CN105477628A - Anticancer composition and uses thereof - Google Patents
Anticancer composition and uses thereof Download PDFInfo
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- CN105477628A CN105477628A CN201410483128.8A CN201410483128A CN105477628A CN 105477628 A CN105477628 A CN 105477628A CN 201410483128 A CN201410483128 A CN 201410483128A CN 105477628 A CN105477628 A CN 105477628A
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Abstract
The invention provides an anticancer composition, containing an anticancer effective ingredient and a pharmaceutically acceptable carrier, wherein the anticancer effective ingredient contains collagenase II, collagenase IV or a combination thereof, preferably collagenase II. The present application further provides uses of the anticancer composition in preparing drugs for treating cancers. The anticancer composition is applicable to injection or implantation in cancer lesions, peri-cancerous injection or implantation, and injection or implantation in a tumor cavity after cancer surgery. The anticancer composition can be made into various forms of drug, preferably an injection.
Description
Technical field
The application relates to a kind of method of anti-cancer composition and Therapeutic cancer, particularly, relate to a kind of comprise collagenase anti-cancer composition and its purposes in the medicine preparing Therapeutic cancer.
Background technology
According to China News Week (on 04 07th, 2013), the whole nation just has a people to be diagnosed as cancer in every 6 minutes, has every day 8550 people to become cancer patient, just has a people to die from cancer in every seven to eight people.Coming 10 years, cancer morbidity and the mortality rate of China will continue to rise.
Cancer diffusion transfer is the main cause causing cancer patient's Endodontic failure.Cancer metastasis is the process of a complicated multifactor participation, its matrix metalloproteinase (MatrixMetalloproteinases, MMPs) play an important role (KumarA in the process, CollinsHM, ScholefieldJH, WatsonSA:Increasedtype-IVcollagenase (MMP-2andMMP-9) activityfollowingpreoperativeradiotherapyinrectalcancer. BrJCancer82:960 – 965,2000).MMPs not only mediate tumor cell to the extracellular matrix (extracellularmatrix comprising basement membrane of host, ECM) degrade, go back modulate tumor neovascularization growth, affect the function of cell adhesion molecule and play an important role in tumor development, infiltration, diffusion, transfer.Therefore for many years, scientist attempts by suppressing or reducing MMPs activity or express the object realizing treating tumor, as used various MMPs inhibitor, anti-mm Ps monoclonal antibody etc. always.But up to the present this type of attempts the precedent that there is not yet clinical success.In addition, also there is research to attempt by activating or promoting that extracellular matrix degradation is to realize treating the object of tumor, but all fail to obtain Preferred effects.
Collagenase is a hypotype of MMP, and it is of a great variety, and function it be unclear that; And relation between different collagenase is also unclear, more needs to be inquired into the relation of other MMPs.Rough collagenase also containing other hydrolytic enzyme, therefore easily produces other beyond thought side effect.
Seeking the key that a kind of effective anti-cancer composition is Therapeutic cancer, is also the focus of research at present.
Summary of the invention
On the one hand, this application provides a kind of anti-cancer composition, it comprises anticancer effective component and pharmaceutically acceptable carrier, and wherein said anticancer effective component comprises collagenase II, collagenase IV or its combination.
In preferred embodiments, the effective ingredient in anti-cancer composition is selected from collagenase II and collagenase IV or its and combines.In a more preferred embodiment, the effective ingredient in anti-cancer composition is collagenase II.
In certain embodiments, above-mentioned anti-cancer composition is formulated into pharmaceutically acceptable dosage form, is preferably injection or implant.In some embodiments, collagenase II concentration is 0.5-250,000U/ml, is preferably 25-25,000U/ml, is more preferably 50-25,000U/ml, most preferably is 500-10,000U/ml.
On the other hand, the purposes of above-mentioned anti-cancer composition in Therapeutic cancer is provided.
In certain embodiments, described cancer can be preinvasive cancer, also can be metastatic carcinoma, and preferably, described cancer is selected from hepatocarcinoma, pulmonary carcinoma, rectal cancer, thyroid carcinoma or its metastatic carcinoma.
On the other hand, anti-cancer composition of the present invention is provided for the preparation of the purposes in the medicine of Therapeutic cancer.
