KR20020042606A - Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients - Google Patents

Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients Download PDF

Info

Publication number
KR20020042606A
KR20020042606A KR1020020027739A KR20020027739A KR20020042606A KR 20020042606 A KR20020042606 A KR 20020042606A KR 1020020027739 A KR1020020027739 A KR 1020020027739A KR 20020027739 A KR20020027739 A KR 20020027739A KR 20020042606 A KR20020042606 A KR 20020042606A
Authority
KR
South Korea
Prior art keywords
phytosphingosine
dimethyl
acetyl
radiation
cells
Prior art date
Application number
KR1020020027739A
Other languages
Korean (ko)
Other versions
KR100459484B1 (en
Inventor
윤연숙
송지영
정인성
Original Assignee
장인순
한국원자력연구소
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 장인순, 한국원자력연구소 filed Critical 장인순
Priority to KR10-2002-0027739A priority Critical patent/KR100459484B1/en
Publication of KR20020042606A publication Critical patent/KR20020042606A/en
Priority to PCT/KR2003/000406 priority patent/WO2003097631A1/en
Priority to AU2003269871A priority patent/AU2003269871A1/en
Application granted granted Critical
Publication of KR100459484B1 publication Critical patent/KR100459484B1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D331/00—Heterocyclic compounds containing rings of less than five members, having one sulfur atom as the only ring hetero atom
    • C07D331/02—Three-membered rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

PURPOSE: A composition for improving the effect of radiotherapy, comprising N-acetyl phyto spingosin and dimethyl phyto spingosin as active ingredients is provided, thereby significantly improving the effect of radiotherapy on a patient. CONSTITUTION: The composition for improving the effect of radiotherapy comprises 5 to 95 wt.%, preferably 40 to 60 wt.% of N-acetyl phyto spingosin represented by formula(I) and its pharmaceutically acceptable salts, and 5 to 95 wt.%, preferably 40 to 60 wt.% of dimethyl phyto spingosin represented by formula(II) and its pharmaceutically acceptable salts as active ingredients, wherein R1, R2 and R3 are independently C1-C4 lower alkyl or substituted lower alkyl, preferably methyl or ethyl.

Description

엔-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신을 유효 성분으로 포함하는 방사선 치료 민감제 조성물{Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients}Radiation therapy sensitizer composition comprising N-acetylphytosphingosine and dimethyl phytosphingosine as an active ingredient {Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients}

본 발명은 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신을 함유하는 방사선 치료 증진제 조성물에 관한 것으로, 더욱 상세하게는, 본 발명은 생체 내암을 치료하기 위하여 암세포에 방사선을 조사하기 전, 또는 조사하는 동안 병용 투여하여 방사선 치료 증진 효과를 나타낼 수 있는 새로운 방사선 치료 증진제 조성물에 관한 것이다.The present invention relates to a radiotherapy enhancer composition containing N-acetyl phytosphingosine and dimethyl phytosphingosine, and more particularly, the present invention is a combination administration before or during radiation of cancer cells to treat cancer in vivo. It relates to a new radiation therapy enhancer composition that can exhibit a radiotherapy enhancing effect.

현재 암환자의 사망률이 1위이며 고식적인 치료법인 수술, 방사선 치료, 화학요법으로는 50% 정도만의 완치율을 나타낸다. 국내의 암 환자 경우 약 35%, 미국의 경우 약 50% 정도가 방사선 치료를 받고 있으며 그 수가 매년 증가하고 있는 추세이므로 방사선 치료의 중요성 또한 증가하고 있다. 하지만 암세포의 방사선 내성 획득이나 고선량의 방사선 치료시 정상 조직의 손상 등이 치료의 효율을 떨어뜨리는 문제점으로 대두되어 왔다. 따라서 이러한 방사선 치료의 효율을 증대시키기 위한 증진제에 관한 연구들이 계속 진행되고 있는 실정이다.Currently, cancer patients have the highest mortality rate, with only 50% cure rate for conventional treatments such as surgery, radiation, and chemotherapy. About 35% of cancer patients in Korea and about 50% in the United States are receiving radiation therapy, and the number is increasing every year, so the importance of radiation therapy is also increasing. However, obtaining radiation resistance of cancer cells or damaging normal tissues in high-dose radiation treatments has been a problem that decreases the efficiency of treatment. Therefore, researches on the enhancer for increasing the efficiency of the radiation therapy is ongoing.

