KR20070032023A - Malignant tumor local infiltration inhibitor containing batroxobin - Google Patents

Abstract

By containing bartroxobin, a malignant tumor local invasion inhibitor which can suppress local tumor invasion, and a malignant tumor capsule which can form or promote the formation of a capsule-like tissue around the malignant tumor tissue. Provide a topic.

Description

MALIGNANT TUMOR LOCAL INFILTRATION INHIBITOR CONTAINING BATROXOBIN}

The present invention relates to a malignant tumor local invasion inhibitor and a malignant tumor tissue encapsulating agent, characterized by containing bartroxobin.

In recent years, the treatment of malignant tumors has been improved and certainly progressed in the success rate of primary carcinoma by surgical surgery, radiotherapy or chemotherapy. However, even in early malignant tumors, it is often seen that malignant tumor cells are locally infiltrated by adjacent tissues and organs. In this case, even if the malignant tumor tissue of the primary focus is surgically removed, the malignant tumor recurs due to the remaining infiltrating malignant tumor cells, and as a result, there are few cases of death. In particular, when the infiltrated organ is an important organ, invasive malignant cells cannot be removed together with normal tissue, so the recurrence rate of the malignant tumor is high and the mortality rate is high. In addition, when malignant tumors occur in important organs, a large amount of tissue including normal tissues is removed in order to avoid local invasion, and thus there is a problem that the function of the important organs is lost. In addition, tumors with high malignancy, such as melanoma, lung cancer, liver cancer and pancreatic cancer, are difficult to detect early, and local tumor invasion of malignant tumors is widely recognized at the time of tumor diagnosis. many.

For local infiltration of such malignancies, radiotherapy does not show good results. In addition, chemotherapeutic agents such as adriamycin, which are currently used clinically, mostly attack malignant tumor cells and exert their effects, but at the same time, they target normal cells, and thus have a strong side effect. The problem is the reality. Therefore, new malignant tumor local infiltration inhibitors are desirable.

It is generally considered that the progression stage of malignant tumor and local infiltration are in the following relationship.

(1) In the early stages of malignant tumors, proliferation of malignant tumor cells due to cell division occurs, and tumors grow. This is observed as dysplasia. In this step, histopathologically, proliferative malignant tumor cells exist locally and can be clearly distinguished from surrounding normal tissues. In many cases, capsule-like tissue is formed around the malignant tumor tissue.

Capsule-like tissues are connective tissues formed by interaction between malignant tumor tissues and normal tissues, and distinguish between malignant tumor tissues and normal tissues, and are tissues that appear to enclose malignant tumor tissues in capsules. The malignant tumor surrounded by the capsule-like tissue is extremely easy to be removed by surgical operation, and also rarely fails to extract the malignant tumor cells, so that there is almost no recurrence of the malignant tumor after the extraction.

(2) However, as the malignant tumor progresses, the capsular tissue is lost, causing local infiltration from the malignant tumor tissue to adjacent normal tissues and organs, and widespread diffusion of the malignant tumor occurs. At this stage, treatment by surgical extraction becomes difficult.

In view of the relationship between the progression stage of the malignant tumor and the local infiltration, it has been suggested that the development of a malignant tumor treatment by promoting the formation of capsule-like tissues is clinically useful. In practice, however, studies on the formation of encapsulated tissues around the malignant tumors and the development of the drug for promoting the formation have not been conducted, focusing only on the local infiltration of the malignant tumors (for example, Clin. Expl. Metastasis 7: 277-282). , 1989). This is because in the related art, local infiltration of malignant tumors is a part of the malignant tumor metastasis process, and it is generally considered that a drug that inhibits the metastasis of malignant tumors can also suppress local infiltration.