In certain embodiments, comprise the medicine of anticancer effective component of the present invention with the mode administration of injecting, pour into or implant, preferably, described medicine is through topical.In preferred embodiments, the intracavitary injection administration after injection in cancer, the injection of cancer week or cancer operation of described medicine, preferably through cancer inner injecting and administering.In another embodiment, described medicine is implanted into through cancer, cancer is all implants or cancer operation posterior tuberosity intracavity drug delivery implant, is preferably implanted into administration through cancer.
In some embodiments, anticancer effective component of the present invention, the dosage being preferably collagenase II is that every kilogram of whose body weight gives 0.01 to 5,000,000U, is preferably 10 to 500,000U, is more preferably 10 to 100,000U, most preferably is 10-50,000U.
Again on the one hand, provide Therapeutic cancer, particularly the method for entity tumor, the method comprises and gives to suffer from cancer individuality by anti-cancer composition and carry out Therapeutic cancer.Described cancer can be preinvasive cancer, also can be metastatic carcinoma, and preferably, described cancer is selected from hepatocarcinoma, pulmonary carcinoma, rectal cancer, thyroid carcinoma or its metastatic carcinoma.
Detailed description of the invention
This application provides a kind of anti-cancer composition, it comprises anticancer effective component and pharmaceutically acceptable carrier, and wherein said anticancer effective component comprises collagenase II, collagenase IV or its combination.
In preferred embodiments, the anticancer effective component that above-mentioned anti-cancer composition comprises is selected from collagenase II and collagenase IV or its and combines.In a more preferred embodiment, described anticancer effective component is collagenase II.
" collagenase II " of the present invention and " collagenase IV " are the members of matrix metalloproteinase (MMPs) family.MMPs is the proteolytic enzyme that a class extracellular matrix (ECM) has special Degradation, the Multiple components of energy degradation of cell epimatrix.Up to the present, the MMPs had been reported has kind more than 20, specificity according to its protein structure and substrate specificity can be divided into 5 hypotypes: (1) collagenase, (2) gelatin, (3) stromelysins, (4) model M TMMPs (MMP14,15,16,17,24,25) and (5) other subgroups (MMP7,12,20,23) etc.Think that collagenase has more than 5 kinds at least at present.Collagenase contains Zn at its avtive spot
2+, and need Ca with the combination of its substrate and the configuration formed needed for complete catalytic activity
2+.By the hydrolysis in site multiple on triple helix, collagen degradation is become small peptide by it.
Collagenase II (also known as MMP-8) is as a kind of metalloproteases, a small amount of proteolytic enzyme is deposited and just can be increased that it is active in case in vivo, the amount of namely existing protease can not high to protease by collagenase digesting to the degree making its inactivation.Collagenase II not only can the multiple collagen protein of cracking, also participation immunity of organism and protein transmembrane motion.Except collagen protein, collagenase II also may have direct or indirect Degradation in various degree to other extracellular matrix and macrophage wherein, immunocyte, cell growth factor, angiogenesis factor.In this article, collagenase II and MMP-8 are used interchangeably.Collagenase IV comprises at least 7 kinds of protease component, and from 68KD to 130KD not etc., it can digest Various Tissues to molecular weight.
The present inventor finds through large quantity research, and apply separately the growth that collagenase II or collagenase IV or its combination can suppress cancer, the growth of particularly applying separately collagenase II pair of cancer has obvious dose-dependent inhibition effect.The Exogenous Collagen enzyme II of the present invention's application may while acting on cancerous cell, also extracellular matrix can be acted on, lose by making tumor growth to the hydrolysis of interstitial and support and necessary nutrition, also may bring out or activate a series of anti tumor immune response simultaneously, thus the growth of Tumor suppression and diffusion.
" pharmaceutically acceptable carrier " described in the application refers to the carrier of the biological activity effectiveness of not interferon activity composition.The pharmaceutically acceptable carrier of the application can be solid or liquid, comprises pharmaceutically acceptable excipient, buffer agent, emulsifying agent, stabilizing agent, antiseptic, diluent, encapsulants, filler etc.Such as, pharmaceutically acceptable buffer agent comprises phosphate, acetate, citrate, borate and carbonate etc. further.
