CN104013640B - Fucoidan application in the medicine of preparation treatment cachexia and cancer - Google Patents
Fucoidan application in the medicine of preparation treatment cachexia and cancer Download PDFInfo
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Abstract
The invention discloses fucoidan application in preparation treatment cachexia and cancer drug.Described cachexia can be caused by selected from the disease of following formed group, state or damage: cancer, immunological incompetence disease, infectious disease, autoimmune disease, metabolic disease and chronic intestinal, liver, kidney, lungs and heart disease, apositia, wound, burn, alimentation be bad and anemia.In an instantiation, the medicine of the present invention can cast the patient suffering from the possibility cachectic disease of generation, such as, cancer etc..Especially, present invention also offers fucoidan application in preparation treatment bladder cancer medicine, particularly in the application suppressing the tumor growth of bladder cancer, neonate tumour blood vessel, cancerous cell to divide a word with a hyphen at the end of a line and in infringement ability.
Description
Technical field
The present invention relates to a kind of cachexia and the New therapies of cancer and pharmaceutical composition.Specifically, the present invention carries
Supply at individuality in need, such as cancer sufferer, used fucoidan to improve or to slow down the side of cachectic symptom
Method.The present invention also relates to fucoidan apply in the medicine of preparation treatment bladder cancer, particularly suppress bladder cancer
Tumor growth, neonate tumour blood vessel, cancerous cell are divided a word with a hyphen at the end of a line and infringement ability.
Background technology
Cachexia (cachexia) is a kind of produced complicated metabolic syndrome under disease event, main
Clinical symptom is muscle consume and weight loss (Evans WJ et al.Clin Nutr.2008;27:793).Face at present
Diagnosing cachectic standard on bed is: patient has the situation of lasting weight loss, such as, loses weight former in 1 year
The 5% of body weight, and with wherein three of following five standards: muscle tone reduction, fatigue, anorexia, low nothing
Fat weight index and biochemical index are abnormal, such as, inflammatory factor rising (e.g., the white-6(IL-6 of interleukin),
Reactive protein (CRP)), anemia (hemoglobin concentration be less than 12g/dL), serum albumin decline (less than 3.2g/dL)
(Evans WJ et al., supra) etc..Cachectic muscle consume symptom cannot be replied by supply nutrition merely,
Itself and because of relevant muscle quality hungry, aging run off, constitutional melancholia or cryptorrhea and the symptom that produces
And differ.Even if cachectic sufferer increases food-intake or improves the picked-up of nutrition, also cannot prevent or stop disease
Suffer from the continuous decrease of body weight.
Cachexia can occur in many chronic diseases or patient with severe symptoms, such as, cancer (e.g., bladder cancer, hepatocarcinoma,
Breast carcinoma, ovarian cancer, gastric cancer, pancreatic cancer, colorectal cancer, osteocarcinoma, leukemia etc.), immunological incompetence disease (e.g., Chinese mugwort
Grow sick etc.), infectious disease (e.g., tuberculosis, septicemia etc.), autoimmune disease (e.g., close by rheumatic
Joint is scorching), metabolic disease (e.g., diabetes etc.) and chronic intestinal, liver, kidney, lungs or the heart
Dirty disease (e.g., liver cirrhosis, renal failure, chronic obstructive pulmonary disease (COPD), chronic heart failure etc.),
Apositia, wound or burn, bad, the anemia of alimentation etc..Cachexia can reduce patient's various physiology merit rapidly
Can, make quality of life decline, last health cannot bear various treatment because of the weakest, accelerates death.
Currently for treatment of cachexia direction to improve patients ' life quality, increase appetite, reduction feeling of fatigue, to subtract
Promoting inflammatory factor less and increase body slimming quality is main, its common drug can be divided into four big classes: (1) protein stimulatory closes
Become agent, such as, abolon (nandrolone decanoate), insulin (insulin), steroid
(corticosteroids) etc.；(2) appetite accelerator, such as, megestrol acetate (megestrol acetate),
Medroxyprogesterone (medroxyprogesterone) etc.；(3) cytokine inhibitors, as Thalidomide (thalidomide),
Melatonin (melatonin) etc.；(4) anti-inflammatory drug, e.g., on-steroidal anti-inflammatory drug etc..But,
Though these medicines can improve appetite or put on weight, but muscle quality do not increase (Donohoe CL et al.,
Gastroenterology research and practice.2011;2011:601434).Therefore, it is still necessary to provide another
One treats cachectic new method.
Fucoidan (Brown algae candy glue, fucoidan) is the polysaccharide body of a kind of sulfuration, can be obtained by multiple Brown algae,
Such as, Thallus Laminariae (Thallus Eckloniae), Thallus Laminariae, horse hair dish etc..Known fucoidan has multiple biological activity, including anti-inflammatory (Li C
et al.,Food and chemical toxicology2011;49:2090-5,Park HY et al.,Food and chemical
toxicology2011;49:1745-52,Cumashi A et al.,Glycobiology.2007;17:541-52), antioxygen
Change (Wang J et al., International journal of biological macromolecules.2008;
42:127-32) and immunomodulating (Zapopozhets TS et al., Antibiotiki i khimioterapiia=Antibiotics
and chemoterapy[sic]/Ministerstvo meditsinskoi i mikrobiologicheskoi promyshlennosti
SSSR.1995;40:9-13) etc., also have research display its for pulmonary carcinoma, malignant melanoma or colorectal cancer have antitumor or
Effect (Ale MT et al., the International journal of biological of anticancer growth
macromolecules.2011;49:331-6,Kim EJ et al.,BMC gastroenterology.2010;10:
96,Koyanagi S et al.,Biochemical pharmacology.2003;65:173-9).But, there is no at present
Any prior art discloses fucoidan and may be used to treat cachexia.
