KR100674604B1 - Radioprotector consisted of cyclic dipeptide - Google Patents
Radioprotector consisted of cyclic dipeptide Download PDFInfo
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- KR100674604B1 KR100674604B1 KR1020050089184A KR20050089184A KR100674604B1 KR 100674604 B1 KR100674604 B1 KR 100674604B1 KR 1020050089184 A KR1020050089184 A KR 1020050089184A KR 20050089184 A KR20050089184 A KR 20050089184A KR 100674604 B1 KR100674604 B1 KR 100674604B1
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- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
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Abstract
Description
도 1은 본 발명의 일 실시예에 따른 실험라인을 나타내는 도면이다.1 is a view showing an experimental line according to an embodiment of the present invention.
본 발명은 싸이클릭다이펩타이드를 주성분으로 하는 방사선 보호제에 관한 것으로, 보다 자세하게는 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린) 또는 이들의 조합을 주성분으로 하는 방사선 보호제에 관한 것이다.BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a radioprotectant comprising a cyclic dipeptide as a main component, and more particularly, to a radioprotectant comprising a cyclo (proline-phenylalanine) and a cyclo (leucine-proline) or a combination thereof.
일반적으로, 일반적으로, 암은 사망을 일으키는 주요 질병의 하나로 암 치료는 국민건강과 보건에 중요한 과제이다. 암의 표준적인 치료방법으로는 수술, 방사선 치료, 항암제 등 세 가지가 있으며, 암 환자의 약 50%-80%는 질병의 경과 중에 완치 또는 증상 완화의 목적으로 방사선 치료를 받게 된다. 방사선 치료는 암치료의 중요한 방법 중 하나로 암이 혈류 등을 타고 전이된 경우가 아니면 수술이나 국소적인 방사선치료로 좋은 효과를 볼 수 있다.In general, cancer is one of the major diseases that cause death, and cancer treatment is an important task for public health and public health. There are three standard treatments for cancer: surgery, radiation therapy, and anticancer drugs. About 50% -80% of cancer patients receive radiation therapy for the purpose of cure or relief of symptoms during the course of the disease. Radiation therapy is one of the important methods of cancer treatment, unless the cancer has metastasized through the blood flow, such as surgery or local radiation therapy can have a good effect.
암치료를 위한 인류의 노력으로 최근 분자생물학적 기전에 의한 유전자 치료법 등이 등장하고 있으나, 이러한 방법이 실용화되는 데는 아직도 수십 년이 경과 될 것으로 예상되고 있어 상기한 바와 같은 방사선에 의한 암치료는 다음 세기에도 중요한 치료법으로서 큰 역할을 하게 될 것이다.As a result of human efforts to treat cancer, gene therapy by molecular biological mechanisms has recently emerged, but it is expected that several decades will still be required for such a method to be put into practical use. Edo will play a big role as an important treatment.
상기한 방사선치료는 질병치료에 방사선을 사용하는 것으로 X선, 감마선과 같은 파동형태의 방사선 또는 전자선, 양성자선과 같은 입자형태의 방사선을 이용하여 암과 같은 악성질병의 성장을 지연시키거나 멈추게 하고 더 나아가서는 파괴 시키는 방법이다. 이와 같은 방사선 치료에 관한 연구로는 인간게놈프로젝트(human genome project)등 분자의학의 발전에 따라 방사선 치료가 잘 듣는 집단을 분자수준에서 찾아내려는 연구가 있으며 분자생물학에 바탕을 둔 새로운 항암제와 방사선치료의 병용연구도 활발하다. 그리고 방사선 민감제, 방사선 보호제 등과 같은 약재 및 약물 연구와 온열치료 연구가 있다.The above-mentioned radiation therapy uses radiation for the treatment of disease, and delays or stops the growth of malignant diseases such as cancer by using wave-like radiation such as X-ray, gamma-ray or particle-type radiation such as electron beam and proton beam. It's a way to destroy it. Such researches on radiation therapy include researches on the molecular level to find out the group that radiation therapy listens to well with the development of molecular medicine such as human genome project, and new anticancer and radiation therapy based on molecular biology. Co-operative research is also active. In addition, there are researches on medicines and drugs such as radiation sensitizers and radiation protection agents, and heat treatment research.