이에 대해 본 발명자들은 체내 세라마이드류와 스핑고신 인산화 효소 억제제를 병용함으로써 체내 세라마이드 풀을 극대화시켜 암의 방사선 치료에 대한 민감도를 증가시키는 것에 관한 기술을 대한민국 특허출원 제 2001-85999호 '세라마이드류 또는 그 유도체와 스핑고신 인산화효소 억제제(sphingosine kinase inhibitor)인 다이메틸스핑고신을 유효 성분으로 포함하는 방사선 치료 민감제' 에 개시한바 있으며, 지속적으로 효과가 우수한 화합물을 합성 내지 검색한 결과 이스트 유래 파이토스핑고신 및 그의 유도체들을 발명하게 되었다.In contrast, the present inventors have described a technique for maximizing the ceramide pool in the body by using a combination of ceramides and sphingosine kinase inhibitors in the body to increase the sensitivity to radiation therapy of cancer. Derivatives and sphingosine kinase inhibitors Radiation therapy sensitizer comprising dimethylsphingosine as an active ingredient ', and the synthesis or search of a compound having excellent effect continuously led to the invention of yeast-derived phytosphingosine and derivatives thereof.

파이토스핑고신은 스핑고지질(sphingolipid)의 일종으로 생체의 주요한 세포막 성분중의 하나로서 구조적인 기능과 함께 신호 전이체계의 신호 전달물질로서 다양한 생물학적 기능을 가지는 생리활성 물질이다. 파이토스핑고신, 스핑고신(sphingosine), 스핑게닌(sphinganine)은 세라마이드의 구성 성분의 하나인 스핑고이드베이스(sphingoid bases)를 이루고 이들 프리스핑고이드베이스(free sphingoid bases)와 유리지방산(free fatty acid)이 세라미다제(ceramidase)의 효소작용에 의해 세라마이드를 생성한다.Phytosphingosine is a type of sphingolipid and is one of the major cell membrane components of a living body. It is a physiologically active substance having various biological functions as a structural signal transduction system and a signal transduction system. Phytosphingosine, sphingosine, and sphinganine form sphingoid bases, one of the constituents of ceramide, and these free sphingoid bases and free fatty acids. Ceramide is produced by the enzymatic action of ceramidase.

스핑고지질은 "스핑고마이에린 사이클"이라는 새로 밝혀진 신호 전이과정을 통해 세포의 성장, 증식, 분화의 조절, 세포사멸(apoptosis)유발 등 생명현상의 핵심적인 역할을 하는 것으로 밝혀지고 있으며 종양괴사인자-α(TNF-α), 인터루이킨-1(IL-1), 인터페론-γ(INF-γ) 및 FAS 리간드(ligand) 등이 관여하는 것으로 밝혀졌다.Sphingolipids have been shown to play a key role in life phenomena, such as the regulation of cell growth, proliferation, differentiation and induction of apoptosis, through a newly discovered signal transduction process called the sphingomyelin cycle. Factor-α (TNF-α), interleukin-1 (IL-1), interferon-γ (INF-γ) and FAS ligands have been found to be involved.

그러나 동물에서 추출하여 사용하던 스핑고지질은 광우병 파동 등으로 더 이상 사용하기 어려우며 순수 합성방법을 이용하여 제조하는 방법은 지나치게 고가여서 경제적인 문제점이 있었다. 또한, 인체내에 존재하는 스핑고지질과는 입체화학적 구조가 다른 경우가 많으며 일정한 입체화학적 구조의 스핑고지질을 얻기가 어려웠다.However, sphingolipids, which were extracted from animals, are difficult to use any longer due to mad cow disease waves, and methods of manufacturing using pure synthetic methods are too expensive and have economic problems. In addition, the sphingolipids present in the human body are often different from the stereochemical structure, and it is difficult to obtain sphingolipids having a constant stereochemical structure.

파이토스핑고신은 최근 들어 피키아 시페라이라는 효모 발효를 통해서 얻는 방법이 개발되어 손쉽게 얻을 수 있게 되었으며, 효모의 발효를 통해 얻은 파이토스핑고신은 인체내에 존재하는 구조와 입체화학적으로 동일한 구조를 가지고 있는 것으로 밝혀져 상업화에 적용, 사용되기 시작하였고 사용량도 급속히 증가하고 있다.Phytosphingosine has recently been developed through a yeast fermentation method called Pichia cifera, and can be easily obtained.Phytosphingosine obtained through fermentation of yeast has been found to have a stereochemically identical structure to that existing in the human body. Applications have begun to be used and usage is increasing rapidly.