The pharmaceutical composition of the application can be rendered as unit dosage form, and can by the known method preparation of arbitrary pharmaceutical field.All methods all comprise the active component of the application and one or more pharmaceutically acceptable carrier-bound steps.Usually, by by active component and liquid-carrier, solid carrier or the two combine to prepare compositions, the product of preparation of shaping as required subsequently.Such as, the compositions being suitable for parenteral can be the sterile aqueous or the non-aqueous based formulations that comprise active component.Can, according to known method, suitable dispersant or wetting agent and suspending agent be used to prepare above-mentioned preparation.In acceptable carrier or solvent, water, ringer's solution and isotonic sodium chloride solution etc. can be used.
In certain embodiments, anti-cancer composition of the present invention is formulated into pharmaceutically or acceptable arbitrary dosage form clinically.In preferred embodiments, described dosage form is slow releasing agent.More preferably, the dosage form of preparation is injection or implant.
" injection " of the present invention refers to the solution (comprising emulsion and suspension) confession being injected in vivo be made up of medicine and for the powder of wiring solution-forming or suspension before use or solution.Described injection includes but not limited to aqueous solution injection, micro-balloon injection, gel-type injection, lipidosome injection, nanoparticle injection, depot controlled release injection, Needleless injection medicine-releasing system etc.
" implant " of the present invention refers to the sterile solid preparations that the little bulk medicine and adjuvant made or strip Gong implant.Implant can adopt special syringe to implant, and also can implant with surgical incision.Implant of the present invention also comprises the implant form being injected in human body in liquid form, changing solid or semi-solid medicament reservoir in physiological conditions into, and namely injection-type original position forms implant (injectableinsituformingimplants).
In preferred embodiments, anti-cancer composition of the present invention is prepared into the aqueous solution of topical application.Preferably, described compositions is prepared into the aqueous solution that collagenase II concentration is higher in relative small size.Alternatively, also by first for anti-cancer composition of the present invention lyophilization, peace can be contained in and cut open in bottle, be mixed with the pharmaceutically acceptable aqueous solution being applicable to be injected in tumor before use.
Preferably, the buffer for the preparation of injectable solution is taken with the deionization sterilized water of fresh distillation.Any suitable buffer solution can be used if phosphate buffer, Ringers buffer or Tris buffer are to prepare anti-cancer composition.The pH scope of preferred buffer is about 6.0 to 8.0, is preferably 6.5 to 7.5.Such as, can working concentration be that 0.1-0.25mol/L, the preferably sodium chloride of 0.15-0.2mol/L dissolve or diluted composition.Again such as, the concentration of the phosphate buffer of use is 0.02-0.2mol/L, is preferably 0.05-0.15mol/L.
In certain embodiments, the concentration of anticancer active constituent collagenase II of the present invention in injection is 0.5-250,000U/ml, is preferably 25-25,000U/ml, is more preferably 50-25,000U/ml, most preferably is 500-10,000U/ml.
The present invention's collagenase II used can be made by oneself, also can be purchased.Can be the albumen of restructuring, also can from people and animal tissue cell's separation and purification.In a preferred embodiment, collagenase II is buied from LifeTechnologies company, and the enzyme activity of cryodesiccated collagenase II is that 16800U/100mg/ props up, and is again dissolved to required concentration with pyrogen-free saline.The activity of all enzymes all represents with every mg iu.A unit collagenase activity is defined as when calcium ion exists, and under temperature is 37 DEG C and pH is the condition of 7.4, can become the collagen enzyme amount of 1 micromole's L-Leu in 5 hours from natural collagen release peptide (being equivalent to 1,2,3-indantrione monohydrate color).Can by the activity of methods known in the art determination collagenase with other enzyme.
On the other hand, the purposes of above-mentioned anti-cancer composition in Therapeutic cancer is provided.
" treatment " used herein comprise suppression, cure and alleviate cancer or its symptom and prevention or delay the transfer of primary carcinoma.
In certain embodiments, described cancer can be preinvasive cancer, also can be metastatic carcinoma, and preferably, described cancer is selected from hepatocarcinoma, pulmonary carcinoma, rectal cancer, thyroid carcinoma or its metastatic carcinoma.