국내의 방사선 치료 수준은, 현재 첨단 방사선 치료 장비들이 많이 도입 및 운영되고 있어 치료수준이 선진국에 비교해도 손색이 없지만 새로운 치료법의 연구나 장비, 약재 개발 연구 등은 아직 많이 뒤져 있는 실정이다. 방사선치료 효율의 극대화를 위해서는 종양 제어율을 최대화하고 치료로 인한 정상조직의 부작용을 최소화해야 하는데, 방사선량을 증가시키거나 방사선 증강제를 병용하여 종양 제어율을 높이고자 많은 노력을 하지만 정상조직의 부작용을 줄이려는 노력은 때때로 간과되는 경우가 있다. Although the level of radiation therapy in Korea is now being introduced and operated with a lot of advanced radiation therapy equipment, the level of treatment is not comparable to that of developed countries. The back is still a lot behind. In order to maximize the efficiency of radiation treatment, it is necessary to maximize the control rate of tumors and minimize the side effects of normal tissues caused by the treatment.In order to increase the control rate of tumors by increasing the radiation dose or using a combination of radiation enhancers, Efforts are sometimes overlooked.
정상조직에 대한 방사선 효과를 둔화시켜 암 치료효과를 높이는 방법에 사용 되는 약제를 방사선 보호제(Radioprotector) 라고 한다. 예를 들어, 흉부 악성종양의 방사선 치료시 폐손상은 방사선량을 제한하는 결정인자이며 치료효율을 높이기 위해서는 폐손상을 줄이기 위한 방사선 보호제가 필요하다. 이와 같이 치료목적으로 사용되는 방사선의 효과로부터 정상세포를 보호해 주는 방사선 보호제에 관한 연구들에서 다루어진 약재들 중에는 황화수소기(-SH)를 가진 복합체들이 많으며 시스테인(Cysteine) 등이 그 예이다. 그 외에 에피네프린(Epineprine), 캡토프릴(Captopril), 세로토닌(Serotonin) 등도 방사선 보호제 역할을 한다.Radioprotector is a drug that is used to slow down the radiation effect on normal tissues and improve cancer treatment. For example, lung injury is a determinant of radiation dose limiting in the treatment of thoracic malignancies, and radiation protection agents to reduce lung injury are needed to increase the treatment efficiency. Among the drugs covered in studies on radioprotectants that protect normal cells from the effects of radiation used for therapeutic purposes, there are many complexes with hydrogen sulfide groups (-SH), such as Cysteine. In addition, epinephrine (epineprine), captopril (sertopin), serotonin (Serotonin), etc. also acts as a radioprotective agent.
그러나, 상기한 바와 같은 방사능 보호제에 대한 종래의 연구 결과는 아직 만족할 만한 방사능 보호제를 제공하고 있지 못한 수준이며, 이에 방사선 보호제와 관련한 기초 및 응용 연구가 활발히 진행되고 있는 실정이다.However, the results of the conventional researches on the radioprotectant as described above have not yet provided a satisfactory radioprotective agent, and thus the basic and applied researches related to the radioprotective agent are actively progressed.
따라서, 본 발명의 목적은 종양 제어율을 높이기 위한 방사선량의 증가 또는 방사선 증강제의 병용에 따른 정상조직의 부작용이 최소화되는 신규한 방사선 보호제를 제공하기 위한 것이다.Accordingly, it is an object of the present invention to provide a novel radioprotective agent which minimizes side effects of normal tissues due to the increase in radiation dose or the combination of radiation enhancers to increase tumor control rate.