Summary of the invention
On the one hand, the invention provides fucoidan application in cachectic medicine is treated in preparation.Additionally,
Present invention also offers one and treat cachectic pharmaceutical composition, it fucoidan including treating effective dose,
And one or more pharmaceutically acceptable carrier.Present invention provides and fucoidan is cast individuality in need
To treat cachectic method.
On the other hand, the invention provides the new therapy of a kind of cancer, it includes casting individuality in need controlling
Treat the anticancer agent of cancer effective amount and/or bestow radiation therapy, and casting the brown for the treatment of cachexia effective dose simultaneously
Algae carbohydrate gum.The present invention also provides one to treat cancer and cachectic pharmaceutical composition, and it includes the first active component,
Described first active component includes the anticancer agent of one or more treatment cancer effective amount；Second active component, described
Second active component includes the fucoidan treating cachexia effective dose, and one or more pharmaceutically acceptable load
Body.
On the other hand, the invention provides fucoidan application in the medicine of preparation treatment bladder cancer.This
Bright still providing a kind of pharmaceutical composition treating bladder cancer, it includes the fucoidan of therapeutically effective amount, and one or
Multiple pharmaceutically acceptable carrier.Particularly, the pharmaceutical composition of the present invention can effectively suppress the swollen of bladder cancer
Tumor growth, neonate tumour blood vessel, cancerous cell are divided a word with a hyphen at the end of a line and infringement ability.The present invention also provides and has been cast by fucoidan
The individuality needed is with the method treating bladder cancer.
The various specific embodiments of the present invention are described in more detail below.Other features of the present invention will be shown under passing through
Close the detailed description of various specific embodiment and claim and clearly appear from.
Believing can be according to herein in the case of be not required to further illustrate those skilled in the art in the invention
Description utilizes the present invention to its widest scope.Therefore, description below should be taken as the purpose of illustration rather than with any side
Formula is as the restriction of the scope of the present invention.
Accompanying drawing explanation
Fig. 1 shows that fucoidan improves or slow down (A) body weight and (B) food-intake in cachexia animal model
Decline；
Fig. 2 shows that fucoidan improves or slow down muscle consume, wherein (A) display in cachexia animal model
Muscular tissue outward appearance, the measurement result of (B) display muscle weight, and (C) display muscle cell form；
Fig. 3 shows that fucoidan reduces the expression promoting skeletal muscle factoring in cachexia animal model, wherein (A)
Display immuning fluorescent dyeing analysis result, and (B) display Western Blotting analysis result；
Fig. 4 shows that fucoidan suppresses the expression of myostatin, wherein (A) in cachexia animal model
Display ferment immunoassay result, and (B) display Western Blotting analysis result；
Fig. 5 shows that fucoidan protected internal organs in cachexia animal model avoid effect of necrocytosis, wherein
And (B) is respectively the bladder of animal and the section statining result of pulmonary (A)；
Fig. 6 shows that fucoidan is protected small intestinal mucosa tissue in cachexia animal model and replys digestive enzyme activity
Effect, wherein (A) shows small intestine's pathological section, and (B), (C) and (D) shows bright ammonia respectively
The activity analysis result of acid peptidase, amylase and lipolytic enzyme；
Fig. 7 shows that Brown algae candy gum sugar glue reduces the expression of inflammatory factor in cachexia animal model, wherein (A)
The result of the Western Blotting of display TNF-α, IL-6, IL-1 β and acute inflammation PROTEIN C RP, and (B),
And (D) display TNF-α, the result of enzyme immunoassay of IL-6 and IL-1 β (C)；
Fig. 8 shows that fucoidan suppresses the growth of tumor in the tumor mouse model of xenotransplantation transitional cell bladder carcinoma cell line,
Wherein (A) shows the appearance of tumors taken off, during (B) shows the tumor weight taken off, and (C) process
The gross tumor volume measured；
Fig. 9 shows that fucoidan reduces HIF-1 α, VEGF at the tumor mouse model of xenotransplantation transitional cell bladder carcinoma cell line
And the expression of CD31, there is effect of suppression neonate tumour blood vessel, wherein (A) and (B) display Western Blotting
Result and quantitative result, and (C), (D) and (E) display immunochemistry staining analysis result；
Figure 10 shows that fucoidan suppresses transitional cell bladder carcinoma cell line at the tumor mouse model of xenotransplantation transitional cell bladder carcinoma cell line
(A) divide a word with a hyphen at the end of a line and (B) invades ability.
Detailed description of the invention
Unless otherwise stated, the whole technology being used herein as and scientific term and the technical field of the invention skill
The same meaning that art personnel are generally understood.
Article as used herein " one " refers to one or the syntax of more than one (that is, at least one) of this article
By word.
In the present invention, non-can expectedly find that fucoidan casts cachectic mice and can be effectively improved or slow down flesh
Meat consume situation, and confirm that it can suppress the expression of skeletal muscle factoring and myostatin.According to this
Bright exposure, cachectic mice, after casting fucoidan, is not only improved muscle consume situation, the most effectively slows down
Lose weight, inappetence and inflammatory response, and suppress the necrocytosis situation of internal organs, reduce small intestinal mucosa damage
And reply zymigen activity.Therefore, fucoidan can be as treating cachectic medicine.
