CN107569485A - A kind of compound preparation for treating BRAF inhibitor drug-resistant type melanomas - Google Patents
A kind of compound preparation for treating BRAF inhibitor drug-resistant type melanomas Download PDFInfo
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- CN107569485A CN107569485A CN201710606528.7A CN201710606528A CN107569485A CN 107569485 A CN107569485 A CN 107569485A CN 201710606528 A CN201710606528 A CN 201710606528A CN 107569485 A CN107569485 A CN 107569485A
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- propranolol
- wei luofeini
- compound preparation
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- braf inhibitor
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Abstract
The invention discloses a kind of compound preparation for treating BRAF inhibitor drug-resistant type melanomas.Medicinal ingredient in the compound preparation includes Wei Luofeini and Propranolol；The weight ratio of the Wei Luofeini and Propranolol are (5-15):1.The compound preparation of the present invention is more economically effective, mitigates the family burden of patient.
Description
Technical field
The invention belongs to biomedicine technical field, and in particular to a kind of BRAF inhibitor drug-resistant type melanomas for the treatment of
Compound preparation.
Background technology
Melanoma, also known as malignant mela noma, a kind of malignant tumour of melanocyte is derived from, is common in skin
Skin, also see the positions such as mucous membrane, ocular choroid.In Asian and coloured race, the melanoma for being primary in skin accounts for 50%
~70%, most common original site is acra, i.e. vola, toes, finger tips and the inferior position of first, secondly black for mucous membrane
Melanoma.70% cutaneous melanoma carries BRAF (V600E) mutation, causes the lasting and excessive activation of MAPK paths, causes
Uncontrolled cellular proliferation.Melanoma is grade malignancy highest knurl kind in skin neoplasin, DISTANT METASTASES IN, therefore early stage easily occurs
Diagnose and treat thus be particularly important.
The medicine for the treatment of melanoma is broadly divided into the dimension Rofe included in target therapeutic agent, such as the present invention at present
Buddhist nun, cell toxicity medicament such as Dacarbazine etc., immunotherapy medicaments such as CTLA-4 monoclonal antibody drugs etc., and angiogenesis suppression
Preparation such as bevacizumab etc..
Wei Luofeini is the first-line drug for being used for the treatment of BRAF saltant types melanoma of FDA approvals, and its is evident in efficacy excellent
In classic chemotherapy medicine, however, with the development for the treatment of, more than 50% patient starts after Wei Luofeini is taken 6-8 months
There is acquired resistance, cause tumor recurrence and Endodontic failure.Although double targeted drugs (BRAF inhibitor and mek inhibitor, such as
Sibutramine Hydrochloride replaces Buddhist nun, Trametinib) it is combined to tackle the therapeutic scheme of resistance also in Clinical practice, but its treatment is expensive and controls
Treat limited, BRAF inhibitor acquired resistance problems are still the generally acknowledged significant challenge in a whole world.
The content of the invention
It is contemplated that overcome the deficiencies in the prior art, there is provided a kind of to treat answering for BRAF inhibitor drug-resistant type melanomas
Square preparation.
In order to achieve the above object, technical scheme provided by the invention is：
Medicinal ingredient in the compound preparation of the treatment BRAF inhibitor drug-resistant type melanomas include Wei Luofeini and
Propranolol；The weight ratio of the Wei Luofeini and Propranolol are (5-15):1.
Preferably, the weight ratio of the Wei Luofeini and Propranolol are (8-12):1.
It is highly preferred that the weight ratio of the Wei Luofeini and Propranolol is 10:1.
Wherein, the BRAF inhibitor is Wei Luofeini.