본 발명의 다른 목적은 방선균인 스트렙스마이세스 속으로부터 분리한 여러 종류의 싸이클릭다이 펩타이드(cyclic dipeptide) 중 특히 정상조직의 부작용이 최소화되는 방사선 보호제를 제공하기 위한 것이다.Another object of the present invention is to provide a radioprotective agent which minimizes side effects of cyclic dipeptides, in particular normal tissues, isolated from the Streptomyces genus.
상기 목적을 달성하기 위한 본 발명의 방사선 보호제는;Radiation protection agent of the present invention for achieving the above object;
방선균인 스트렙스마이세스 속으로부터 분리된 싸이클릭다이펩타이드를 주성분으로 하여 구성됨을 특징으로 한다.It is characterized by consisting of a cyclic dipeptide isolated from the genus Streptomyces genus as a main component.
본 발명의 다른 구성에 따르면, 상기 싸이클릭다이펩타이드는 싸이클로(프롤린-페닐알라닌)임을 특징으로 한다.According to another configuration of the present invention, the cyclic dipeptide is characterized in that the cyclo (proline-phenylalanine).
본 발명의 또 다른 구성에 따르면, 상기 싸이클릭다이펩타이드는 싸이클로(류신-프롤린)임을 특징으로 한다.According to another configuration of the invention, the cyclic dipeptide is characterized in that the cyclo (leucine-proline).
본 발명의 또 다른 구성에 따르면, 상기 싸이클릭다이펩타이드는 싸이클로(프롤린-페닐알라닌)와 싸이클로(류신-프롤린)의 조합임을 특징으로 한다.According to another configuration of the present invention, the cyclic dipeptide is characterized in that a combination of cyclo (proline-phenylalanine) and cyclo (leucine-proline).
상기와 같이 구성되는 본 발명의 방사선 보호제는 방선균인 스트렙스마이세스 속으로부터 용이하게 분리될 수 있어 용이하게 입수할 수 있을 뿐 아니라 특히, 본 발명의 두 종류의 싸이클릭다이펩타이드인 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린)은 그 이화학적 성질이 정상조직에 부작용을 최소화할 수 있는 우수한 효과를 가져 방사선 보호제로서 유용하게 이용될 수 있다.The radiation protection agent of the present invention configured as described above can be easily separated from the actinomycetes Streptomyces genus, and can be easily obtained. In particular, the two kinds of cyclic dipeptides of the present invention, cyclo (proline- Phenylalanine) and cyclo (leucine-proline) can be usefully used as radiation protection agents because their physicochemical properties have an excellent effect of minimizing side effects on normal tissues.
이하, 본 발명을 실시예로 보다 자세히 설명하지만, 본 발명의 범위가 여기에 한정되는 것이 아님은 물론이다.Hereinafter, although an Example demonstrates this invention in detail, of course, the scope of the present invention is not limited to this.
실시예Example 1 One
싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린)의 방사선 보호제로서의 효과Effects of Cyclo (Proline-Phenylalanine) and Cyclo (Leucine-Proline) as Radiation Protection Agents
본 발명은 스트렙토마이세스 속 AMLK-335(기탁번호 KCTC 10300BP) 균주로부터 이 등의 방법(Rhee, K.H. K.H. Choi, C.J, Kim, and C.H. Kim. Identification of Streptomyces sp. AMLK-335 Producing Antibiotic Substance Inhibitory to vnacomycin-resistant enterococci. J. Microbial. Biotech. 2001. 11(3), 469-474)에 따라, 발효에 의해 싸이클릭다이펩타이드를 수득하였다.The present invention is derived from Streptomyces genus AMLK-335 (Accession No. KCTC 10300BP) strains (Rhee, KHKH Choi, CJ, Kim, and CH Kim. Identification of Streptomyces sp.AMLK-335 Producing Antibiotic Substance Inhibitory to vnacomycin) Cyclic dipeptides were obtained by fermentation according to -resistant enterococci J. Microbial Biotech. 2001. 11 (3), 469-474).