Recently, however, a pathway of tumor metastasis that does not involve local invasion has been found in many malignancies (see, eg, BMC Medicine, 2 (9): 1-8, 2004). For example, there have been reports of clinically confirming the presence of malignancy that causes metastasis, although local infiltration is not seen (eg Virchows Arch. Pathol. Anat. 390: 121-126, 1981 and Surgery Today 25: 369). -372, 1995). In addition, it has been reported that there is a drug that is effective for local invasion of malignant tumors but is not effective for metastasis, but rather promotes metastasis (for example, Breast Cancer Res. Treat. 40: 209-223, 1996). In contrast, there are reports of in vivo experiments with drugs that inhibit the metastasis of malignancies but do not inhibit local infiltration (see, for example, Clinical & Experimental Metastasis 19: 95-105, 2002). These reports suggest that the local invasion process of malignant tumors is not caused during metastasis, but is a phenomenon caused by a separate process from local infiltration and metastasis.

Apart from the above point of view, a close relationship between malignant tumors and coagulation and fibrinolysis systems has been suggested by a number of basic and clinical studies. For example, in malignant tumor patients, it is known that microcirculation disorders are caused by abnormal coagulation system such as an increase in plasma fibrinogen, an increase in blood viscosity, and an abnormality in blood rheology. In addition, the increase in the plasma fibrinogen or the malignant tumor cells secrete fibrinogen by itself, resulting in the deposition of fibrinogen or fibrin in the extracellular matrix of the malignant tumor tissue, which is a member of the extracellular matrix, which proliferates and infiltrates And has been reported to have a promoting effect on metastasis (eg, Cancer Research 60: 2033-2039, 2000, Ann NY Acad. Sci. 936: 406-425, 2001 and Blood 96: 3302-3309, 2000 See).

Focusing on the relationship between these malignancies and coagulation system, Bothrops It has been reported that the barromosobin , a thrombin-like serine protease derived from the venom of atrox moojeni , inhibits the proliferation and metastasis of malignant tumors, such as Anthrod, another thrombin-like serine protease (for example, Eur. J. Cancer 16: 919-923, 1980). However, in this report, tumor weight is employed as an indicator of the inhibitory effect of malignant tumor proliferation, the number of metastatic foci in the metastatic stroma as an index of malignant tumor metastasis, and local infiltration of malignant tumor is adopted. No ratings are made for.

In addition, in the experimental model using fibrinogen-deficient mice, the metastasis of malignant tumors depends on fibrinogen and fibrin, but the proliferation and local infiltration of malignant tumors are not dependent on fibrinogen. Not reported (see, eg, Blood 96: 3302-3309, 2000). However, nothing is said about the association between bartroxobin and local infiltration of malignancies.

Disclosure of the Invention

Accordingly, an object of the present invention is to provide a new drug capable of suppressing local infiltration of malignant tumors, and a new drug capable of forming capsule-like tissues or promoting the formation of capsule-like tissues around the malignant tumor tissues. It is done.

MEANS TO SOLVE THE PROBLEM In order to solve the said subject, the present inventors earnestly researched about the local invasion of malignant tumors in vivo, and it turns out that barloxobin can suppress local invasion of malignant tumors, and malignant tumors. It has been discovered that capsule-like tissue can be formed or promoted around the tissue. This invention is made | formed based on this knowledge.

That is, the present invention,

(1) a malignant tumor local infiltration inhibitor, characterized by containing bartroxobin, and

(2) It relates to a malignant tumor tissue encapsulating agent, characterized by containing bartroxobin.

To practice the invention  Best form for

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The malignant tumor local infiltration inhibitor and the malignant tumor tissue encapsulating agent of the present invention are characterized by containing bartroxobin as an active ingredient.

Vatroxobin , Bothrops atrox It is a thrombin-like serine protease derived from the venom of moojeni . Vatroxobin favors only fibrinopeptide A from fibrinogen and produces Des A fibrin (also called fibrin I) (eg, Thromb. Haemost. 36: 9-13, 1976 and Thromb Diath.Haemorrh. 45 Suppl: 63-68, 1971). In addition, the primary structure of barloxobin has already been determined (eg, J. Biol. Chem. 262 (7): 3132-3135, 1987}.

Batroxobin is a serine protease like thrombin. However, bartroxobin only releases fibrinopeptide A from fibrinogen to produce Des A fibrin, whereas thrombin liberates fibrinopeptide A and fibrinopeptide B from fibrinogen to produce thrombin Is different. In addition, while bartroxobin does not act on blood coagulation factors other than fibrinogen, thrombin differs in that it also acts on other blood coagulation factors.