The Brown algae candy gum sugar glue that the present invention uses has another name called fucoxanthine, fucoidin, fucoidin or pheophytin.Brown
The glutinous sliding composition that Brown algae cell is exclusive taken from by algae carbohydrate gum.Chemically, it is a kind of based on " fucose "
Polysaccharide body, the heteromeric polysaccharide component of water solublity being made up of fucose (fucose) and sulfate (sulphate),
Wherein fucose becomes major key with α-(1 → 2), α-(1 → 3) or α-(1 → 4) bond mutually, and sulfate is combined in C-2
Or on the reducing end of C-4.Specifically, to have cellular construction as follows for fucoidan:
Fucoidan can be by obtained commercially, and it can be extracted by multiple Brown algae and obtain, and includes but not limited to, Thallus Laminariae (Thallus Eckloniae),
The common edible algaes such as Thallus Laminariae, horse hair dish, Thallus Laminariae (Thallus Eckloniae), Fucus Vesiculosus.Brown algae is distributed in many marine sites, the world,
Taiwan is found in the regions such as the north, northeast corner, the permanent spring peninsula, east littoral sea and Penghu, Lutao, Lanyu,
Obtain easily, this area can be used it is well known that method extract fucoidan from Brown algae, such as, with hot water or
Organic acidity solvent concentration processes Brown algae, and optionally also with fermentation or ferment digestion step, further by macromole
The little molecule that fucoidan (general molecule weight up to 500,000Da) is cut into higher absorption rate and more curative effect is brown
Algae oligosaccharide is (such as 100,000Da, 50,000Da, 10,000Da, 5,000Da, 1,000Da or 500Da or more
Low).
The molecular weight of fucoidan can be by this area it is well known that method records, such as, and gel filtration (gel
Filtration).Generally, polymeric molecular weight is to represent with mean molecule quantity.Therefore, as used herein " point
Son amount ", except as otherwise noted, refer to mean molecule quantity, it can thus record by art-known methods, such as, with
The pattern (pattern) that gel filtration presents determines.In this article, when molecular weight represents with a special value,
This numerical value includes its molecular weight in the range of upper and lower 20%.Such as, with 50, as a example by the molecular weight of 000Da, its table
Show the molecular weight of 40,000Da to 60,000Da.
" individual " as used herein word includes the mankind and non-human animal, such as, companion animals (e.g., Canis familiaris L.,
Cat and fellow), farm-animals (e.g., cattle, sheep, pig, horse and fellow) or laboratory animal (e.g., rat,
Mice, guinea pig and fellow).
" treatment " as used herein word refers to cure, heals, alleviates, releives, changes, corrects,
Improve, improve or affect this disease, the symptom of this disease, deformity that this disease causes or the tendency suffering from this disease
Purpose, and the compositions comprising one or more activating agent is used or administration is to the disease suffering from this disease, this disease
Shape or have the individuality of the tendency suffering from this disease.
" effective dose in treatment " as used herein word refers to compared to not accepting the corresponding individual of this amount, a medicine
Thing or medicament can cause the content of the effective ingredient of therapeutic purposes.Such as, treatment cachexia effective dose for can prevent,
Improve or slow down the dosage of muscle consume, or it is sick to prevent, improve or slow down one or more other cachexia further
Levy the dosage of (e.g., weight loss, tired, anorexia, unable, weak, inflammation etc.).Such symptom can use
Means known in the art are also measured based on the various indexs relevant to the course of disease and assess, such as, relevant to inflammation
Cytohormone and albumen, e.g., IL-6, TNF-α, IL-1 β and CRP, clean body weight (lean body mass, LBM),
Haemachrome, measurement of muscule strength dynamometry, food-intake, tired test, weak grade (can be found in Malnutrition, fatigue, frailty,
vulnerability,sarcopenia and cachexia:overlap of clinical features.Curr Opin Clin Nutr
Metab Care.2012May;15(3):213-9.；Anorexia,cachexia and fatigue.Clin Med.2010
Oct;10(5):476.；Diagnostic criteria of cachexia and their assessment:decreased muscle
strength and fatigue.Curr Opin Clin Nutr Metab Care.2008Jul;11 (4): 417-21.).The most such as,
Treatment cancer effective amount can be minimizing tumor size or growth of cancer cells, divide a word with a hyphen at the end of a line or the dosage of infringement ability etc., also may be used
Therapeutic effect is assessed by mode known in the art.The visual various factors of effective dose and change, such as, dosing way,
Accept individual body weight and the species of this medicament, and dispensing purpose.Those skilled in the art can be according to taking off herein
The method shown and set up empirically determines the dosage of each individual case.In a particular instance, the medicine of the present invention
The oral dose of compositions is every day 10 to 1,000mg/kg, relatively specifically for 50 to 500mg/kg every day, more
Specifically for 60 to 400mg/kg every day, it is the most particularly 70 to 350mg/kg every day, still more specific for every day 80
Effective ingredient to 300mg/kg.In another particular instance, the oral dose of the pharmaceutical composition of the present invention is
Every day, about 80mg/kg, relatively specifically for about 160mg/kg every day, was particularly effective one-tenth of about 300mg/kg every day
Point.As a example by the adult of body weight about 50 kilograms, taking dose is every day about 4-15 gram, relatively specifically for every day about 8
The effective ingredient of mg/kg.In this article, when dosage represents with a special value, this numerical value include its upper and lower 20%
In the range of dosage.Such as, as a example by the dosage of 500mg, it represents the dosage of 400mg to 600mg.
The pharmaceutical composition of the present invention can be used for the cachexia that treatment is individual.Specifically, the drug regimen of the present invention
Thing can be applied to have and produces cachexia risk or experience cachexia and be correlated with the individuality of symptom, to avoid cachectic
Give birth to or improve or postpone cachectic progress.
In some embodiments, the pharmaceutical composition of the present invention can be applied to have and may result in cachectic disease
Sick, state or the individuality of damage, such disease, state or damage include but not limited to, cancer (e.g., bladder cancer,
Hepatocarcinoma, breast carcinoma, ovarian cancer, gastric cancer, pancreatic cancer, colorectal cancer, osteocarcinoma, leukemia etc.), immunological incompetence disease (e.g.,
Acquired immune deficiency syndrome (AIDS) etc.), infectious disease (e.g., tuberculosis, septicemia etc.), autoimmune disease (e.g., rheumatic close
Joint inflammation), metabolic disease (e.g., diabetes etc.), chronic intestinal, liver, kidney, lungs or heart disease
(e.g., liver cirrhosis, renal failure, chronic obstructive pulmonary disease (COPD), chronic heart failure etc.), apositia,
Wound or burn, bad, the anemia of alimentation etc..