상기 수득된 싸이클릭다이펩타이드 중 하기 <화학식 I>의 화학식를 갖은 싸이클로(프롤린-페닐알라닌)과 하기 <화학식 II>의 화학식을 갖은 싸이클로(류신-프롤린)을 선별하여 그의 방사선 보호제로서의 효과를 다음과 같이 방사선 단독 처리군과 상기 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린)의 투여를 방사선 조사와 병행한 군의 조직세포에 대한 방사선 보호효과를 실험하였다.
Cyclo (proline-phenylalanine) having a chemical formula of <Formula I> and a cyclo (leucine-proline) having a chemical formula of <Formula II> were selected from the obtained cyclic dipeptides, and their effects as radioprotectants were as follows. The radiation protection effect on the tissue cells of the radiation alone group and the administration of the cyclo (proline-phenylalanine) and the cyclo (leucine-proline) group in combination with irradiation was examined.
즉, 실험 동물로는 생후 4-5개월, 체중 250-300g의 수컷 흰쥐 40여 마리를 사용하여 다음 표 1과 같이 각 처리군으로 나누어 방사선 보호 효과에 대해 실험하였다. 상기 흰쥐를 Ketamine(카타라, 유한양행, 50mg/ml) 60mg/kg을 복강 내로 주사하여 마취시킨 후 앙아위로고정틀에 사지를 고정하고 137Cs 실험용 방사선 조사기를 이용하여 선원중심축 거리는 80cm, 분당 선량율은 2Gy로 좌측 흉곽에 12.5Gy의 방사선을 단일조사하였다. 한편, 약물 병용 투여군은 싸이클릭다이펩타이드를 식수에 섞어 방사선 조사 1주 전부터 실험종료시인 8주까지 투여하였다.That is, the experimental animals were used for 40 male rats of 4-5 months of age and 250-300 g in weight, and then divided into the respective treatment groups as shown in Table 1 below. Ketamine the rat (Kathara, Yuhan Corp., 50mg / ml) 60mg / kg of injection into the peritoneal cavity to secure the limb to the flange top angah was anesthetized and 137 Cs experimental radiation using an irradiation distance axis crew center 80cm, per dose rate Was irradiated with 2Gy of 12.5Gy to the left chest. On the other hand, the drug combination group was mixed with cyclic dipeptide in drinking water from 1 week before irradiation to 8 weeks at the end of the experiment.
상기 본 발명에 따른 싸이클릭다이펩타이드의 실험동물에서의 조직세포의 방사선 보호효과 확인은 광학현미경과 면역 조직화학 검사를 통하여 실시하였다.Confirmation of the radiation protection effect of the tissue cells in the experimental animal of the cyclic dipeptide according to the present invention was carried out through optical microscopy and immunohistochemistry.
광학현미경에 의한 조사는 방사선 단독 투여군과 약물 병용 투여군(방사선 + 싸이클릭다이펩타이드)의 동물에 대해 방사선 조사 후 2주(잠복기)와 8(급성 폐렴기)주에 ketamine으로 마취하여 흰쥐를 개흉한 뒤, 양측 폐를 적출하여 광학 현미경을 통하여 조사하였으며, 면역 조직화학검사는 상기 폐를 고정액(0.67M phosphate buffer saline, pH 7.3에 용해시킨 4% paraformaldehyde 용액)에 24시간 이상 고정한 뒤, 3 mm 두께로 절단하여 통상의 조직검사 처리과정을 거친 다음 파라핀에 포매하고, 파라핀 포매절편은 hematooxylin-eosin (H-E) 염색, Masson-Trichrome 염색을 시행하여 TNFα와 TGFβ의 발현변화(폐포상피 및 폐포강의 대식에포에서의 TNFα와 TGFβ 의 발현 수치 비교, 유효성 :P< 0.05)를 관찰하였다. Irradiation by light microscopy was performed to anesthetize rats by anesthesia with ketamine at 2 weeks (latency) and 8 (acute pneumonia) after irradiation in animals of radiation alone group and drug combination group (radiation + cyclic dipeptide). Then, both lungs were extracted and examined through an optical microscope. Immunohistochemistry revealed that the lungs were fixed in a fixed solution (0.67M phosphate buffer saline, 4% paraformaldehyde solution dissolved in pH 7.3) for at least 24 hours, and then 3 mm thick. After normal biopsy, the cells were embedded in paraffin, and paraffin embedding fragments were hematooxylin-eosin (HE) stained and Masson-Trichrome stained to change the expression of TNFα and TGFβ (for alveolar epithelial and alveolar macrophages). Comparison of the expression levels of TNFα and TGFβ in the cells and their efficacy: P <0.05) were observed.