Batroxobin used in the present invention may be natural or may be a genetic recombinant.

Batroxobin is itself a known substance, and can be prepared, for example, according to the method described in Japanese Patent Laid-Open No. 57-10718 (Japanese Patent No. 1118129). Or it is easily available in a market (made by Tobishi Pharmaceutical Co., Ltd. and its subsidiary Beijing Tobishi Pharmaceutical Co., Ltd., Beijing, China).

Subjects of the present invention are malignancies. Malignant tumors can be largely divided into epithelial malignancies and non-epithelial malignancies by the developing mother tissue. Non-epithelial malignancies can also be classified as malignant tumors from mesenchymal tissues, malignant tumors from neural tissues and malignancies of undifferentiated cells. Below, the specific example of each malignant tumor is illustrated.

Epithelial malignancy

Adenocarcinoma (adenocarcinoma derived from adenocarcinoma), which occurs in various parts of the body, including the stomach, intestines, pancreas, organs, lungs, mammary gland, ovary, uterus and prostate, and accounts for 70-80% of human cancers Squamous cell carcinoma (derived from stratified squamous epithelium, for example, cancers in epithelial tissues such as epidermis, lips, tongue, pharynx, esophagus, anus, vulva, cervix, and non-small cell lung cancer) Lung squamous cell carcinoma), basal cell carcinoma (derived from skin and appendages), transitional cell carcinoma (derived epithelium-derived, eg bladder cancer), hepatocellular carcinoma (derived by hepatic parenchymal cells), Renal cell carcinoma (derived from renal epithelium), cholangiocarcinoma (from bile duct), choriocarcinoma (from placental epithelium)

Non-cortical malignancy

Malignant tumor derived from mesenchymal tissue

Fibrosarcoma (derived from connective and fibrous tissue), liposarcoma (derived from connective and adipose tissue), chondrosarcoma (derived from connective and cartilage tissue), osteosarcoma (derived from connective and bone tissue), angiosarcoma (derived from vascular tissue), lymphatic vessel Sarcoma (derived from lymph vessels), Myeloid leukemia (derived from hematopoietic cells), Monocytic leukemia (derived from hematopoietic cells), Malignant lymphoma (derived from lymphoid tissue), Lymphoid leukemia (derived from lymphoid tissue), Plasma cell tumor (from multiple myeloma) (From lymphoid tissue) ), Hodgkin's cell (derived from lymphoid tissue), smooth muscle sarcoma (derived from smooth muscle), rhabdomyosarcoma (derived from rhabdomyo)

Malignant tumor derived from neural tissue

Neuroblastoma (from neuroblastoma), Medulloblastoma (from marrow cell), malignant astrocytoma (Astrocyte) Derived), retinoblastoma (from retinoblastoma), glioblastoma (from glioblastoma), malignant neurilenoma (from Schwann cells), melanoma (from neuroectodermal) )

Malignant tumor of undifferentiated cell

Malignant teratoma (derived from pluripotent cells), nephroblastoma (derived from renal cells), hepatoblastoma (derived from hepatocytes), mixed tumor (derived from multiple types of cells)

The malignant tumor local infiltration inhibitor and the malignant tumor encapsulant of the present invention, among these malignant tumors, will have an excellent effect on the malignant tumors derived from neural tissues, especially melanoma and lung cancer, which are epithelial malignancy and non-epithelial malignant tumor Can be.

Local invasion of malignant tumors refers to the invasion of tumor cells into surrounding adipose tissues or other connective tissues, and is distinguished from widespread invasion (infiltration into other organs continuously from the primary cow).

Encapsulation of malignant tumor tissue refers to the formation of encapsulated tissue around the malignant tumor tissue. Capsule-like tissue is a connective tissue formed by the interaction between a malignant tumor tissue and a normal tissue, and refers to a tissue that appears to enclose a malignant tumor tissue in a capsule by blocking the malignant tumor tissue from the normal tissue. .