On the other hand, anti-cancer composition of the present invention is provided for the preparation of the purposes in the medicine of Therapeutic cancer.In preferred embodiments, the effective ingredient of described medicine is collagenase II, collagenase IV or its combination.In a more preferred embodiment, described anticancer effective component is collagenase II.
In preferred embodiments, anticancer effective component of the present invention, the preferably dosage of collagenase II are that every kilogram of whose body weight gives 0.01 to 5,000,000U, be preferably 10 to 500,000U, be more preferably 10 to 100,000U, most preferably be 10-50,000U, such as 10-1,000U.The dosage of collagenase II can be selected according to the requirement of doctor when practical application.
Dosage can by the effect of the characteristic of the age of patient, disease, gross tumor volume, compositions and route of administration change.Such as, to the tumor being less than 3g, the dosage that single is inculcated can be applied.Inculcating dosage can be 0.01-5ml, preferably containing 25-25,000U/ml collagenase II.Lentamente drug injection is entered tumor, according to appointment 5-10 minute.When tumor is 5 to 10g, the anti-cancer composition of larger dose again can also be used after first time injected dose.Such as, first time uses 5ml and pours into dosage.Then, use the same combination of second part of 20-40ml lentamente, such as administration time is 10-20 minute.Can order of administration if needed, but be generally no more than 80ml cumulative volume.Such as, this treatment can again be applied, as being administered once weekly or monthly.For the tumor being greater than 10 to 15g, the perfusion dosage of first time administration can be at most 60ml, can apply larger dosage subsequently, but generally be no more than the cumulative volume of 100ml.
In certain embodiments, said medicine is with the mode administration of injecting, pour into or implant, and preferably, described medicine is through topical.This compositions is applied topically to treatment of cancer.Topical comprises by medicinal application in internal organs and/or cancerous cell or tumor or near it, is preferably in tumor.Topical also comprises by medicine encirclement cancerous tumour or by the surface of medicinal application in cancerous tumour.In one embodiment, medicine is delivered medicine to cancer local by direct intra-tumoral injection or perfusion.Such as, 2ml or less medicine pass through drug administration by injection to low capacity according to appointment.Larger capacity is if the medicine of more than 8ml is then by slowly pouring into about 10-30 minute administration.
In preferred embodiments, the intracavitary injection administration after injection in cancer, the injection of cancer week or cancer operation of described medicine, preferably through cancer inner injecting and administering.In other preferred embodiments, described medicine is implanted into through cancer, cancer is all implants or cancer operation posterior tuberosity intracavity drug delivery implant, is preferably implanted into administration through cancer.
Alternatively, other modes arbitrarily can be passed through, in the cancer that enzyme spcificity led or around cancer.The mode that can select such as utilizes different carrier systems compositions to be sent and is delivered to required position.Can slow releasing composition be applied, such as, can provide this preparation with slow release implantation, or with microcapsule or be adsorbed in biodegradable polymer and provide this preparation.Other carrier system document is existing to be described, such as, enzyme preparation is embedded in the method in biodegradable vesicle, is conducive to specificity and send with the activity of protective enzyme and pass.Such as enzyme can be embedded in liposome or other biodegradable microcapsule, be connected with the tissue specificity monoclonal antibody for specific localization.Various forms of enzyme embedding techniques can be used for Encapsulated Enzyme, includes but not limited to living cells ghost, the polymer microcapsule of synthesis and the lipid vesicle (liposome) etc. that is made up of cholesterol, lecithin and phosphatidic acid.Send with the erythrocyte of receptor itself and pass organized enzyme and can avoid by potential immunity in synthetic vectors (as liposome and microcapsule) caused by application enzyme and physiological problem.Polyethylene Glycol (PEG) is covalently attached to enzyme and can makes these protein non-immunogenicities, extend their circulating half-life, thus escape the inhibitory action of native enzyme inhibitor, and enzymatic activity can be improved when reducing isophagy.The connection of PEG and protein can adopt method well known in the art to realize, and can obtain uniform product in addition by ultrafiltration purification.
