KR920005685B1 - Anti-tumoric agent from lactobacillus sporogenes - Google Patents

Anti-tumoric agent from lactobacillus sporogenes Download PDF

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KR920005685B1
KR920005685B1 KR1019890016183A KR890016183A KR920005685B1 KR 920005685 B1 KR920005685 B1 KR 920005685B1 KR 1019890016183 A KR1019890016183 A KR 1019890016183A KR 890016183 A KR890016183 A KR 890016183A KR 920005685 B1 KR920005685 B1 KR 920005685B1
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이정치
김태한
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일동제약 주식회사
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Abstract

An antitumor compsn. is prepared by (a) culturing Lactobacillus sporogens IL-101 in a medium at 35-55 deg.C (pref. 42-47 deg.C) for 1-4 day(s), (b) filtrating the medium to remove the supernatant, and washing the obtd. cells with saline or distilled water, and (c) suspending the cells in distilled water, sterelizing it at 100 deg.C water bath for 60 min., and freeze-drying the obtd. cell-suspended soln. Pref. the medium contains 5g proteose peptone, 5g yeast extract, 5g glucose, 2g K2HPO4, 0.5g KH2PO4, 0.5g NaCl, 0.01g MgSO4, 0.3g MnSO4, 0.01g FeSO4, 0.01g CoSO4, 0.01g CuSO4 and 0.01g ZnSO4.

Description

유산균을 이용한 항 종양제Antitumor Drugs Using Lactic Acid Bacteria

본 발명은 유산균을 이용해서 만든 항 종양제, 상술하면 공지균주 락로바실러스 스포토제네스(Lactobacillus sporogenes)IL-101의 균체를 유효성분으로 하는 후술하는바의 특성을 갖는 신규의 항종양 물질에 관한 것이다. 근래에 이르러, 여러가지 유형의 암 환자에 대한 면역 기능을 향상시키고 이에 수반하여 항암효과를 얻을 수 있을 약재에 대한 연구가 활발하게 진행되고 있으며, 그 결과 세균의 균체 혹은 균체 추출물을 항 종양제로 사용하는 예가 많아졌다.The present invention relates to an anti-tumor agent made using lactic acid bacteria, and more particularly to a novel anti-tumor substance having the following characteristics, which is described below as an active ingredient of the known strain Lactobacillus sporogenes IL-101. . In recent years, there are active researches on medicines that can improve the immune function of various types of cancer patients and thus have anti-cancer effects. As a result, the use of bacteria or extracts of bacteria as anti-tumor agents There are many examples.

세균을 이용할 경우에는 균체 추출물을 이용하는 경우와 비교해서 제조상 추출, 분리, 정제 등의 복잡한 처리가 필요치 않은 이점이 있으며, 인체에 유익한 유산균을 이용하게 되면 균체에 의한 부작용도 일어나지 않게 된다. 일본특공소 62-34727은 유산균의 항종양 효과에 대하여 언급하고 있으며, 그중 가장 우수한 균주인 락토바실러스 카제이 YIT-9018(L.casei YIT-9018)와의 비교시험결과, 본 발명에서 제조된 균주의 효과가 보다 좋은 결과를 나타냈으며, 또한 시판 용연균 제제보다도 좋은 결과를 얻을 수 있었다. 따라서 본 발명의 목적은 항종양 효과가 탁월한 신규의 항종양제를 제공하는 것이다.The use of bacteria does not require complex processing such as extraction, separation, and purification in manufacturing compared to the use of cell extracts, and the use of beneficial lactic acid bacteria to the human body does not cause side effects caused by the cells. Japanese special public service 62-34727 mentions the anti-tumor effect of lactic acid bacteria, and the result of comparative test with Lactobacillus casei YIT-9018 (L.casei YIT-9018), the most excellent strain among them, The effect was shown to be better, and also the result was more favorable than the commercially available fungal bacterium preparation. It is therefore an object of the present invention to provide novel antitumor agents with excellent antitumor effects.