For cancer, when the course of disease enters latter stage, there is 80% sufferer to there will be cachectic symptoms, be to cause sufferer dead
The main cause died.Therefore, the present invention also provides a kind of cancer therapy, and it includes carrying out individuality in need
Chemotherapy and/or radiation therapy, and cast the fucoidan for the treatment of cachexia effective dose simultaneously so that in treatment cancer
While, it is to avoid cachectic generation or improvement or postpone cachectic progress.Casting of fucoidan can be with chemotherapy
And/or radiation therapy simultaneously (synchronization) or sequentially carry out.
Therefore, the present invention still provides one to treat cancer and cachectic pharmaceutical composition, and it includes that the first activity becomes
Point, including the anticancer agent of one or more treatment cancer effective amount；Second active component, has including treatment cachexia
The fucoidan of effect amount；And one or more pharmaceutically acceptable carrier.Active component herein can be mixed in phase
With unit or be separately placed in different units, can prepare the known method in field according to this.
" chemotherapy " described herein is sufferer to cast anticancer agent to treat cancer.Anticancer agent include but not
Being limited to, alkylating agent (alkylating agents), such as, Ace reaches (fosfamide), cyclophosphamide
And Dakar bar piperazine (dacarbazine) (cyclophosphamide)；Antimetabolite (antimetabolites),
Such as, capecitabine (capecitabine), carmofur (carmofur) and Gemcitabine (gemcitabine)；Plant
Bases medicine (plant alkaloid agents), such as, Campto (irinotecan), Paclitaxel (paclitaxel)
And Campto (irinotecan)；Antibiotics, such as, actinomycin D (actinomycin D), Mo Li
Pungent (bleomycin) and ametycin (mitomycin C)；Platinum medicine, such as, oxaliplatin (oxaliplatin),
Good platinum Supreme Being (carboplatin), cisplatin (cisplatin) and nedaplatin (nedaplatin)；Hormone preparation (hormonal
Agents), such as, An Meida ingot (Anastrozole), chlormadinone (chlormadinone) and Tamoxifen
(tamoxifen)；Molecular target class medicine (molecular target drugs), such as, for Buddhist nun (Imatinib),
Ai Ruisha (gefitinib), gemtuzumab Ozogamicin Mylotarg CDP 771 (gemtuzumab) and appropriate former times monoclonal antibody (rituximab) etc..Anticarcinogen
The mode that casts of agent is different according to medicament categories difference, can be oral or injection, such as intramuscular or intravenous injection.
" radiation therapy " described herein is sufferer to cast lonizing radiation to treat cancer.Radiation therapy
Method of application includes but not limited to External radiotherapy, such as, and intraoperative radiotherapy (intraoperative
Radiotherapy) and preventive head radiation (prophylactic cranial irradiation, PC)；Internal radiation is controlled
Treat, such as, the treatment of tissue interstitial radiation treatment (interstitial radiation therapy), intraluminal radiotherapy
Radiation treatment (intraluminal radiation in (intracavitary radiation therapy) and pipeline
Therapy)；General radiation treatment (systemic radiation therapy)；Stereoscopic localized radiosurgery
(stereotactic (stereotaxic) radiosurgery)；Three-dimensional space conformal radiotherapy (three-dimensional
Conformal radiotherapy, 3D CRT)；And IMRT technology (Intensity Modulated
Radiation Therapy, IMRT).The energy source of radiation therapy include but not limited to X-ray, gamma ray,
Particle beam (particle beams), proton beam (proton beam) and high-energy photon beam (high-energy photon
Radiation).
On the other hand, also find that fucoidan itself has the therapeutic effect of excellence for bladder cancer.Therefore, the present invention
The application in the medicine of preparation treatment bladder cancer of a kind of fucoidan is provided.The present invention still provides a kind of for treating
The pharmaceutical composition of bladder cancer, it includes the fucoidan of therapeutically effective amount, and one or more is pharmaceutically acceptable
Carrier.Particularly, the pharmaceutical composition of the present invention can suppress the tumor growth of bladder cancer, neonate tumour blood vessel,
Cancerous cell is divided a word with a hyphen at the end of a line and infringement ability.
According to the present invention, bladder cancer refers to the various malignant tumor coming from bladder, including epithelial tumour, including breast
Head tumor, transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma etc., and Non-epithelial Tumor.Clinically, 90%
Above bladder cancer belongs to transitional cell (Transitional cell carcinomas, TCCs), according to dividing a word with a hyphen at the end of a line
Property cell carcinoma invade Musclar layer tissue degree can be divided into: Ta, papillary tumor in urothelium with plan towards
Tract develops；Tcis, urothelium is confirmed as in the section of smooth pathological tissues；T1, papillary tumor invades epithelium
Tissue；T2, tumor is invaded toward smooth muscle sarcocyte；T3, tumor invasion fat deposit；And T4, tumor invasion prostatitis
Gland, urethra, vagina, renal pelvis or abdomen wall.
Bladder cancer treatment includes surgical treatment, immunotherapy, radiation cure and chemotherapy at present, and table is shallow
Property bladder cancer can merge via cystoscope tumor resection and postoperative give chemotherapy.Cisplatin is normal for treatment bladder cancer
Chemicals, but kidney is had toxicity (Dos Santos NA et al., Arch Toxicol.2012
Aug;86 (8): 1233-50), therefore many use (Cohen MH et al., Oncology. are merged with Gemcitabine
2001;19:1229-31).But, accept the bladder cancer patients of multiplicity therapy, five after its local and remotely diffusion
Annual survival rate the most about fifty percent (George L et al., Urology.2004;64:488-93).The present invention provide for
The pharmaceutical composition of bladder cancer, especially can reduce it and divide a word with a hyphen at the end of a line or infringement ability, it is possible to provide effective treatment of bladder cancer.