The compound preparation for the treatment of BRAF inhibitor drug-resistant type melanomas of the present invention can be according to side known in the industry
Prepared by method, i.e., by the way that Wei Luofeini and Propranolol are admixed to obtain with appropriate inert solid or liquid pharmaceutical carrier.Can be with
Oral compound preparation is made, the formulation for being adapted to oral compound preparation can be tablet, granula, capsule, supensoid agent, syrup
Agent.Wherein tablet, granula, capsule can contain the carrier and/or assistant agent commonly used in pharmaceuticals industry.Such as Icing Sugar, starch, suction
Receive agent (such as dextrin), disintegrant (such as Tween-80), lubricant (such as 50% ethanol), magnesium stearate etc..Wherein it is suspended
Agent, syrup can also contain the carrier and/or assistant agent commonly used in pharmaceuticals industry.Such as diluent (such as water, distilled water, second
Alcohol, polyethylene glycol, glycerine etc.), conventional additive (such as suspending liquid, preservative, flavouring etc.).Tablet, granula can be by dry
It is prepared by method or wet granulation technology.The appropriate mixture of compound can be inserted in soft or hard gelatine capsule and is made by capsule.
Supensoid agent and syrup can add the appropriate mixture of compound water-soluble mixed with being made in the diluent of suspending agent, preservative etc.
Liquid, the diluent are preferably distilled water, and suspending agent is preferably tragacanth, and preservative is preferably nipalgin second, the third fat, syrup
In be preferably added flavouring, flavouring is sucrose.
Due to studies have found that Propranolol its there are antineoplastic action, some clinical epidemiologies to a certain extent
Research, which reports Propranolol, can significantly reduce the occurrence and development and transfer of breast cancer, melanoma etc..Wei Luofeini is long-term
Treatment occurs after acquired resistance, it is necessary to drug combination could preferably control the development of tumour, the present invention by Propranolol with
Wei Luofeini is combined, and from the discovery of internal experiment in vitro, both, which share, can effectively solve Wei Luofeini resistance problems, and inquire into both
Share the mechanism that treatment Wei Luofeini drug resistance melanomas may relate to.At present, so far there are no Propranolol and dimension Rofe
The compound preparation of both medicines of Buddhist nun.
The invention provides a kind of Wei Luofeini convenient to take, safe to use and the compound treatment drug-resistant type of Propranolol
Melanoma preparation, it is focused on produces acquired resistance by solving the problems, such as that Wei Luofeini is long-term use of, and it can reduce dimension sieve
Non- Buddhist nun's drug resistance, and tumor recurrence can be effectively prevented to a certain extent.Double targets are used for solving resistance problems at present
It is combined to medicine (BRAF inhibitor and mek inhibitor, as Sibutramine Hydrochloride replaces Buddhist nun, Trametinib), its expensive and treatment is limited,
The compound preparation of the present invention is more economically effective, mitigates the family burden of patient.
Brief description of the drawings
Fig. 1 is that Propranolol shares the potential mechanism experimental result picture that Wei Luofeini overcomes resistance；MT1F is in persister
Expression and overexpression MT1F share influence A, B, RT-PCR the detection A375p of Wei Luofeini reversing drug resistances to Propranolol,
MT1F mRNA level in-site in A375R, P-8P, P-8R, * * * * represent P 0.0001, compared with parent plant, C, D, and A375R and P-
After 8R cell transfectings MT1F is overexpressed plasmid, 20 μM of Propranolols, 0.5 μM of Wei Luofeini is individually or after sharing processing 24h,
AlarmBlue detect cell viability, * * * * represent P 0.0001, unloaded group compared with transfecting after MT1F composite reagents, E,
After A375R and P-8R cell transfectings MT1F is overexpressed plasmid, 20 μM of Propranolols, 0.5 μM of Wei Luofeini is independent or shares place
After managing 24h, Tunel detection Apoptosis；
Fig. 2 is that Propranolol shares therapeutic effect the results of the Wei Luofeini to drug-resistant type melanoma mouse model
Figure；A, B gross tumor volume represent the average value of each 6 mouse tumor volumes for the treatment of group, C, the Kaplan-Meier lifes of each treatment group
Curve is deposited, D, the average weight of each treatment group, * * * * * represent P 0.00001, compared with Pro groups；
Fig. 3 is that Propranolol shares Wei Luofeini induction nude mice resistant models Apoptosis the result figures；Propranolol
Share influence A, HE dyeing (400X, n=6) of the Wei Luofeini to nude mice resistant models cell apoptosis and proliferation, B, Tunel dyeing
(400X, n=6) C, immune group groupization detect Ki67 expression (100X, n=6)；
Fig. 4 is that Propranolol shares Wei Luofeini induction A375R and P-8R Apoptosis the result figures；Propranolol closes
With Wei Luofeini induction A375R and P-8R Apoptosis persister shared through 20 μM of Propranolol and 0.5 μM of Wei Luofeini or
Individually processing A375R and P-8R is after 24 hours, Tunel dyeing detection Apoptosis.