본 발명에 사용하는 미생물로는 락토바실러스속에 속하는 미생물 특히 공지미생물로 락토바실러스 스포로제네스을 사용하며, 그 세균학적 특성은 후술하는 바와 같다.As a microorganism used in the present invention, Lactobacillus sporogenes is used as a microorganism, in particular, a known microorganism belonging to the genus Lactobacillus, and the bacteriological characteristics thereof are described below.

(Ⅰ) 형태(Ⅰ) Form

(1) 세포의 형태 : 막대형, (2) 세포의 다형 : 없음, (3) 운동성 : 없음, (4) 포자 : 있음, (5) 그람염색 : 그람양성(1) cell morphology: rod, (2) cell polymorphism: none, (3) motility: none, (4) spores: present, (5) gram staining: gram positive

(Ⅱ) 배양 매질의 증식 상태(II) Growth state of the culture medium

(1) 한천 평판 및 사면 배양 매질(1) agar plate and slope culture medium

외형 : 원형, 크기 : 약 1㎜, 표면 : 매끈함, 색 : 유백색Appearance: Round, Size: about 1㎜, Surface: Smooth, Color: Milky white

(2) 액체 배양 매질(2) liquid culture medium

증식도 : 활발, 탁도 : 흐림, 침전 : 있음, 기체 : 있음.Proliferation: Active, Turbidity: Cloudy, Precipitation: Yes, Gas: Yes.

(Ⅲ) 생리학적 특성(III) Physiological Characteristics

카탈라아제 : +, 산소에 대한 동향 : 호기성, 인돌생성 : -, 젖산생성 : +, 전분가수분해 : +, 포도당으로부터 가스생성 : -, 증식범위 : 온도 30∼55℃, PH 4.0∼8.0항종양 물질을 제조하는 과정은 다음과 같다.Catalase: +, Trend for Oxygen: Aerobic, Indole Formation:-, Lactate Formation: +, Starch Hydrolysis: +, Gas from Glucose:-, Growth Range: Temperature 30-55 ℃, PH 4.0-8.0 The manufacturing process is as follows.

Figure kpo00001
Figure kpo00001

(1) 균의 배양(1) cultivation of bacteria

호기성균 배양에 대한 통상적인 방법으로 배양한다. 비프추출물, 여러가지 펩톤 등 같은 질소원, 이스트 추출물등 같은 비타민원, 염화나트륨 등 같은 무기염, 포도당, 유당같은 탄소원, 기타 버터 등을 첨가한 배양 매질에 수산화나트륨 수용액을 가해 pH를 4내지 8로, 바람직하게는 5.5내지 7.0으로 조절하고 균을 접종한후 호기성 조건하에서 35℃ 내지 55℃ 바람직하게는 42℃ 내지 47℃로 1내지 4일간 바람직하게는, 1내지 4일간 교반 배양시키거나 정치 배양시켜 생성을 억제시켜 간균 상태에서 배양을 중지시킨다. 특히 표1에 기술된 배양매질을 사용함이 바람직하다.Incubate in a conventional manner for aerobic culture. Aqueous sodium hydroxide solution is added to a culture medium to which beef extracts, nitrogen sources such as peptones, vitamin sources such as yeast extracts, inorganic salts such as sodium chloride, glucose, carbon sources such as lactose, and butter are added, and the pH is adjusted to 4-8. Preferably it is adjusted to 5.5 to 7.0 and inoculated with the bacteria, and then produced by stirring or incubating for 1 to 4 days, preferably 1 to 4 days at 35 ° C to 55 ° C, preferably 42 ° C to 47 ° C, under aerobic conditions. To stop the culture in the bacilli state. In particular, it is preferable to use the culture medium described in Table 1.