According to the present invention, the effective ingredient of therapeutically effective amount can be deployed into appropriate dosage forms with pharmaceutically acceptable carrier
Pharmaceutical composition, to reach conveying and the purpose absorbed.Depending on dispensing pattern, the pharmaceutical composition of the present invention is preferable
Containing the active ingredient of about 0.1 weight % to about 100 weight %, percentage by weight is in terms of total composition.
" pharmaceutically acceptable " refers to that the effective ingredient that this carrier can be contained with in compositions is compatible herein, and it is preferable
For this active component and harmless to treated individuality can be stablized.This carrier can as the diluent of active component,
Carrier, excipient or substrate.The example of some suitable vehicle include lactose, dextrose, sucrose, sorbose,
Mannose, starch, arabic gum, calcium phosphate, alginate, gum tragacanth, gelatin, calcium silicates, crystallite are fine
Dimension element, PVP, cellulose, aquesterilisa, syrup and methylcellulose.Compositions can comprise additionally in
Lubricant, such as, Pulvis Talci, magnesium stearate and mineral oil；Wetting agent；Emulsifying and suspending agent；Preservative agent, example
As, methyl hydroxybenzoate and propyl ester；Sweeting agent；And flavoring agent.The compositions of the present invention is by this area
After the method preparation known, the quick, lasting of active component can be provided after administration to patient or postpone the effect of release.
Form according to said composition of the present invention can be lozenge, pill, powder, lozenge, medicated bag, tablet, elixir,
Suspension, Emulsion, solvent, syrup, soft hard gelatin capsule, suppository, sterile solution for injection and packaging powder.
The compositions of the present invention can be via any approach that physiologically can accept, and such as, oral, parenterally is (such as,
Muscle, vein, subcutaneous, intraperitoneal), percutaneous, rectum, the mode such as suction carried.For parenteral
Dispensing, be most preferably with sterilized water solvent version use, it can contain other material, such as, enough salt or Portugal
Grape sugar is so that this solution and blood are isoosmotic pressure.Need to (preferably pH value be 3 by suitably buffering when aqueous solution needs
To 9).Under aseptic condition, prepare applicable parenteral constituent can pass through mark well-known to those skilled in the art
Quasi-pharmaceutical technology method completes, without paying extra creative work.
More clearly describe the present invention referring now to specific examples below, its purpose is for illustrating and not to as limit
System.
The application in treatment cachexia and cancer of embodiment 1 fucoidan
1. material and method
1.1 fucoidan
Fucoidan is to be extracted by Taiwan Brown algae and obtain, and first with hot water treatment, then digests through ferment, obtains molecular weight
Fucoidan for 500Da or lower.In cell line experiments, concentration is 25,50,100 μ g/ml, dynamic
The dosage of thing experiment be every day 80,160,300mg/kg.
1.2 cells are cultivated
Transitional cell bladder carcinoma cell line T24 is purchased from National Cell storehouse, is derived from female human's bladder and moves shape cell carcinoma, growth
Characteristic is attaching type cell monolayer.T24 cell be incubated at containing 10% hyclone (Fetal Bovine Serum,
FBS), 0.2%NaHCO3, 100u/ml penicillin (Penicillin), 100 μ g/ml streptomycin (Streptomycin)
RPMI1640 complete culture solution.37 DEG C of incubators containing 5%CO2 and saturated steam are cultivated, often
Within three days, change a culture fluid regular successive transfer culture, periodically with inverted microscope observation of cell form during cultivation
Integrity and the speed of growth.
1.3 animal experiment
The animal that this research uses is female BALB/c nude mice of six week old, and every body weight is about 25 grams, purchased from country
Animal center.Raise and having 12 hours periodicity of illuminations (AM7:00-PM7:00), and give proper temperature and humidity
Keyholed back plate, fill part supply feedstuff and drinking-water.
1.4 set up cachexia animal model
1 × 10 is implanted in in-situ injection mode at female BALB/c nude mice intravesical of six week old at the 0th day6/100μl
T24 cell, every three days record food rations and body weight change, start to give fucose with oral way after 14 days
Glue, additionally, cisplatin (Cisplatin;75mg/m2Give lumbar injection) it is to give weekly to be once a cycle,
Two cycles of injection have a rest a cycle；Gemcitabine (Gemcitabine;1000mg/m2Give lumbar injection) it is with often
Giving in week twice to be a cycle, two cycles of injection have a rest a cycle；And fucoidan with within 24 hours, be administered orally to
Medicine once (160mg/kg/day), successive administration 21 days.The body weight of assessment animal and appetite change, at the 22nd day
With carbon dioxide by nude mice put to death, take off heart, lungs, stomach, liver, spleen, kidney, bladder, small intestinal,
Lower limb muscles is stored in-80 DEG C of refrigerators, carries out subsequent analysis.
1.5 small intestinal enzyme activity tests
With carbon dioxide, the small intestinal after death taken off at nude mice acquisition fragment is struck off intestinal mucosa, take 0.2 gram and add 4 DEG C
0.9%NaCl solution, it contains 1 μM of benzyl sulfonylation fluorine of protease inhibitor
(phenylmethylsulfonylfluoride, PMSF) and 2.2mM iodoacetic acid (iodoacetic acid), then
With homogenizer homogenize centrifugal after take supernatant and drip in slide (Fuji DRI-CHEM slides), and in analyser
(Fuji DRI-CHEM3030Analyzer (Fuji Photo Film Co.Ltd., Tokyo, Japan) carries out ferment and lives
Property measure.