Embodiment
Propranolol shares the potential mechanism that Wei Luofeini overcomes resistance：
Build MT1F and be overexpressed plasmid, after being transfected to A375R and P-8R cells, 20 μM of Propranolols, 0.5 μM of dimension
Rofe Buddhist nun individually or share processing transfection after cell 24h after, AlarmBlue and Tunel dyeing detect cell viability respectively
With apoptosis, as a result as shown in figure 1, MT1F is overexpressed reduces Propranolol and share inhibitory action of the Wei Luofeini to cell viability
(such as Fig. 1 C, D, P 0.0001), MT1F are overexpressed inducing action (such as Fig. 1 E, P alleviated with medication to Apoptosis
0.0001).Data above prompting MT1F is probably that regulation and control Propranolol shares the important factor in order that Wei Luofeini overcomes resistance.
Propranolol shares Wei Luofeini and the therapeutic effect of drug-resistant type melanoma mouse model is verified：
Medicinal ingredient in the compound preparation of the treatment BRAF inhibitor drug-resistant type melanomas include Wei Luofeini and
Propranolol；The weight ratio of the Wei Luofeini and Propranolol are (5-15):1.Preferably (8-12):1.More preferably
10:1.Wherein, the BRAF inhibitor is Wei Luofeini.
Method：
A. the preparation of cell suspension：The A375 cell expansion cultures into knurl will be needed, energetic (vigor is big by pollution-free
In 95%) tumour cell digest centrifugation, be suspended in it is dual anti-containing 5%, in 10%matrigel and 2%FBS precooling DMEM,
Cell density is greater than 1*107/ml.
B. subcutaneously into knurl, after the sterilization of nude mice injection site chelated iodine, every mouse plantation 0.2ml cell suspension is in small
Mouse armpit is subcutaneous, and presses injection site with cotton swab, prevents liquid from flowing out, pays attention to the not too deep arrival muscle layer of inserting needle, otherwise can
Cause metastases animal dead
C. after tumor planting, the growing state of reaction of animals and knurl body is observed daily, carries out experimental record
D. the treatment of nude mice model：Inoculating cell inoculation start within second day, twice a week observe nude mice body weight and
Knurl body growing state, with length (L, the unit of vernier calliper dipstick metering knurl body：Mm), wide (W, unit：Mm) high (H, unit：), mm tumour
Volume calculation formula is T=π/6 × L × W × H when knurl body reaches 30mm3During left and right, the nude mice into knurl is randomly divided into 4 groups,
Every group 6, PBS groups, Propranolol low dose group (2mg/kg/day), Wei Luofeini groups (10mg/kg/day) Wei Luofeini conjunctions
With Propranolol group, gastric infusion, during treatment, continuous processing is spaced two days for 5 days, coprocessing 21 days, measures knurl body length daily,
Width, high, nude mice weight are rear and observe the growing state of reaction of animals and knurl body.During treatment, the body weight of nude mice is measured daily
And tumorous size.Experiment is in triplicate.