Anticancer active constituent of the present invention, or comprise the anti-cancer composition of this active component or the treatable cancer of medicine includes but not limited to: scale cancer, adenocarcinoma, mesothelioma, central nerve neuroma, glioma, respiratory system tumor, pulmonary carcinoma, genitourinary system tumor, renal carcinoma, bladder cancer, digestive system tumor, hepatocarcinoma, carcinoma of gallbladder, the esophageal carcinoma, gastric cancer, cancer of pancreas, straight colon cancer, tumor of head and neck, mouth neoplasm, thyroid carcinoma, skin carcinoma, hemangioma, bone tumor, lymphoma, osteosarcoma, breast carcinoma, Retinal neoplasms, nasopharyngeal carcinoma, cervical cancer, ovarian cancer, carcinoma of endometrium, carcinoma of prostate etc.Treatable cancer also comprises the metastatic tumor of above-mentioned primary cancer, the hepatic metastases of such as colorectal cancer, the Bone tumour of breast carcinoma, the brain metastes etc. of general tumour.Preferably, described cancer is selected from hepatocarcinoma, pulmonary carcinoma, rectal cancer, thyroid carcinoma or its metastatic carcinoma.
In one embodiment, compositions of the present invention contains collagenase II, is used for the treatment of hepatocarcinoma.Such as, by local injection compositions Hepatoma therapy in liver.Can pass through percutaneous puncture route of administration, the administration volume of the compositions applied is 0.001ml to 80ml, preferably contains the collagenase II of 0.5 to 250,000U/ml; More preferably, containing 50 to 25, the collagenase II of 000U/ml.
In one embodiment, compositions of the present invention contains collagenase II, for the treatment of pulmonary carcinoma.Such as, pulmonary carcinoma is treated by local injection compositions in lung.Can pass through percutaneous puncture route of administration, the administration volume of the compositions applied is 0.001ml to 80ml, preferably containing 0.5 to 250,000U/ml collagenases II; More preferably, containing 50 to 25, the collagenase II of 000U/ml.
In one embodiment, compositions of the present invention is used for the treatment of breast carcinoma.Such as, by local injection compositions treatment breast carcinoma in mammary gland.By under touch control and/or ultrasound wave guidance, the fine needle of a length can be inserted in mammary gland and carries out intramammary injection.This injection is normally carried out under local anesthesia, and injection solution can dilute with iodine caine.In injection process, pin can reorientation every now and then, obtains distributing best to make compositions.
In one embodiment, compositions of the present invention is used for the treatment of carcinoma of prostate.Such as, carcinoma of prostate is treated by local injection compositions in prostate.Intraprostetic injection can through peritoneum or per rectum path, and the administration volume of the compositions applied is 0.001ml to 80ml, preferably contains the collagenase II of 0.5 to 25,000U/ml; More preferably, containing 50 to 25, the collagenase II of 000U/ml.
In another embodiment, said composition contains collagenase II and/or collagenase IV, for rectum cancer treatment; In yet another embodiment, said composition contains collagenase II and/or collagenase IV, for treatment of thyroid carcinoma.
Therefore, on the other hand, this application provides the method utilizing anti-cancer composition Therapeutic cancer, the method comprises the anticancer active constituent giving diseased individuals treatment effective dose.Preferably, this amount is enough to blood vessel, tumor cell and various cytokine in degraded tumor, mesenchyma stroma of tumors, interstitial, cures or alleviates cancer.Preferably, described anticancer active constituent is collagenase II, collagenase IV or its combination.More preferably, described anticancer active constituent is collagenase II.
In preferred embodiments, anticancer effective component of the present invention, the preferably dosage of collagenase II are that every kilogram of whose body weight gives 0.01 to 5,000,000U, be preferably 10 to 500,000U, be more preferably 10 to 100,000U, most preferably be 10-50,000U, such as 10-1,000U.
Effective ingredient in anti-cancer composition of the present invention is more single, and curative effect is easy to control and confirm; Toxic and side effects is little.And, in some embodiments, anticancer effective component just can obtain obvious anticancer function with quite low dosage, and such as dosage is that the collagenase II (being about equivalent to 10 ~ 308U/kg) of 0.04-0.9mg/kg whose body weight can the growth of remarkable Tumor suppression.
" individuality " described in the application, refers to mammal, includes but not limited to the rodent of primate, cattle, horse, pig, sheep, goat, Canis familiaris L., cat and such as rat and mouse.