1.6Western Blotting
Proteinaceous sample to be analyzed is separated with gel electrophoresis, then running gel (SDS-PAGE gel) is transferred
To poly-difluoride membranes (polyvinylidene fluoride, PVDF).After having transferred, poly-difluoride membranes is put
In the TBST buffer containing the defatted milk powder of 5%, rock reaction 1 hour at room temperature, to close poly-two
The binding site of non-specific position on fluoride film film.Then with TBST buffer solution for cleaning, add one and resist, in
Shaken at room temperature reacts 2 hours or is optionally placed in 4 DEG C overnight.After TBST buffer solution for cleaning, add two and resist,
Rock reaction 1 hour at room temperature, then with the poly-difluoride membranes of TBST wash buffer, finally add appropriate
Chemical luminescence reagent (ECL), after colour generation 1-2 minute, be placed in tabletting in piece pressing clip together with egative film.
1.7 immunochemistry staining analysiss (IHC)
Cell is cleaned with TBS buffer (pH value 7.5-7.6) after being dewaxed by tissue slice.Add containing 30%H2O2
Methanol put and act on ten minutes under room temperature to remove endogenous peroxidating ferment.With TBS buffer solution for cleaning cell,
Remove nonspecific combination, 3% hyclone (FBS) is added in cell cultivation sheet (coverslips) and makes
It is enough to cover surface, puts room temperature lower ten minutes.Remove hyclone, after TBS buffer solution for cleaning cell,
Addition one is anti-is placed in 4 DEG C of reaction overnight.Remove one resist, after TBS buffer solution for cleaning cell, add two resist in
React one hour under room temperature.Remove two to resist, after TBS buffer solution for cleaning cell, add hydrogen peroxide ferment altogether
The Streptavidin (peroxidase-conjugated streptavidin) of yoke reacts 20 minutes at room temperature.Remove
The Streptavidin of hydrogen peroxide ferment conjugation, after TBS buffer solution for cleaning cell, adds diaminobenzidine
(diaminobenzidine, DAB) makees color reaction in about two minutes.After again to clean in TBS buffer, make
Contaminate nucleus with hemotoxin (hemotoxin), to carry out mounting after TBS wash buffer, can make after mounting
Take pictures with microscope.
1.8 cytohormone concentration measure
By 96 porose discs of cytohormone antibody to be surveyed that are combined in advance, add standard substance and the sample of 100 μ l, in
Placing after two hours for 37 DEG C and poured out by content, the mensuration reagent adding 100 μ l acts on 1 hour in 37 DEG C.Clean
After, moisture in porose disc is patted dry, lucifuge adds tetramethyl biphenyl (tetramethylbenzidine, TMB) substrate
The generation color change that catalysis peroxidase makes.It is eventually adding acid solution stopped reaction, measures with wavelength 450nm
Light absorption value.
1.9 tumor growth analyses
Within 0th day, inject 2 × 10 at the six right backs of week old BALB/c nude mice with injected s. c6The T24 of/100 μ l
Cell, starts to be administered with oral way after 14 days, within every 24 hours, is administered once, successive administration 28 days, and the 29th
Nude mice is put to death by it with carbon dioxide, takes off tumor.Record tumor size change in every three days.
1.10 statistical analysis technique
The graphic of this result of study all represents with mean+/-standard error, and statistical method is according to Initial experiments number
According to, and with the most variant, if having between more each group of single-factor analysis of variance method (one-way ANOVA)
Statistically difference then carries out statistical analysis with Student t-test checking method.If P < 0.05, it is considered as there is significant difference.
2. result
2.1 improvement lose weight and appetite is low
This research uses cachexia animal model to be analyzed, and the most each treated animal processing mode is as follows:
The mice with tumor of injection T24 cell was administered after the 14th day in the above described manner, and every three days records are taken the photograph each group and moved
The appetite of thing and body weight change.
As Fig. 1 (A) shows, the body weight of control group (mice with tumor) is relatively low compared to normal group, and when being good for
Behind pool and two kinds of chemotherapeutics of cisplatin (the 3rd group), the obvious thin and weak many of outward appearance, body weight at least reduces substance and weighs 5%
Above, simultaneously observe mice action edge decline, weak and cannot normal activity；In comparison, chemotherapeutics closes
And giving the group (the 4th group and the 5th group) of fucoidan, body weight all has increase, the brightest with the 5th group of improvement
Aobvious, action edge also has significant improvement.Additionally, as Fig. 1 (B) shows, give Gemcitabine and two kinds of chemotherapeutics of cisplatin
Animal (the 3rd group), its average food ration for minimum compared to other groups, but merge and gives fucoidan and then may be used
Increase food ration (the 4th group and the 5th group).
These results display fucoidan can obviously improve or slow down losing weight and appetite reduction of cachexia animal
Etc. symptom.
2.2 reduce muscle consume
By nude mice with sacrificed by carbon dioxide after, lower limb muscles is taken off observation.Chemotherapeutic is merged by outward appearance visual tumors
The overall muscular tissue of thing group is significantly smaller, and after giving fucoidan combined treatment, muscular tissue and outward appearance are significant
Increase and normal, see Fig. 2 (A), and the measurement result of muscle weight also shows that consistent result, sees figure
2(B).
Additionally, by each group skeletal muscle tissue to carry out haematoxylin-eosin stains (H&E after specimens paraffin embedding slices
Statin), in basis of microscopic observation normal group muscle cell kenel.Result shows, the muscle cell type of normal group
State is the ellipse of marshalling, and the muscle cell kenel of tumor group has produced change, in long and narrow and atrophy kenel,
After giving chemotherapeutics, amyotrophy situation is more serious, and after giving fucoidan, muscle cell arrangement is the tightest
Close, close to the kenel of normal muscle tissues, especially improve the most significant with Gemcitabine+fucoidan group, see Fig. 2 (C).
These results display fucoidan can dramatically the muscle degraded consume improving or slowing down cachexia animal.
2.3 reduce the expression promoting skeletal muscle factoring
Ubiquitin ligase (ubiquitin ligase) Atrogin-1(MAFbx in muscle cell) and MuRF1 activation
Time can promote the atrophy of muscle, these factors can be regulated and controled by many transcription factor, such as, FoxO and NF-κ B.