[표 1]TABLE 1

Figure kpo00002
Figure kpo00002

(Ⅱ) 배양물로부터 균의 수득(II) Obtaining Bacteria from Cultures

전술한 바와 같이 상청액을 제거한다. 상청액의 제거 공정은 원심분리, 여과 보조제를 사용하는 여과법 등 통상적인 방법으로 수행할 수 있다. 또한 수득한 균은 생리 식염수 혹은 증류수로 3회 이상 세척한다.The supernatant is removed as described above. The removal of the supernatant may be carried out by conventional methods such as centrifugation and filtration using a filter aid. In addition, the obtained bacteria are washed three times or more with physiological saline or distilled water.

(Ⅲ) 항종양 물질 제조(III) Antitumor Substance Preparation

세척하여 얻은 균체를 증류수에 적당히 현탁시킨 후 100℃ 수욕열탕에서 60분정도 열처리하여 균을 사멸시킨 후 동결 건조시켜 항종양 물질을 제조한다.The cells obtained by washing are appropriately suspended in distilled water, and then heat-treated in a 100 ° C. water bath for 60 minutes to kill the bacteria and freeze-dried to prepare an anti-tumor material.

다음에 실시예로서 더욱 상세히 본 발명을 설명한다.Next, the present invention will be described in more detail by way of examples.

[실시예 1]Example 1

증류수 리터당 5g의 프로테오즈 펩톤, 5ｇ의 이스트추출물과 포도당, 2ｇ의 인산수소칼륨, 0.5ｇ의 인산이 수소나트륨과 염화나트륨, 0.3ｇ의 황산망간, 각 0.01ｇ의 황산마그네슘, 황산철, 황산코발트, 황산동, 황산아연을 함유하는 배지를 500ml들이 삼각프라스크에 200ml씩 넣는다. 배지를 120℃에서 30분간 멸균한다. 배지를 냉각한 후 상술한 바와 같은 조성을 갖는 배지중에서 배양하여 미리 제조한 락토바실러스 스포로제네스 1L-101 전배양용액 10ml를 접종한후 45℃에서 2일간 진탕하면서(140회/분)배양한 후에 배양물을 수거하여 원심분리하여(8,000rpm, 10분)균체를 얻는다.5 g of proteose peptone, 5 g of yeast extract and glucose, 2 g of potassium hydrogen phosphate, 0.5 g of sodium dihydrogen and sodium chloride, 0.3 g of manganese sulfate, 0.01 g of magnesium sulfate, iron sulfate, cobalt sulfate 200 ml each of 500 ml of Erlenmeyer flasks are added to the medium containing copper sulfate and zinc sulfate. The medium is sterilized at 120 ° C. for 30 minutes. After cooling the medium and inoculated with 10ml of pre-cultured Lactobacillus sporogenes 1L-101 pre-culture solution by incubation in the medium having the composition as described above and incubated with shaking at 45 ℃ for 2 days (140 times / min) The cultures are harvested and centrifuged (8,000 rpm, 10 minutes) to obtain cells.

수득된 균체에 멸균 증류수를 가해 현탁시킨 후 원심분리하여(8,000rpm, 10분)세척한다. 상술한 세척과정을 3회 실시한 후 균체를 500ml의 증류수에 현탁시켜 100℃에서 60분간 수욕열탕시켜 균을 사멸시킨 다음 균현탁액을 동결건조시켰다(0.05 Torr이하).Sterilized distilled water was added to the obtained cells, suspended and centrifuged (8,000 rpm, 10 minutes). After performing the above-described washing process three times, the cells were suspended in 500 ml of distilled water, and heated with a water bath at 100 ° C. for 60 minutes to kill the bacteria, and the bacteria suspension was lyophilized (0.05 Torr or less).

[실시예 2]Example 2

육종-180세포(sarcoma-180 cel1)에 대한 함암작용.Carcinogenic activity against sarcoma-180 cel1.