Herein, effective ingredient, active component and active component can be used alternatingly, unless otherwise stated.
In the specification and claims, word " comprises ", " comprising " and " containing " mean " including but not limited to ", and be not intended to get rid of other parts, additive, component or step.
Should be appreciated that, the feature described in particular aspects of the present invention, embodiment or embodiment, characteristic, component or step, be applicable to any other aspect, embodiment or embodiment described herein, unless contradiction with it.
Above-mentioned disclosure generally describes the present invention, by the further example the present invention of the following examples.Describe these embodiments and be only explanation the present invention, instead of limit the scope of the invention.Although employ special term and value herein, these terms and value are understood to exemplary equally, not delimit the scope of the invention.Unless specifically stated otherwise, the experimental technique in this description and technology are Method and Technology known in those skilled in the art.
Embodiment
The male mouse of kunming that the laboratory animal used in following examples is body weight 20-26g, purchased from anti-Pharmaceutical Group center, Shandong, Shandong laboratory animal room.The cancer cell of injection is provided by Shandong Academy of Medical Sciences.The collagenase II used in experiment, collagenase IV and MMP-7 are purchased from LifeTechnologies company.
The measuring method of gross tumor volume: major diameter and the minor axis of measuring tumor with slide gauge respectively, the computing formula of gross tumor volume is: V=(major diameter * minor axis
2)/2.
Statistical method: result represents with mean value ± standard error.Adopt t-check analysis between two groups of data, many group results contrast adopt one factor analysis of variance Tukey inspection (One-wayANOVATukey'stest) to analyze, and P<0.05 is that difference has significance.
The impact that the collagenase of embodiment 1 various dose grows rectal neoplasm
By 2x10
5individual rectal cancer oncocyte subcutaneous injection, in the hypochondrium of white mice, is divided into after 7 days following 10 groups (often organizing 6, in table 1) until tumor growth.1st group is matched group, and 2-4 group is collagenase II treatment group, and 5-7 group is collagenase IV treatment group, and 8-10 group is MMP-7 treatment group.Medicine is through intratumor injection, and dosage calculates (concrete dosage is in table 1) by kg body weight (mg/kg), and every day is administered once, totally 3 times.Within after treatment the 15th day, measure gross tumor volume size, the therapeutic effect (see table 1) of relatively more each group.The vigor of collagenase II used is 342U/mg, and the vigor of collagenase IV is the vigor of 180U/mg, MMP-7 is 186U/mg.The vigor of the MMP-8 (collagenase II) in other embodiments is also 342U/mg.
Table 1
| Group (n=6) | Accept treatment | Gross tumor volume (mm 3) | P value |
| 1 | Contrast | 2000±401 | |
| 2 | Collagenase II, 0.04mg/kg | 1429±192 | <0.05 |
| 3 | Collagenase II, 0.08mg/kg | 1086±94.3 | <0.01 |
| 4 | Collagenase II, 0.16mg/kg | 514±54.3 | <0.001 |
| 5 | Collagenase IV, 0.10mg/kg | 1886±291 | >0.05 |
| 6 | Collagenase IV, 0.20mg/kg | 1543±266 | >0.05 |
| 7 | Collagenase IV, 0.40mg/kg | 1086±214 | <0.01 |
| 8 | MMP-7,0.10mg/kg | 2086±414 | >0.05 |
| 9 | MMP-7,0.20mg/kg | 2057±340 | >0.05 |
| 10 | MMP-7,0.40mg/kg | 2029±303 | >0.05 |
As shown in the result of table 1, very large to the inhibitory action difference of tumor growth when different MMP applies separately.And also there were significant differences for tumor killing effect when different collagenases is applied separately.Such as, collagenase II, when being only 0.04mg/kg, just can significantly grow by Tumor suppression; And MMP-7 up to during 0.40mg/kg still without obvious tumor-inhibiting action.Collagenase IV can not grow by Tumor suppression effectively in 0.10 and 0.20mg/kg, when being increased to 0.40mg/kg, significant inhibitory action (P<0.01) is created to tumor, but still is starkly lower than the tumor killing effect (P<0.001) of the collagenase II of 0.16mg/kg.