상기와 같이 하여 실험쥐의 폐 손상의 광학현미경을 통한 병리조직학적 소견(혈관내피세포 및 폐포상피세포의 파괴유무) 평가는 방사선조사를 하지 않은 동년배 흰쥐의 폐에서 보이는 변화를 정상대조군으로 하고 각각 방사선 단독 투여군과 약물 병행 투여군에서 보이는 변화를 비교하여, 방사선조사 직후 조직 손상의 정도를 각각 1+ 내지 3+로 분류하여 평가하였으며, 면역조직화학검사에서 보이는 반응은 폐포 상피세포, 폐포강내에 있는 대식세포, 기관지 주변에 있는 림프조직에서 양성반응 정도에 따라 1+ 내지 3+로 분류하였다. 여기서, 1+는 10%이하의 폐조직에 양성세포가 있는 경우, 2+는 10 내지 50%인 경우, 3+는 50%이상의 조직에서 강한 양성반응을 보이는 경우로 하였다. 각각 방사선 단독 투여군과 약물 병행 투여군에서 병리조직과 사이토카인 발현의 차이는 2+ 이하와 3+ 이상으로 나누어 Fisher's exact test (SPSS program)로 검정하고 유의 수준은 5% 이하로 한다As described above, the histological findings of the lung damage in rats (destruction of vascular endothelial cells and alveolar epithelial cells) were evaluated using the normal control group. We compared the changes seen in the radiation alone group and the drug-administered group, and evaluated the extent of tissue damage immediately after irradiation, classified as 1+ to 3+, respectively. The response seen in immunohistochemistry was found in alveolar epithelial cells and alveolar cavity. Macrophages, lymphoid tissue around the bronchus were classified as 1+ to 3+ according to the degree of positive response. Here, 1+ is the case where there are positive cells in 10% or less of lung tissue, 2+ is 10 to 50%, and 3+ is a case of showing a strong positive reaction in 50% or more of tissue. The difference in pathological tissue and cytokine expression in the radiation alone group and the drug combination group was divided into 2+ or less and 3+ or more by the Fisher's exact test (SPSS program), and the significance level was 5% or less.
그 결과 본 발명에 따른 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린)의 투여군은 거의 대조군에 유사한 결과를 나타내어 방사선 보호 효과가 우수한 것으로 판단되었다.As a result, the administration group of cyclo (proline-phenylalanine) and cyclo (leucine-proline) according to the present invention almost showed similar results to the control group was judged to have excellent radiation protection effect.