By forming a capsule-like tissue around the malignant tumor tissue, the surgical range can be easily reduced during surgical treatment of the malignant tumor. In addition, the encapsulation facilitates the complete extraction of the malignant tumor tissue, and as a result, it is possible to prevent tumor recurrence caused by the remaining infiltrating malignant tumor cells. In addition, even when malignant tumors occur in important organs, according to the present invention, by forming capsule-like tissues around the malignant tumor tissues, it is possible to extract malignant tumor tissues in a minimum range, thereby preventing the loss of the function of the important organs. Can be avoided.

In the causal relationship between the malignant tumor local invasion inhibitory action and the malignant tumor tissue encapsulation action of the active ingredient bartoxobin, the local infiltration is suppressed even if the encapsulation of the malignant tumor tissue is not recognized (see Example below). Because of this, encapsulation of malignant tumor tissue may not be considered an essential requirement for local tumor invasion inhibition. However, encapsulation of malignant tumor tissue can be considered to be at least accelerated against malignant tumor local infiltration.

The malignant tumor local infiltration inhibitor and the malignant tumor tissue encapsulating agent of the present invention may be composed of a bartroxobin unit or may be combined with other active substances.

Other active substances include metabolic antagonists such as Fluorouracil, antitumor antibiotics such as adriamycin, alkylating agents such as dacarbazine, plant-derived anticancer agents such as Paclitaxel, and the like. Can be mentioned.

As the dosage form of the malignant tumor local infiltration inhibitor and the malignant tumor tissue encapsulating agent of the present invention, the dosage form in the general rule of Japanese Pharmacopoeia can be applied, and for example, injections (suspensions, emulsions) applied directly to the body Includes); Ointments (including oil-based ointments, emulsion ointments (creams), water-soluble ointments, etc.), inhalants, solutions (including eye drops, nasal drops, etc.), suppositories, patches, poultices, External preparations such as lotions; Or solvents such as tablets (including sugar coating, film coating, gelatin coating), liquids, capsules, granules, powders (including granules), pills, syrups, troches Etc. can be mentioned. Such a formulation can be formulated by the method described in General Regulations of Japan International.

In addition, the malignant tumor local infiltration inhibitor and the malignant tumor tissue encapsulating agent of the present invention may include a pharmaceutically acceptable solid or liquid carrier or interventional treatment agent depending on the dosage form. Pharmaceutically acceptable solid or liquid carriers include solvents, stabilizers, preservatives, dissolution aids, emulsifiers, suspending agents, buffers, isotonic agents, colorants, bases, thickeners, excipients, lubricants, binders, disintegrants, Coating agents, corrigents, and the like.

As specific examples, sugars and sugar alcohols such as water and lactose, white sugar, fructose, glucose, mannitol and sorbitol, crystalline cellulose, methyl cellulose, ethyl cellulose, hydroxy propyl cellulose, low-substituted hydroxypropyl cellulose and hydroxypropyl methyl Cellulose and its derivatives such as cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, camelos, camelos calcium, sodium camelos, croscarmellose sodium, carboxymethylethylcellulose, cellulose acetate phthalate, Starch such as corn starch, wheat starch, rice starch, potato starch, dextrin, alpha starch, partially alpha starch, hydroxypropyl starch, sodium carboxymethyl starch, cyclodextrin, pullulan and related derivatives, agar, sodium alginate , Gum arabic, gelatin, collagen, Natural polymers such as lac, tragacanth and xanthan gum (seaweeds, plant derivatives, proteins, etc.), polyvinylpyrrolidone, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, carboxyvinyl polymers, polyvinyl alcohols, Synthetic polymers such as dimethylpolysiloxane, oils such as olive oil, cacao butter, carnauba wax, bee tallow, hardened oil, soybean oil, sesame oil, camellia oil, paraffin, liquid paraffin, yellow beeswax, white petrolatum, palm oil and microcrystalline wax Fatty acids and derivatives thereof, such as stearic acid, aluminum stearate, calcium stearate, magnesium stearate, triethyl citrate, triacetin, medium chain triglycerides, hard fats, isopropyl myristin, glycerin, stearyl alcohol, three Alcohols and polyhydric alcohols such as tanol, propylene glycol, macrogol, zinc oxide, calcium hydrogen phosphate, precipitated knife , Synthetic aluminum silicate, silicic anhydride, kaolin, dry aluminum hydroxide gel, synthetic hydrotalcite, titanium oxide, talc, bentonite, magnesium aluminate silicate, potassium aluminum sulfate, bismuth subgallate, bismuth tea salicylic acid, lactic acid Inorganic substances such as calcium and sodium bicarbonate and metal salt compounds, sucrose fatty acid esters, stearic acid polyoxyl, polyoxyethylene hardened castor oil, polyoxyethylene polyoxypropylene glycol, sesquioleic acid sorbitan, trioleic acid sorbitan, monostearic acid sorbate And surface-active substances such as mourning, sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glycerin monostearate, sodium lauryl sulfate, lauromacrogol, pigments and fragrances.