Each group skeletal muscle tissue to carry out immuning fluorescent dyeing analysis after specimens paraffin embedding slices, is observed ubiquitin by this research
Ligase and the expression of associated transcription factor.Result shows when tumor merges chemotherapeutic drug therapy, ubiquitin ligase
And associated transcription factor all great expression, and merging can suppress it to express after giving fucoidan, sees Fig. 3 (A).
Similar ubiquitin ligase and the protein expression of associated transcription factor change also in Western Blotting result
It is further characterized by, is seen Fig. 3 (B).
The expression of 2.4 suppression myostatins
Myostatin (myostatin) is also played an important role in skeletal muscle atrophy.Therefore, this research
Taking part muscular tissue and carry out enzyme immunoassay, result shows in mice with tumor, myostatin
Expression is higher than normal group, then after giving chemotherapeutics, it is expressed situation and becomes apparent from, and merges and give fucose
Glue, it is possible to decrease the expression of myostatin, sees Fig. 4 (A).Demonstrate,prove the most further at Western Blotting
Real, relevant with promoting muscle growth IGF-1/AKT information path, gives chemotherapeutics group in tumor group and merging
IGF-1 and the expression of phosphorylation AKT be below normal group, and the minimizing of phosphorylation AKT can promote FoxO
Activation and myolysis, therefore myostatin (myostatin)/ActR II B/FoxO for suppression muscle
The main information path of growth, tumor group and merging give the expression that chemotherapeutics group can promote myostatin
Increase, and after giving fucoidan, not only can suppress myostatin and the expression of accepter ActR II B thereof,
The most also suppress the activity of transcription factor FoxO, see Fig. 4 (B).
The effect of 2.5 protection internal organs
By nude mice with carbon dioxide sacrifice, the bladder taken off, lungs and small intestinal are to carry out Lignum Sappan after specimens paraffin embedding slices
Purple-eosin stains (H&E statin).The bladder of tumor group is found because of tumor growth quickly, in basis of microscopic observation
Necrocytosis (necrosis) occur, cancerous cell is also invaded to hip, then after giving chemotherapeutics (the 3rd group: strong
Pool+cisplatin) cancerous cell infringement degree can be slowed down, it is down to Musclar layer, but the situation of necrocytosis there is no improvement, so
And (the 4th group: Gemcitabine+cisplatin+fucoidan, TGCF) can anticancer growth speed after merging fucoidan
Degree makes necrocytosis situation be improved and affects tumor invading ability, sees Fig. 5 (A).Additionally, in tumor group
Lungs section find the pulmonary edema that causes because of inflammatory response and infiltration, cause alveolar collapse, but give chemotherapeutic
Thing and chemotherapeutics merging fucoidan all can reach suppression lung inflammation and improve pulmonary edema situation, sees Fig. 5 (B).
These results display fucoidan avoids damage to and the effect of necrocytosis at the protected internal organs of cachexia animal.
2.6 protection small intestinal mucosa tissues and reply digestive enzyme activity
Transfer to for cancerous cell fast-growth characteristic owing to chemotherapeutics presses down the machine of cancer, act on cell cycle, therefore
The small intestinal mucosa cell equally with this characteristic also can be destroyed, and therefore the damage situation also for small intestine is entered
Row assessment.The small intestine of nude mice is done check pathological section, finds compared to tumor, group Gemcitabine+cisplatin group (the
3 groups) even more serious to the destruction of small intestinal mucosa, but animal this breakoff phenomenon of the most significant minimizing giving fucoidan,
Intestinal mucosa is protected, and the form of intestinal villi also remains complete, sees Fig. 6 (A).Chemotherapeutics causes intestinal
Gastropore mucosa cells damages so that digestive enzyme secretion and activity reduce, and causes the absorption function digesting animal bad.
Collect the small intestinal extract of nude mice, analyze its enzyme activity, three kinds of dominant digestion of result display Gemcitabine+cisplatin group
The activity of enzyme (leucine peptidase, amylase and lipolytic enzyme) is below control group, and far below normal group, and give
After giving fucoidan combined treatment, three kinds of enzyme activity numerical value the most substantially increase, and especially increase with Gemcitabine+fucoidan group
At most, Fig. 6 (B), 6(C are seen) and 6(D).
These results display fucoidan at cachexia animal protected small intestinal mucosa tissue and replys digestive enzyme activity
Effect, this is with aforementioned improvement or slows down and loses weight and result that appetite is low is consistent.
2.7 expression reducing inflammatory factor
In tumor microenvironment, cancerous cell and host produce reciprocal action and derive many cytohormones, such as,
TNF-α, IL-6, IL-1 β, and cause internal generation inflammatory response and then drive cachectic generation, thin in blood
The expression of intracellular hormone is also for one of clinical diagnosis cachexia standard.This research is with Western blot method and ferment immunoassay
The experiment of method analyzing animal gives the expression whether fucoidan can suppress inflammatory factor.
Western Blotting result shows, in tumor group and tumor merge the animal of chemotherapeutics group, and muscle groups
In knitting, these inflammatory factor expressions are above normal group, and merge and give fucoidan, then can obviously reduce
TNF-α, IL-6, IL-1 β and the expression of acute inflammation PROTEIN C RP, see Fig. 7 (A).Enzyme immunoassay
Result displays that, in the serum of tumor group and the animal of tumor merging chemotherapeutics group, and TNF-α, IL-6, IL-1 β
Content be above normal group, and merge and give fucoidan, the most significant minimizing its express, see Fig. 7 (B), 7
And 7 (D) (C).
These results display fucoidan has the effect reducing inflammatory factor generation cachexia animal.