Collagenase II can significantly grow by Tumor suppression, and its effect shows obvious dose-effect relationship.Such as, the gross tumor volume of 0.04mg/kg collagenase II treatment group is 1429 ± 192mm
3(P<0.05, compared to the gross tumor volume 2000 ± 401mm of matched group
3); When treating with 0.08mg/kg collagenase II, gross tumor volume has dropped to 1086 ± 94.3mm
3(P<0.01, compared to the gross tumor volume 2000 ± 401mm of matched group
3); The gross tumor volume of 0.16mg/kg collagenase II treatment group is then down to 514 ± 54.3mm further
3(P<0.001, compared to the gross tumor volume 2000 ± 401mm of matched group
3).
These data show, collagenase II just can produce significant function of tumor inhibition at dosage well below during other MMP.And, collagenase II in dose-dependent mode to neoplasm growth.
Embodiment 2 collagenase II compares the inhibition of thyroid carcinoma when different approaches administration
By 8x10
5individual thyroid carcinoma oncocyte subcutaneous injection, in white mice hypochondrium, is divided into after 7 days following 10 groups (often organizing 6, in table 2), by different approaches Collagenase II until tumor growth.Drug dose calculates by kg body weight (mg/kg).Administering mode is respectively tail vein injection (IV), intratumor injection (IT) and lumbar injection (IP).Every day is administered once, totally 3 times.Within after treatment the 15th day, measure gross tumor volume size, the therapeutic effect (see table 2) of relatively more each group.
Table 2
| Group (n=6) | Accept treatment | Gross tumor volume (mm 3) | P value |
| 1 | Contrast | 2435±325 | |
| 2 | 0.10mg/kg，IT | 1542±160 | <0.05 |
| 3 | 0.30mg/kg，IT | 812±142 | <0.01 |
| 4 | 0.90mg/kg，IT | 487±69.0 | <0.001 |
| 5 | 0.10mg/kg，IV | 2354±459 | >0.05 |
| 6 | 0.30mg/kg，IV | 1786±303 | >0.05 |
| 7 | 0.90mg/kg，IV | 1218±308 | <0.05 |
| 8 | 0.10mg/kg，IP | 2191±584 | >0.05 |
| 9 | 0.30mg/kg，IP | 2029±519 | >0.05 |
| 10 | 0.90mg/kg，IP | 1380±402 | <0.05 |
As shown in the result of table 2, the route of administration of collagenase II is different, and to the suppression degree of tumor growth, there were significant differences.The effect of intratumor injection collagenase II (group 2-4) Tumor suppression growth is than intravenous injection (group 5-7) and lumbar injection (group 8-10) several times at least by force.
Embodiment 3 collagenase II compares the inhibition of hepatocarcinoma when different approaches administration
By 5x105 hepatocarcinoma oncocyte subcutaneous injection in the hypochondrium of white mice, be divided into after 7 days following 10 groups (often organizing 6, in table 3), by different approaches Collagenase II until tumor growth.1st group is contrast, and 2-4 group is collagenase II intratumor injection (IT) group, and 5-7 group is collagenase II tumor week injection (PT) group, and 8-10 group is collagenase II subcutaneous injection (SC, distance borderline tumor 1-2 centimetre) group.The dosage of medicine calculates by kg body weight (U/kg), and every milliliter of injection is containing 1000U collagenase II.Every day is administered once, totally 3 times.Within after treatment the 15th day, measure gross tumor volume size, the therapeutic effect (see table 3) of relatively more each group.
Table 3
| Test group (n=6) | Accept treatment | Gross tumor volume (mm 3) | P value |
| 1 | Contrast | 4500±1016 | |
| 2 | IT，100U/kg | 1707±365 | <0.05 |
| 3 | IT，300U/kg | 1086±116 | <0.01 |
| 4 | IT，900U/kg | 621±178 | <0.001 |
| 5 | PT，100U/kg | 3724±745 | <0.05 |
| 6 | PT，300U/kg | 2638±442 | <0.05 |
| 7 | PT，900U/kg | 1551±481 | <0.05 |
| 8 | SC，100U/kg | 4655±993 | >0.05 |
| 9 | SC，300U/kg | 3336±737 | >0.05 |
| 10 | SC，900U/kg | 2405±613 | <0.05 |
As shown in the result of table 3, the route of administration of collagenase II is different, has notable difference to the suppression degree of tumor growth.Intratumor injection group (group 2-4) and tumor week injection group (group 5-7) are at several different dosage (100U/kg, 300U/kg and 900U/kg) all can significantly grow by Tumor suppression, wherein the tumor-inhibiting action of intratumor injection group is the most obvious, and presents dose dependent.By contrast, subcutaneous injection group (group 8-10) is the tumor-inhibiting action that 900U/kg just produces statistical significance at dosage.