Examples of the interventional treatment base include stents, artificial blood vessels, and the like.

The dosage of the malignant tumor local infiltration inhibitor and the malignant tumor encapsulant of the present invention usually varies depending on the weight of the patient and the nature and condition of the disease, but, for example, when administered to an adult once a day, As roxobine, it is 1-20 Batroxobin Unit (abbreviated as BU).

The bartroxobin unit is a unit indicating the amount of enzymatic activity of bartroxobin, and at 37 ° C., when 0.1 ml of bartroxobin solution is added to 0.3 ml of standard human citric acid-added plasma, the amount of active clotting is 19.0 ± 0.2 seconds. 2BU.

As a method for administering the malignant tumor local invasion inhibitor and the malignant tumor tissue encapsulating agent of the present invention, it is preferable to properly dilute the bartroxobin, and to administer intravenously, intravenously, intraarterally, intramuscularly or topically. .

The acute toxicity of bartroxobin in mice, rats, rabbits and dogs {LD ₅₀ (BU / kg)} is shown in Table 1 below. Acute toxicity studies were assessed by intravenous administration of batloxine, according to the method described in Pharmacometrics (Oyoyakuri) 25: 339-346,1983.

Table 1 Acute Toxicity of Vatroxobin (iv)

  Animal species LD ₅₀ inch (BU / kg)   Mouse (ddy system)   192-210   Rat (Wistar system)   105 to 110   Rabbit (NW system)   > 300   Dog (hybrid)   190-208

FIG. 1 is a micrograph of solid cancer tissue of a mouse with B16-BL6 melanoma cancer that was not administered bartroxobin.

FIG. 2 is a micrograph of solid cancer tissue of a mouse having B16-BL6 melanoma cancer administered bartroxobin.

Figure 3 is a micrograph of solid cancer tissue from mice with LA795 lung cancer that did not receive bartroxobin.

Fig. 4 is a micrograph of solid cancer tissue of a mouse having LA795 lung cancer administered bartroxobin.

Although an Example is shown to the following and it concretely demonstrates, this invention is not limited by an Example.

Example 1 Inhibitory Effect of Batroxobin on Local Infiltration of Melanoma

Physiological formulas of B16-BL6 malignant melanoma cells (solid cancer cells, Academy of Chinese Medical Sciences, Beijing, China) derived from C57BL / 6j mice (highly invasive mice) passaged with Animal Institute of Academy of Medical Sciences, Beijing, China It was suspended in saline to prepare a melanoma cell suspension with a concentration of 5x10 ⁶ / ml. 0.2 ml of the obtained melanoma cell suspension was inoculated subcutaneously in the right dorsal portion of a male C57BL / 6j mouse of 7 weeks of age (18-20 g in weight) to prepare a tumor-bearing mouse model.

The murine cancer mouse model was randomly divided into a control group (5 mice) and a bartroxobin group (10 mice). In the vathroxobin group, 40 BU / kg bacloxobin was intraperitoneally injected once every other day from day 4 to day 20 after tumor cell inoculation. In the control group, intraperitoneal injection of the same volume of physiological saline (2 ml / kg) was used instead of bartroxobin. At the end of the experiment (20 days after tumor inoculation), tissue specimens including tumor tissue, surrounding skin and muscle of solid cancer were collected, paraffin embedded after formalin fixation, and hematoxylin and eosin stained samples were prepared. The prepared specimens were observed under an optical microscope to evaluate the inhibitory effect of bartroxobin on local infiltration of malignancies.