E. mouse was put to death at the 21st day for the treatment of, takes out knurl body tissue and be used for subsequent experimental.
As a result：
Using BALB/C male nude mouses as animal research models, A375R subcutaneously into after knurl, persistently gives 15mg/kg/day
Wei Luofeini, successfully constructed when knurl body grows resistant models, at 2mg/kg/day Propranolols and 20mg/kg/day Wei Luofeini
Nude mice is managed after 21 days, as shown in Fig. 2 Propranolol, which shares Wei Luofeini groups, significantly suppress the growth of knurl body, alone Propranolol
It is too late to share obvious (such as Fig. 2 A, B)；Share medicine and significantly extend animal survival (such as Fig. 2 C, P 0.00001), share medicine
Nude mice body weight is not significantly inhibited (such as Fig. 2 D).Data above shows that Propranolol shares Wei Luofeini and significantly inhibits dimension sieve
The growth of non-Buddhist nun's drug-resistant tumor.
Propranolol shares Wei Luofeini induction nude mice resistant models Apoptosis checkings：
Method：
1) reagent needed for HE Coloration experiments：
A. the mother liquors of 10Hoechst 33258 are prepared：By 1 milligram of 33258 powder of Hoechst, 20 milliliters of double steamings are dissolved in
Water, then filter, be kept in dark place and mother liquor is diluted to working solution, ultimate density with 10 times of distilled water when 4 DEG C of refrigerators, use
For 5g/ml, the concentration that general nuclear targeting uses is 0.5-10g/ml.
B. mounting liquid is prepared：50mM Na2HPO4,50%glycerine, 20mM citric acid, finally adjust pH value
For 5.5.
C. cell fixer：4% paraformaldehyde or 70% ice ethanol
Specific experiment step:
A. the cell climbing sheet of A375R and P-8R cells is made, concrete operations are as follows：
A) will be standby by the cover glass soaked overnight of cleaning with absolute ethyl alcohol, dried up in sterile super-clean bench, then use PBS
Washing time, then washed one time with culture medium, the cover glass washed then is put into six orifice plates, by A375R and P-8R cell kinds
In implantation, cell confluency rate up to when 70% or so carry out next step operation.
B) after 20 μM of Propranolols and 0.5 μM of Wei Luofeini handle the processing of A375R and P-8R cells 24 hours respectively,
Culture medium is outwelled, 1 milliliter of 4% paraformaldehyde is then added, fixes 30 minutes in 37 DEG C of incubators or 4 DEG C of refrigerators were fixed
Night.
C) 4% paraformaldehyde is gently outwelled, then physiological saline (0.9% sodium chloride) or PBS, are placed on shaking table, low speed
Degree washing 3 times, 4 minutes every time, blotting paper blotted unnecessary liquid.
D) the Hoechst dyeing liquors that 500 μ l concentration are 5 μ g/ml are added per hole, lucifuge is placed on shaking table, room temperature dyeing
10min。
E) six orifice plates are washed：2 milliliters of physiological saline or PBS is added per hole, is put on shaking table, washing 3 times, every time
4min。
F) slide by cleaning marks, and 1 drop mounting liquid is added dropwise, and pays attention to avoiding producing bubble, from 6 orifice plates at gripping
The cover glass managed, cell face interior contact mounting liquid, are placed on slide.
Remarks：Slide room temperature is dried, then taken pictures with fluorescence microscope, Detection wavelength and reference wavelength difference
It is 360 nanometers and 450 nanometers.
G) excitation wavelength of fluorescence and launch wavelength are 350 nanometers and 460 rans respectively, visible blue cell under mirror
Core.
2) Tunel colouring methods embodiment in the following example.