ICR종 마우수(수컷 무게 20±2ｇ)의 겨드랑이에 1마리당 0.1m1(1×106개)의 육종 180세포를 피하에 이식한다.Subcutaneously implant 0.1 m1 (1 × 10 6 ) sarcoma 180 cells per animal in the axillary arm of ICR species (male weight 20 ± 2 g).

다음에 수득한 항종양 물질과 용연균 제제를 멸균 생리식염수에 적당 농도로 현탁시키고 현탁액 0.1ml를 암세포를 이식한 다음날부터 5일동안 1일 1회씩 정맥주사 혹은 암이식부위에 피하주사한다. 대조군에는 종양물질 현탁액대신 멸균 생리 식염수를 전술한 방법으로 투여한다. 이에 대한 결과는 다음 표 2에 제시되어 있다. 실험결과는 다음 방정식에서 얻어지는 저지율로 계산된다.Next, the obtained anti-tumor substance and the lytic bacterium preparation are suspended in sterile physiological saline at an appropriate concentration, and 0.1 ml of the suspension is injected intravenously or subcutaneously at the site of cancer transplantation once a day for 5 days from the day following transplantation. The control group is administered sterile saline instead of the tumor suspension in the manner described above. The results are shown in Table 2 below. The experimental result is calculated by the blocking rate obtained from the following equation.

Figure kpo00003
Figure kpo00003

[표 2]TABLE 2

Figure kpo00004
Figure kpo00004

[실시예 3]Example 3

면역 자극 작용Immune stimulating action

ICR종 마우스 (수컷무게 20±2ｇ)에 본 발명의 향종양물질을 생리 식염수에 현탁시켜 복강 투여한 3일후에 마크로파지를 분리시켜 미리 항체로 옵소나이즈시킨 양피 적혈구를 가해 5% CO2배양기중에서 37℃ 1시간 배양시키고, 식균되지 않은 적혈구를 염화암몬으로 용혈 제거시킨 후 현미경으로 관찰하여 마크로파지 100개당 식균된 양피 적혈구의 수를 측정한다. 이에 대한 결과는 표 3에 제시되어 있다.ICR-type mice (male weight 20 ± 2 g) were suspended in physiological saline by suspending the fragrant tumor of the present invention in physiological saline 3 days after separation of macrophages and the addition of sheep's red blood cells opsonized with antibody in 5% CO 2 incubator. After incubation for 1 hour at 37 ° C., hemolysed the un phagocytic erythrocytes with ammonium chloride and observed under a microscope to determine the number of phagocytic erythrocytes per 100 macrophages. The results are shown in Table 3.

[표 3]TABLE 3

Figure kpo00005
Figure kpo00005

* 대조군은 항종양물질대신 생리식염수를 복강 투여하였음.* The control group was intraperitoneally administered saline instead of anti-tumor.

상기 실험사실로부터 본 발명의 항암제가 공지 항암제에 비하여 우수한 효능을 갖고 있음을 알 수 있다.It can be seen from the experimental fact that the anticancer agent of the present invention has superior efficacy as compared to known anticancer agents.

[실시예 4]Example 4

급성 독성Acute toxicity

본 발명에 의해 얻어진 항종양 물질의 마우스(ICR종 수컷무게 20±2ｇ정맥투여)에 대한 LD50은 50㎎/㎏이상이다.LD 50 of the anti-tumor substance mouse (ICR species male weight 20 ± 2 g intravenous administration) obtained by the present invention is 50 mg / kg or more.

전술한 바의 약물학 실험에서 명백한 바와 같이, 본 발명의 수득 물질이 항종양제로 유용하고 다양한 암질환에 대한 효과를 다양한 제형으로 제형화할 수 있으며, 주사제로 사용할 경우 피하주사, 근육주사, 정맥주사로 투여할 수 있다.As evident from the pharmacological experiments described above, the obtained material of the present invention is useful as an antitumor agent and can be formulated in various formulations for various cancer diseases, and when used as an injection, it can be used as a subcutaneous injection, intramuscular injection or intravenous injection. May be administered.