(1) observation by microscope

1 shows a microscope image (magnification × 200 ×) of the control group. Fig. 2 shows a microscopic image (magnification × 100 ×) of the bartroxobin group (upper view: encapsulation around tumor tissue, lower view: encapsulation around tumor tissue (other mice)).

In the control group, melanoma cells (T) and the surrounding skin or muscle (M) were closely adhered to each other, and melanoma tissue and muscle were almost inseparable (FIG. 1). This indicates that the capsule tissue is not formed.

On the other hand, in the bartroxobin group, a capsular tissue (connective tissue) could be seen between melanoma cells (T) and muscle (M). Because of the presence of these capsular tissues, the infiltration of melanoma cells (T) was limited, so that local infiltration into the subcutaneous connective tissue and flank muscles was hardly seen (FIG. 2, top and bottom views). In addition, since the capsule-like tissue is present in the barroxobin group, the melanoma tissue is not closely adhered to the surrounding skin and muscles, and the tumor tissue can be easily separated from the skin and muscles, and the whole can be extracted. there was.

(2) Quantitative Evaluation of Local Infiltration

Local infiltration of melanoma cells was evaluated by the presence or absence (with local infiltration: positive) of local infiltration into the flank abdominal muscle layer. In addition, the presence or absence of capsule-like tissues (with capsule-like tissue: positive) around melanoma tissue was also evaluated. The results are shown in Table 2.

Table 2 . Inhibitory Effect of Batroxobin on Local Infiltration of Subcutaneously Transplanted B16-BL6 Melanoma

  Treatment group  Local infiltration in the flank abdominal layer [positive water / total number (%)]   Capsule-like tissue [positive water / total number (%)]   Control     3/5 (60%)     1/5 (20%)  Badloxobin 0/10 (0%) ^* 9/10 (90%) ^*

^* : P <0.05, comparison with control

From Table 2, a significant difference was recognized between the control group and the batroxobin group in terms of local infiltration inhibition and capsule tissue formation. From these results, it is understood that bartroxobin can effectively inhibit local invasion of melanoma, and can form or promote the formation of a capsular tissue around melanoma tissue.

Example 2 Inhibitory Effect of Batroxobin on Local Infiltration of Lung Cancer

LA795 pulmonary adenocarcinoma cells (solid cancer cells, Academy of Chinese Medical Sciences, Beijing, China) derived from mice with high local invasiveness passed to male T739 mice (Animal Institute of Academy of Medical Sciences, Beijing, China) were suspended in saline solution. A lung cancer cell suspension was prepared at a concentration of 5 × 10 ⁶ / ml. 0.2 ml of the obtained lung cancer cell suspension was inoculated subcutaneously to the right dorsal part of 7-week-old (18-20 g) male T739 mice to prepare a lung cancer cholecarcinoma mouse model.

The lung cancer gallbladder mouse model was randomly divided into a control group (18 mice) and a bartroxobin group (18 mice), and administration was performed. In the vathroxobin group, intramuscular injection of 40BU / kg bacloxobin once every other day from 2 to 18 days after tumor cell inoculation. In the control group, intramuscular injection of the same volume of physiological saline (2 ml / kg) was used instead of bartroxbin. At the end of the experiment (19 days after tumor inoculation), tissue specimens including tumor tissue, surrounding skin and muscle of solid cancer were collected, paraffin embedded after formalin fixation, and hematoxylin-eosin stained samples were prepared. The prepared specimens were observed under an optical microscope to evaluate the inhibitory effect of barloxobin on local infiltration of malignancies.

(1) observation by microscope

3 shows a microscope image (magnification x 200 times) of the control group. 4 shows a microscopic image (magnification × 100 ×) of the bartroxobin group (upper view: encapsulation around cancer tissue, lower view: encapsulation around cancer tissue (other mouse)).