The inhibitory action of embodiment 4 collagenase II pair of different volumes tumor compares
The white mice of identical sex, close body weight is divided into following 3 groups, respectively by the lung cancer tumor cell subcutaneous injection of varying number in white mice hypochondrium, wherein the 1st group of subcutaneous injection 2x10
5individual oncocyte, the 2nd group of subcutaneous injection 5x10
5individual oncocyte, the 3rd group of subcutaneous injection 2x10
6individual oncocyte.Measure tumorous size until tumor growth after 14 days, then often organize and be divided into two groups (n=6) more at random, wherein a small group accepts collagenase II intratumor injection, shot 0.02ml in tumor, and every milliliter of injection is containing 10000U collagenase II; Another group injection 0.02ml normal saline.Within after treatment the 10th day, again measure gross tumor volume size, comparison of tumor growth inhibition ratio (see table 4).
Table 4
The data of table 4 show, the Tumor growth inhibition degree of collagenase II pair of different volumes of application equivalent is different.Gross tumor volume is larger, and the drug dose realizing identical inhibition needs is larger.
Although be appreciated that the present invention is illustrated with some form, the present invention is not limited to content that is shown in this description and that describe.It should be apparent to those skilled in the art that and also can to make a variety of changes under the prerequisite not departing from scope of the present invention.These changes are all in the scope of protection of present invention.
Claims (10)
1. an anti-cancer composition, it comprises anticancer effective component and pharmaceutically acceptable carrier, and wherein said anticancer effective component comprises collagenase II, collagenase IV or its combination.
2. anti-cancer composition as claimed in claim 1, wherein said anticancer effective component is selected from collagenase II, collagenase IV or its combination, and preferably, described anticancer effective component is collagenase II.
3. anti-cancer composition as claimed in claim 1 or 2, it is formulated into pharmaceutically acceptable dosage form, is preferably injection or implant.
4. anti-cancer composition as claimed in claim 3, the concentration of wherein said collagenase II is 0.5-250,000U/ml, is preferably 25-25,000U/ml, is more preferably 50-25,000U/ml, most preferably is 500-10,000U/ml.
5. the anti-cancer composition according to any one of claim 1-4 is for the preparation of the purposes in the medicine of Therapeutic cancer, and wherein said anticancer effective component comprises collagenase II, collagenase IV or its combination.
6. purposes as claimed in claim 5, wherein said medicine is with the mode administration of injecting, pour into or implant, and preferably, described medicine is through topical.
7. the purposes as described in claim 5 or 6, the dosage of wherein said anticancer effective component is that every kilogram of whose body weight gives 0.01 to 5,000,000U, is preferably 10 to 500,000U, is more preferably 10 to 100,000U, most preferably is 10-50,000U.
8. the purposes according to any one of claim 5-7, the intracavitary injection administration after injection in cancer, the injection of cancer week or cancer operation of wherein said medicine, preferably through cancer inner injecting and administering.
9. the purposes as described in any one of claim 5-7, wherein said medicine is implanted into through cancer, cancer is all implants or cancer operation posterior tuberosity intracavity drug delivery implant, is preferably implanted into administration through cancer.
10. the purposes according to any one of claim 5-9, wherein said cancer is preinvasive cancer or metastatic cancer, and preferably, described cancer is selected from hepatocarcinoma, pulmonary carcinoma, rectal cancer, thyroid carcinoma or its metastatic carcinoma.
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| CN114681596A (en) * | 2020-12-29 | 2022-07-01 | 杭州观苏生物技术有限公司 | Method for treating cancer by intratumoral injection of variant collagenase |
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| CN105477628B (en) | 2021-04-30 |
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