본 발명의 항암제는 통상으로 약학적제제의 제조에 사용되는 부형제, 담체, 희석제, 보존제, 산화방지제, 현탁화제, 용제 등과 혼합하여 주사제, 정제, 캡슐제, 산제 및 기타 통상의 제형으로 제제화할 수 있다. 이들 보조제들은 이 분야에 통상의 지식을 가진자들에게는 잘 알려져 있다.The anticancer agents of the present invention can be formulated into injections, tablets, capsules, powders and other conventional formulations by mixing with excipients, carriers, diluents, preservatives, antioxidants, suspending agents, solvents, and the like, which are commonly used in the manufacture of pharmaceutical preparations. have. These adjuvants are well known to those of ordinary skill in the art.

[실시예 5]Example 5

실시예 1에서 얻어진 균체 50㎎을 0.5%포도당 수용액에 현탁시켜 주사제를 제조한다.50 mg of the cells obtained in Example 1 was suspended in an aqueous 0.5% glucose solution to prepare an injection.

[실시예 6]Example 6

실시예 1의 방법으로 제조된 균체 10ｇ을 탈지분유 90ｇ과 혼합한 후 경질캡슐에 500㎎씩 충진하여 캡술제로 제조한다.10 g of the cells prepared by the method of Example 1 were mixed with 90 g of skim milk powder, and then 500 mg of the hard capsules were filled to prepare a capsulant.

[실시예 7]Example 7

실시예 1의 방법으로 제조된 균체 10ｇ을 락토스 45ｇ 및 옥수수전분 45ｇ과 혼합한 후 스테아린산 마그네슘 소량을 가하여 혼합한 다음 500㎎으로 타정하여 정제를 제조한다.10 g of the cells prepared by the method of Example 1 were mixed with 45 g of lactose and 45 g of corn starch, and then mixed with a small amount of magnesium stearate, followed by compression to 500 mg to prepare a tablet.

[실시예 8]Example 8

실시예 1의 방법으로 제조된 균체 20㎎을 바이알에 충진하고 멸균 생리식염수 1ml를 충진하여 현탁시켜 주사제를 제조한다.20 mg of the cells prepared by the method of Example 1 was filled into a vial and filled with 1 ml of sterile physiological saline to suspend to prepare an injection.

Claims (2)

락토바실러스 스포로제네스 1L-101의 미생물을 배양하고 배양액으로부터 균체를 분리하여 세척하고 멸균시켜서 얻어진 항암제.An anticancer agent obtained by culturing the microorganisms of Lactobacillus sporogenes 1L-101, separating the cells from the culture, washing and sterilizing. 제1항에서, 미생물이 포자를 형성하기전 사멸된 간균체를 사용하는 항암제.The anticancer agent according to claim 1, wherein the bacterium is killed before the microorganisms form spores.
KR1019890016183A 1989-11-09 1989-11-09 Anti-tumoric agent from lactobacillus sporogenes KR920005685B1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002512615A (en) * 1997-04-18 2002-04-23 ガネデン バイオテック，インコーポレイテッド Topical use of symbiotic Bacillus spores to prevent or control microbial infection

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100426256B1 (en) * 2002-01-28 2004-04-08 도레이새한 주식회사 Biaxially stretching polyester matte film

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002512615A (en) * 1997-04-18 2002-04-23 ガネデン バイオテック，インコーポレイテッド Topical use of symbiotic Bacillus spores to prevent or control microbial infection
EP0975227A4 (en) * 1997-04-18 2003-05-21 Ganeden Biotech Inc Topical use of probiotic bacillus spores to prevent or control microbial infections
EP1629846A3 (en) * 1997-04-18 2008-02-27 Ganeden Biotech, Inc. Topical use of probiotic bacillus spores to prevent or control microbial infections

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