHS-114 joint metacortandracin group.
6.2.2 gross tumor volume changes percentage
Fig. 4 be administration last day (the 28th day) each group gross tumor volume change percentage (Vchange%=(V t-V0)/
V0 × 100), solvent control group each mouse tumor volume is all big compared with initial volume as seen from the figure, this group totally 8 mouse, tumour body
Long-pending all compared with more than 1 times of primary tumor volume increase (>100%).Abiraterone acetate -170mg/kg group, AHS-114-300mg/
Kg, AHS-114-200mg/kg and metacortandracin -2mg/kg group gross tumor volume change percent profile situation and solvent control group phase
Imitative；Two drug combination group gross tumor volumes change percentages are integrally less than normal, and Abiraterone acetate joint metacortandracin group 8 is merely hit and had 5
Gross tumor volume increase within 1 times compared with primary tumor volume (<100%), wherein there are 3 gross tumor volumes compared with primary tumor volume
Reduce (<0%)；AHS-114 joint metacortandracin group 8 merely hit have 5 gross tumor volumes compared with primary tumor volume increase within 1 times (<
100%).Illustrate that two drug combination groups are more obvious to the inhibitory action of tumour growth.
6.2.3 knurl weight and tumor-like hyperplasia
As shown in table 4 and Fig. 5, solvent control group average ratings knurl weight is 0.431 ± 0.066g, metacortandracin -2mg/kg group
Knurl weight is 0.656 ± 0.230g.Abiraterone acetate -170mg/kg group, AHS-114-300mg/kg and AHS-114-200mg/
Kg group knurl weight is suitable with solvent control group.Two drug combination group Abiraterone acetate joint metacortandracins, AHS-114 combine bold and vigorous Buddhist nun
Pine group effect is relatively preferable, and average knurl weight is respectively 0.234 ± 0.077g, 0.204 ± 0.038g, and tumor-like hyperplasia is respectively
45.67%th, 52.56%.
Compared with solvent control group, Abiraterone acetate joint metacortandracin group knurl weight conspicuousness reduces (P<0.05), AHS-
114 joint metacortandracin group knurl weight pole conspicuousnesses reduce (P<0.01).That there are no significant compared with solvent control group is poor for other each groups
Different (P >=0.05).
Compared with metacortandracin -2mg/kg group, the equal conspicuousness of two drug combination group knurl weights reduces (P<0.05).
Compare between two drug combination groups, there was no significant difference for knurl weight (P >=0.05).
Fig. 6 is each group tumor tissue in vitro digital photograph.
Table 4 knurl weight and tumor-like hyperplasia (Mean ± SEM)
Remarks：*P<0.05, * * P<0.01vs. solvent control group；▲P<0.05,▲▲P<0.01vs. metacortandracin group；#P<
0.05,##P<0.01 Abiraterone acetate joint metacortandracin group vs.AHS-114 joint metacortandracin group.
6.3 blood-serum P SA detections
As shown in table 5 and Fig. 7, solvent control group blood-serum P SA concentration is 64.67 ± 10.27ng/ to each group blood-serum P SA concentration
ML, Abiraterone acetate joint metacortandracin group blood-serum P SA concentration is 40.16 ± 16.25ng/mL, AHS-114 joint metacortandracin group
Blood-serum P SA concentration is 22.23 ± 6.80ng/mL.
Compared with solvent control group, Abiraterone acetate joint metacortandracin can to a certain degree reduce blood-serum P SA content, but no
Significant difference (P >=0.05)；AHS-114 joint metacortandracin energy pole conspicuousness reduces blood-serum P SA content (P<0.01)；Other are each
Group there are no significant compared with solvent control group difference (P >=0.05).
Compared with metacortandracin -2mg/kg group, AHS-114 joint metacortandracin energy conspicuousness reduces blood-serum P SA content (P<
0.05).
Compare between two drug combination groups, there was no significant difference for blood-serum P SA content (P >=0.05).
6.4 prostates and weight of seminal vesicle
Each group prostate and weight of seminal vesicle are as shown in table 6, difference that between each group, there are no significant (P >=0.05).