As a result：Display substantially increases (such as Fig. 3) with reference to medication group nuclear fragmentation and pyknosis；To explore resistance knurl body cell
Apoptosis situation, Tunel dyeing detection histocyte apoptosis, as a result as shown in Fig. 3 B, Propranolol shares Wei Luofeini groups
Tunel positive cells are obvious not as good as combination group compared with other three groups of showed increaseds, alone Propranolol group apoptosis；Meanwhile immune group
Change the expression of detection propagation Antigens Ki67.Share medicine group Ki67 expression to be remarkably decreased compared with PBS groups and Wei Luofeini groups, Propranolol
Independent treatment group Ki67 reduction degree is obvious not as good as combination group.The result above result prompts general naphthalene Lip river to share Wei Luofeini rush
Enter cells of resistant tumors necrosis, Apoptosis and Inhibit proliferaton.
Propranolol shares Wei Luofeini induction A375R and P-8R Apoptosis checkings：
Method：20 μM of Propranolols and 0.5 μM of Wei Luofeini are alone or after sharing processing A375R and P-8R cells 24h,
Tunel dyeing detection cell viabilities:
A. experiment equipment and reagent：
Experiment equipment：Come card fluorescence microscope, staining jar, lucifuge wet box, cover glass, pipettor, tip heads, suction pipe
Kit (Roche)：
10×TdT：Enzyme Solution enzyme solutions (No. 1 blue cap)
1×dUTP：Fluorescein-labeled dUTP (No. 2 purple lids)
The HRP of mark fluorescent element antibody：Converter-POD (No. 3 brown bottles)
No. 3 (brown bottle) Converter-POD:The HRP of mark fluorescent element antibody；
Other provide reagent for oneself：Phosphate buffer (PBS), ddH2O, dimethylbenzene, the ethanol of various concentrations；
Proteinase K working solutions (10-20mg/L, are diluted with 10mmol/L Tris/HCl and prepared, PH=7.4), carefully
The penetrating liquid of born of the same parents (adds 1 milliliter of Triton X-100, concentration 0.1%) in 1000 milliliter of 0.1% sodium citrate solution
B. concrete operation step is as follows：
A) a thin layer of poly-D-lysine will be applied on slide, is rinsed in deionized water after drying, 4 DEG C of guarantors after drying
Deposit；
B) A375R (8000/hole) of exponential phase and P-8R (6000/hole) cell are planted in 24 orifice plates respectively
In, per pore volume 1ml, after cultivating 24 hours, 20 μM of Propranolols are independent or share 0.5 μM of Wei Luofeini (Plx4032) place
Manage A375R and P-8R cells 24 hours；
C) by the A375R handled well and P-8R each group cell tryptase enzymic digestion, about 1 × 106 cell, PBS is collected by centrifugation
Wash once, be resuspended, be added on the poly-D-lysine slide completed, spontaneously dry, cell is adsorbed onto well on slide；
D) slide of adherent cell is fixed 30 minutes in 4% paraformaldehyde；
E) PBS embathes secondary, each 5min；
F) slide of adherent cell is handled 10 minutes in 0.2% Triton X-100；
G) appropriate Proteinase K are added dropwise to slide, is placed in 37 DEG C of incubators and handles 20 minutes, then PBS washings
2 times, every time 3 minutes
H) negative control and positive control are set：Positive control with 100 μ l DNaseI 37 DEG C processing 10 points in after, PBS
Washing, then TUNEL reaction mix are added dropwise, negative control directly adds the fluorescein-labeled dUTP buffer of 50 μ l；
I) TUNEL reacts mix preparation：The fluorescein-labeled dUTP buffer of 450 μ l and 50 μ l TdT are mixed in proportion
It is even, 50 μ l are then added dropwise and are handled 60 minutes under the conditions of 37 DEG C in wet box to tissue, covered, lucifuge；
J) wash：Slice, thin piece is immersed in PBS, washed 3 times, every time 5 minutes；
K) dyeing of Hoechst 33258 is set to nucleus：Working concentration by Hoechst dye-dilutions to 2 μ g/ml, so
After be added drop-wise on slice, thin piece, 37 DEG C of lucifuges dye 10 minutes；
L) wash：Slice, thin piece is immersed in PBS, washed 3 times, every time 5 minutes；、
M) an anti-fluorescence quenching of drop is added dropwise on slice, thin piece, is then covered with cover glass, lucifuge is thin with fluorescence microscope
Born of the same parents' apoptosis situation：There is red fluorescent in the cell of apoptosis, and Hoechst dyeing visible cell cores concentrate, chromatin divided,
Marginalisation, nuclear membrane crush imperfect；Normal cell loses red fluorescent, and Hoechst staining cell cores are oval, pale blue
Color, between two parties.