2.8 suppression tumor growths
This research also carries out suppressing tumor growth analysis test at the mice with tumor of xenotransplantation transitional cell bladder carcinoma cell line.Little
The right shoulder of Mus is implanted T24 human bladder and is moved shape epithelial cell JEG-3 after two weeks, gives different agent with oral way
The fucoidan of amount, respectively every day 80mg/kg, 160mg/kg or 300mg/kg, measures tumor in every three days big
Little, surrounding by a definite date, after finally sacrificing, tumor is taken off weighing.Result shows, gives fucoidan 160mg/kg
Or the gross tumor volume of the group of 300mg/kg and weight are significantly less than control group, see Fig. 8 (A), 8(B) and
8(C).This result shows, fucoidan also has the effect of the tumor growth of suppression bladder cancer.
2.9 suppression HIF-1 α and angiogenic growth factor are expressed
Under anaerobic environment, tumor cell must do some genes and adjust and the strain of range of information conducting path,
In the hope of continuing survival and growth, wherein hypoxia inducible factor (hypoxia-inducible factor, HIF-1) is i.e.
The one important core factor.Study confirmation cancerous cell HIF-1 α under anaerobic environment and have the situation of overexpression.This
The VEGF that outer HIF-1 α is regulated and controled also can great expression, and then stimulate angiogenesis and cause and make prognosis be deteriorated
(Folkman et al.The Journal of investigative dermatology.1972;59:40-3).
In the mice with tumor of xenotransplantation transitional cell bladder carcinoma cell line is tested, the tumor tissues taken off after being sacrificed by nude mice is carried out
Tissue protein extracts, and observes the expression of angiogenesis promoting albumen HIF-1 α and VEGF.Result shows every day
Give fucoidan 160mg/kg and 300mg/kg and all have inhibition for the expression of HIF-1 α and VEGF,
See Fig. 9 (A) and 9(B).Meanwhile, by tumor tissues to carry out immunochemistry dyeing point after specimens paraffin embedding slices
Analysis, result shows and gives the HIF-1 α of fucoidan group and vegf expression all declines, see Fig. 9 (C) and
9(D).Additionally, CD31 is prevalent in endotheliocyte, frequently as the index of angiogenesis.The immunity of this research
Chemical staining analysis result shows, control group (matched group) great expression CD31 of non-administration, represents that tumor has
Angiogenesis phenomenon；And giving the group of fucoidan, CD31 expresses decline, and display angiogenesis situation is subject to
Suppression, sees Fig. 9 (E).This result shows, fucoidan can reduce the expression of HIF-1 α and VEGF, and then
Reach to suppress neonate tumour blood vessel situation.
2.10 suppression transitional cell bladder carcinoma cell lines are divided a word with a hyphen at the end of a line and infringement ability
With anoxia as chemoattractant, induce dividing a word with a hyphen at the end of a line and invading phenomenon, result display fucose of T24 transitional cell bladder carcinoma cell line
Glue can suppress transfer and the infringement of transitional cell bladder carcinoma cell line.As Figure 10 (A) shows, T24 cancerous cell is dense in normal oxygen
I.e. having the behavior (19.27%) divided a word with a hyphen at the end of a line under degree, after being quantified by area, anoxia 24 hours, scope of dividing a word with a hyphen at the end of a line was more aobvious
Write (61.29%), but after giving fucoidan, the scope divided a word with a hyphen at the end of a line rises with fucoidan concentration and reduces, point
It is not 38.23%, 31.73% and 24.57%.Additionally, as Figure 10 (B) shows, compared to the group of normal oxygen,
After anoxia 24 hours, transitional cell bladder carcinoma cell line invades the significant raising of ability (26.81%), and after giving fucoidan,
Infringement ability is suppressed, and is reduced to 15.23%, 11.98% and 6.32% respectively.
3. conclusion
Comprehensive above result of study, we in cachexia animal model it has proven convenient that fucoidan can be effectively improved evil
The muscle consume situation of sick matter animal, wherein, the rush skeletal muscle factoring of animal and the table of myostatin
Reach and be suppressed, therefore muscle consume situation can be slowed down；And fucoidan effectively slow down the losing weight of animal,
Inappetence, inflammation, weak and muscle weakness, and improve the necrocytosis situation of internal organs, reduce small intestinal mucosa damage
Wound and reply zymigen activity.Additionally, fucoidan also confirms that the effect with treatment bladder cancer, it is possible to press down
The tumor growth of bladder cancer processed, neonate tumour blood vessel and cancerous cell are divided a word with a hyphen at the end of a line and infringement ability.
Those skilled in the art will be appreciated by above-mentioned specific embodiment can be changed and still invention without departing from its broad sense general
Read.It is therefore to be understood that the present invention is non-is limited only to disclosed certain specific embodiments, and appended right should be contained
Change in the spirit and scope of the defined invention of claim.
From above-mentioned explanation, those skilled in the art can confirm the principal character of the present invention easily, and the most inclined
Lower from the spirit and scope of the present invention makes various changes and modification, to adapt to various purposes and situation.
Therefore, other specific embodiments also belong in the range of the claims in the present invention.
Claims (5)
1. fucoidan accepts the chemotherapy of anticancer agent at preparation treatment cancer individuality and cachectic medicine of causing
In application.
Apply the most as claimed in claim 1, it is characterised in that wherein said anticancer agent is cisplatin and/or is good for
Pool.
Apply the most as claimed in claim 1 or 2, it is characterised in that wherein said medicine can improve or slow down institute
State the cachexia symptom of the muscle consume of individuality.
Apply the most as claimed in claim 1 or 2, it is characterised in that wherein said medicine can improve or slow down institute
State the body weight reduction of individuality, anorexia, inflammation, the weak or cachexia symptom of muscle weakness.
Apply the most as claimed in claim 1 or 2, it is characterised in that wherein said medicine can make described individuality
Small intestinal mucosa tissue is protected and digestive enzyme activity is replied.
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