Table 6 prostate and weight of seminal vesicle (Mean ± SEM)
Remarks：*P<0.05, * * P<0.01vs. solvent control group；▲P<0.05,▲▲P<0.01vs. metacortandracin group；#P<
0.05,##P<0.01 Abiraterone acetate joint metacortandracin group vs.AHS-114 joint metacortandracin group.
6.5 body weight
Each group changes of weight percentage is as indicated, the prolongation in time of each group body weight all assumes continuous decrease trend, between group
No significant difference (P >=0.05).
Conclusion
Alone group of (n=5) mean relative tumor volume of solvent control group (n=8) and metacortandracin presents steady-state growth and becomes
Gesture, compared with solvent control group, Abiraterone acetate joint metacortandracin group (n=8) is administered the 4th day relative tumour volume conspicuousness
Reduce, administration reduces on the 7th day to off-test relative tumour volume all pole conspicuousnesses；AHS-114 joint metacortandracin group (n=8)
It is administered the 10th day, reduce within the 19th day to the equal conspicuousness of off-test relative tumour volume；Other each administration group tumour growth situations
Similar with solvent control group.In administration last day, alone group of T/C (%) of metacortandracin is 105.64 ± 18.14, tumor-like hyperplasia
For -18.78%, no tumor inhibition effect compared with solvent control group；Abiraterone acetate combines metacortandracin group T/C (%)
41.39 ± 7.46, AHS-114 joint metacortandracin group T/C (%) they are 55.03 ± 7.60, all conspicuousness can suppress tumour growth, but
It is to also fail to reach《Cell toxicant series antineoplastic medicament non-clinical study technological guidance's principle》The effective standard of medicine in effective
Standard (T/C (%)≤40), two groups of tumor-like hyperplasia respectively 45.67%, 52.56%, obvious to knurl weight inhibitory action；Separately
Outward, AHS-114 joint metacortandracin can also reduce tumor-bearing mice blood-serum P SA concentration in pole conspicuousness ground, also further illustrates by reagent
Castration-resistant prostate cancer tumor-bearing mice tumour can be increased after AHS-114 joint metacortandracin has more significantly suppression to make
With.Compare between two drug combination groups, each index there are no significant difference.
Each group all has skin at individual mice tumour cracking and necrosis, and each group body weight is generally on a declining curve simultaneously,
Each group is all inconspicuous to the improvement situation of body weight.
In sum, after by reagent AHS-114-200mg/kg joint metacortandracin, to castration-resistant prostate cancer lotus knurl
Mouse tumor increases more obvious inhibitory action, does not assume obvious toxic-side effects, with the positive drug acetic acid under Isodose
Abiraterone joint metacortandracin is suitable to the inhibitory action of tumour, but is also not up to《Cell toxicant series antineoplastic medicament non-clinical is ground
Study carefully technological guidance's principle》Effective standard.
Above the specific embodiment of the present invention is described.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make various modifications or modification within the scope of the claims, this not shadow
Ring the flesh and blood of the present invention.
Claims (3)
1. a kind of pharmcokinetic evaluation method of abiraterone derivative is it is characterised in that comprise the steps：
Male mice is carried out castration Post operation, inoculates LNCaP/AR cell；
It is divided into equivalent for described male mice Abiraterone acetate -170mg/kg group, Abiraterone acetate joint metacortandracin group, is subject to
Reagent abiraterone derivative -300mg/kg group, abiraterone derivative -200mg/kg group, abiraterone derivative are combined bold and vigorous
Buddhist nun's pine group, solvent control group and totally seven groups of metacortandracin -2mg/kg group；
Using oral gastric infusion, all groups of other male mices are administered once a day according to group, successive administration 28 days, fixed
Phase measures body weight and gross tumor volume, 24 hours after last dose, collects determination of serum PSA (PSA) concentration,
And take tumour, seminal vesicle and prostate to be weighed, and it is calculated relative tumour volume, the Relative tumor rate of increase, tumour body
Long-pending change percentage, tumor-like hyperplasia and changes of weight percentage.
2. the pharmcokinetic evaluation method of abiraterone derivative as claimed in claim 1 is it is characterised in that described male
Mouse is the male CB17SCID mouse of 6～7 week old.
3. the pharmcokinetic evaluation method of abiraterone derivative as claimed in claim 1 is it is characterised in that inoculate
The gross tumor volume of the male mice of LNCaP/AR cell is 100～250mm3.
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