In the control group, the lung cancer cells (T) and the surrounding muscles (M) were closely mixed so that the lung cancer solid cancer tissues and the muscles could hardly be separated (FIG. 3). This indicates that the capsule tissue is not formed.

On the other hand, in the bartroxobin group, a capsule-like tissue (connective tissue) could be seen between lung cancer cells (T) and muscles (M). Due to the presence of such capsular tissues, infiltration of lung cancer cells (T) is limited, and local infiltration into the subcutaneous connective tissue and flank muscles was hardly seen. Specifically, the upper right of the upper view of Figure 4 is the lung cancer solid cancer cells (T), the tissue that is oblique in the middle of the picture with the capsule-like tissue between the muscle tissue (M). The top half of the bottom view of FIG. 4 is lung cancer solid cancer tissue (T), and the bottom half is muscle tissue (M). The capsule-like tissue can be seen between the cancerous and muscular tissues. In addition, since the capsule-like tissue is present in the bartroxobin group, the close contact between the cancer tissue and the surrounding skin and muscle does not occur, and the cancer tissue can be easily separated from the skin and muscle, and thus the whole can be extracted.

(2) Quantitative Evaluation of Local Infiltration

Local invasion of lung cancer cells was evaluated by the presence or absence (with local infiltration: positive) of local infiltration into the flank abs muscle layer. In addition, the presence or absence of capsule-like tissues (including capsule-like tissues) around lung cancer tissues was evaluated. The results are shown in Table 3.

Table 3 . Inhibitory Effect of Batroxobin on Local Infiltration of Subcutaneously Transplanted LA795 Lung Cancer

     Treatment group     Local infiltration in the flank abdominal layer [positive water / total number (%)]     Capsule-like tissue [positive water / total number (%)]      Control        14/18 (77.8%)       4/18 (22.2%)   Badloxobin 6/18 (33.3%) ^* 10/18 (55.6%) ^*

^* : P <0.05, comparison with control

From Table 3, a significant difference was recognized between the control group and the batroxobin group in terms of local infiltration inhibition and capsular tissue formation. From these results, it is understood that bartroxobin can effectively suppress local invasion of lung cancer, and can form or promote the formation of capsular tissue around melanoma tissue.

[Industry availability]

As shown in the above embodiment, the present invention can effectively suppress local infiltration of malignant tumors, and can form or promote the formation of capsule-like tissues around the malignant tumor tissues. Therefore, in the surgical treatment of malignant tumors, the extraction range can be reduced by suppressing local invasion, so that surgery can be easily performed. In addition, since capsule-like tissue can be formed around the malignant tumor tissue, it can contribute to the complete extraction of the malignant tumor tissue, and is also advantageous for the prevention of tumor recurrence caused by the remaining infiltrating malignant tumor cells caused by conventional incomplete extraction. Can be used. In addition, the radiation dose can be reduced during the radiation treatment to reduce the exposure dose. Therefore, the present invention can be used as a malignant tumor local infiltration inhibitor and a malignant tumor tissue encapsulating agent.

Claims (10)

A malignant tumor local invasion inhibitor, characterized in that it contains bartroxobin. The malignant tumor local infiltration inhibitor of claim 1, wherein the malignant tumor is an epithelial malignant tumor. The malignant tumor local infiltration inhibitor of claim 1, wherein the malignant tumor is a non-epithelial malignant tumor. The malignant tumor local infiltration inhibitor according to claim 1, wherein the malignant tumor is a malignant tumor derived from neural tissue. The malignant tumor local infiltration inhibitor according to claim 1, wherein the malignant tumor is melanoma or lung cancer. A malignant tumor tissue encapsulating agent, characterized by containing bartroxobin. The malignant tumor encapsulating agent of claim 6, wherein the malignant tumor is an epithelial malignant tumor. The malignant tumor encapsulating agent of claim 6, wherein the malignant tumor is a non-epithelial malignant tumor. The malignant tumor encapsulating agent according to claim 6, wherein the malignant tumor is a malignant tumor derived from neural tissue. The malignant tumor encapsulating agent of claim 6, wherein the malignant tumor is melanoma or lung cancer.

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