As a result：As shown in figure 4, to share Wei Luofeini group Apoptosis situations bright compared with Propranolol list medicine group for Propranolol
Aobvious, Propranolol group apoptosis situation is slightly higher compared with Wei Luofeini groups.The Notes of Key Data Propranolol shares Wei Luofeini induction dimensions
Rofe Buddhist nun's mdr cell apoptosis.
Claims (4)
1. a kind of compound preparation for treating BRAF inhibitor drug-resistant type melanomas, it is characterised in that in the compound preparation
Medicinal ingredient includes Wei Luofeini and Propranolol；The weight ratio of the Wei Luofeini and Propranolol are (5-15):1.
2. compound preparation as claimed in claim 1, it is characterised in that the weight ratio of the Wei Luofeini and Propranolol
For (8-12):1.
3. compound preparation as claimed in claim 2, it is characterised in that the weight ratio of the Wei Luofeini and Propranolol
For 10:1.
4. the compound preparation as described in any one of claims 1 to 3, it is characterised in that the BRAF inhibitor is Wei Luofeini.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710606528.7A CN107569485A (en) | 2017-07-24 | 2017-07-24 | A kind of compound preparation for treating BRAF inhibitor drug-resistant type melanomas |
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| CN201710606528.7A CN107569485A (en) | 2017-07-24 | 2017-07-24 | A kind of compound preparation for treating BRAF inhibitor drug-resistant type melanomas |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110898054A (en) * | 2019-12-16 | 2020-03-24 | 中国人民解放军第四军医大学 | Pharmaceutical composition for treating BRAFV600E mutant melanoma |
| CN112168821A (en) * | 2020-11-09 | 2021-01-05 | 中南大学湘雅医院 | Combined medicine for treating vemurafenib-resistant melanoma and application thereof |
| CN114224875A (en) * | 2021-11-04 | 2022-03-25 | 中南大学湘雅医院 | New application of alcohol compound and antitumor drug |
-
2017
- 2017-07-24 CN CN201710606528.7A patent/CN107569485A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| CHENGFANG ZHOU ET AL: "Abstract 1186: Propranolol could overcome BRAF inhibitors resistance by multiple mechanisms in melanoma", 《PROCEEDINGS: AACR ANNUAL MEETING 2017》 * |
| CHENGFANG ZHOU ET AL: "Propranolol induced G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway", 《ONCOTARGET》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110898054A (en) * | 2019-12-16 | 2020-03-24 | 中国人民解放军第四军医大学 | Pharmaceutical composition for treating BRAFV600E mutant melanoma |
| CN112168821A (en) * | 2020-11-09 | 2021-01-05 | 中南大学湘雅医院 | Combined medicine for treating vemurafenib-resistant melanoma and application thereof |
| CN112168821B (en) * | 2020-11-09 | 2022-10-14 | 中南大学湘雅医院 | Combined medicine for treating vemurafenib-resistant melanoma and application thereof |
| CN114224875A (en) * | 2021-11-04 | 2022-03-25 | 中南大学湘雅医院 | New application of alcohol compound and antitumor drug |
| CN114224875B (en) * | 2021-11-04 | 2023-08-11 | 中南大学湘雅医院 | New use of alcohol compound and antitumor drug |
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Application publication date: 20180112 |