실시예Example 2 2
싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린)의 방사선 보호제 효과 및 두 약물의 상승효과Cycloprotective Effects of Cyclo (Proline-Phenylalanine) and Cyclo (Leucine-Proline) and Synergistic Effects of Two Drugs
인체유래의 정상폐 섬유아세포(Human normal lung fibroblast cell)를 이용하여 방사선 단독군과 각각 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린) 및 이들의 조합의 투여를 방사선 조사와 병행한 군의 조직세포에 대한 방사선 보호효과를 실험하였다. 즉, 폐암 환자의 폐 부위 중 정상 부위만을 절제한 후, 면역조직화합법(immunohistochemistry)을 실시하여 정상 조직임을 확인한 세포만을 사용였으며, 상기 세포는 각각 피채취 폐암환자에 따라서 각각 K2288 등과 같이 표기하였다.Human normal lung fibroblast cells (Human normal lung fibroblast cells) using a group of radiation alone and cyclo (proline-phenylalanine), cyclo (leucine-proline) and a combination of them to the irradiation of the tissue The radiation protection effect on the cells was examined. That is, after resecting only the normal part of the lung area of the lung cancer patient, only cells confirmed to be normal tissues by performing immunohistochemistry were used, and the cells were labeled as K2288 according to each of the lung cancer patients to be collected.
도 1은 본 실시예에 따른 실험라인을 나타낸 도면으로, 도 1에 나타난 바와 같이 각 싸이클릭다이펩타이드 1 ㎍/㎖의 노출 시간은 24 시간으로 하고, 방사선은 137Cs 실험용 방사선 조사기를 이용하였다. 방사선 조사 후 배지를 새로운 배지로 교체하여 그 시점을 0 day로 하여 4일간 배양한 후, 생존율을 SRB 어세이(assay)를 이용하여 측정하여 그 결과를 다음 표 2에 나타냈다. 1 is a diagram illustrating an experimental line according to the present embodiment. As shown in FIG. 1, an exposure time of 1 μg / ml of each cyclic dipeptide was 24 hours, and radiation was used for a 137 Cs experimental irradiation machine. After irradiation, the medium was replaced with fresh medium, and then cultured for 4 days at 0 day. The survival rate was measured using an SRB assay, and the results are shown in Table 2 below.
상기 표 2의 결과는 모든 경우를 총 5회 실험하여 생존율의 평균값을 구한 것으로, 상기 표 2의 결과에서 알 수 있는 바와 같이 방사선 단독 투여군에 비하여 본 발명의 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린) 투여군에서 세포의 생존율이 향상되었으며, 특히, 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린)의 조합 투여군에서 생존율이 거의 90%를 상회하는 것을 알 수 있다. 따라서 본 발명에 따른 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린)은 방사선 보호효과가 우수한 것임을 알 수 있다.The results in Table 2 were obtained by a total of five experiments in all cases to obtain the average value of the survival rate, as can be seen in the results of Table 2 compared to the radiation alone group of the present invention cyclo (proline-phenylalanine) and cyclo (leucine) The survival rate of the cells was improved in the proline-administered group, and in particular, the survival rate in the combined-treated group of cyclo (proline-phenylalanine) and cyclo (leucine-proline) exceeded almost 90%. Therefore, it can be seen that the cyclo (proline-phenylalanine) and the cyclo (leucine-proline) according to the present invention are excellent radiation protection effect.
상기와 같이 구성되는 본 발명의 싸이클릭다이펩타이드를 주성분으로 하는 방사선 보호제는 방선균인 스트렙스마이세스 속으로부터 용이하게 분리될 수 있어 용이하게 입수할 수 있을 뿐 아니라 상기 싸이클릭다이펩타이드 중 특히 싸이클로(프롤린-페닐알라닌)과 싸이클로(류신-프롤린)은 방사선 조사에 대한 정상조직의 부작용을 최소화할 수 있는 우수한 효과를 가져 방사선 보호제로서 유용하게 이용될 수 있는 유용한 발명이다.The radioprotectant based on the cyclic dipeptide of the present invention constituted as described above can be easily separated from Streptomyces, which is actinomycetes, and can be easily obtained, and especially among the cyclic dipeptides ( Proline-phenylalanine) and cyclo (leucine-proline) are useful inventions that have an excellent effect of minimizing side effects of normal tissues on irradiation and can be usefully used as radiation protection agents.
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GB2488500B (en) * | 2009-12-25 | 2013-04-24 | Suntory Holdings Ltd | Substances for use as anti-depressants or as a learning motivation improver |
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