따라서 본 발명이 이루고자 하는 기술적 과제는 방사선 치료와 병용하여 정상세포에는 부작용을 주지 않으면서 다양한 종류의 암세포에 살상 효과를 증가시키는 방사선 치료 증진제를 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a radiotherapy enhancer that increases the killing effect on various types of cancer cells without adverse effects on normal cells in combination with radiation therapy.

도 1은 다양한 N-아세틸 파이토스핑고신 처리에 의한 암세포의 생존률 변화를 나타낸 그래프이다.1 is a graph showing the change in survival rate of cancer cells by various N-acetyl phytosphingosine treatment.

도 2는 다이메틸 파이토스핑고신 처리에 의한 암세포의 생존률 변화를 나타낸 그래프이다.Figure 2 is a graph showing the survival rate change of cancer cells by dimethyl phytosphingosine treatment.

도 3은 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신의 복합처리에 의한 방사선 민감 효능의 증가를 나타낸 그래프이다.Figure 3 is a graph showing the increase in radiation sensitivity efficacy by a combination of N-acetyl phytosphingosine and dimethyl phytosphingosine.

도 4는 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신의 복합처리에 의한 방사선에 의해 유발되는 세포사멸의 증가를 보여주는 도면이다.4 is a diagram showing an increase in apoptosis induced by radiation by a combination treatment of N-acetyl phytosphingosine and dimethyl phytosphingosine.

도 5는 폐암, 자궁암, 유방암 세포를 대상으로 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신의 복합처리에 의한 방사선 민감 효능의 증가를 나타낸 도면이다.5 is a diagram showing the increase in radiation sensitivity of the lung cancer, uterine cancer, breast cancer cells by a combination treatment of N-acetyl phytosphingosine and dimethyl phytosphingosine.

도 6은 종양이식 마우스에 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신의 병용처리에 의한 종양축소 및 방사선 민감 증가작용을 나타낸 도면이다.6 is a view showing tumor reduction and radiation sensitivity increase by the combination treatment of N-acetyl phytosphingosine and dimethyl phytosphingosine in tumor transplantation mice.

도 7은 종양이식 마우스에 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신의 병용처리에 의한 생존율 증가를 나타낸 도면이다.7 is a diagram showing the survival rate increase by the combination treatment of N-acetyl phytosphingosine and dimethyl phytosphingosine in tumor transplantation mice.

따라서 본 발명의 목적은 하기 일반식(Ⅰ)로 표시되는 N-아세틸 파이토스핑고신 또는 이의 약제학적으로 허용가능한 염 5∼95 중량%와 하기 일반식(Ⅱ)로 표시되는 다이메틸파이토스핑고신 또는 이의 약제학적으로 허용가능한 염 5∼95 중량%를 유효성분으로서 함유하는 방사선 치료 민감제 조성물을 제공하는 것이다.Accordingly, an object of the present invention is 5 to 95% by weight of N-acetyl phytosphingosine represented by the following general formula (I) or a pharmaceutically acceptable salt thereof and dimethyl phytosphingosine represented by the following general formula (II) Radiation therapy containing from 5 to 95% by weight of acceptable salt as an active ingredient It is to provide a sensitizer composition.

(일반식 1)(Formula 1)

(일반식 2)(Formula 2)

상기 식에서,Where

R1,R2, R3는 각각 서로 독립적으로 탄소수 1∼4의 저급알킬 또는 치환된 저급알킬이다.R 1 , R 2 and R 3 are each independently of the other lower alkyl having 1 to 4 carbon atoms or substituted lower alkyl.

또한 상기 R1,R2, R3는 각각 서로 독립적으로 메틸 또는 에틸임을 특징으로 하고, 상기 일반식(Ⅰ)로 표시되는 N-아세틸 파이토스핑고신 또는 이의 약제학적으로 허용가능한 염 40∼60 중량%와 상기 일반식(Ⅱ)로 표시되는 다이메틸파이토스핑고신 또는 이의 약제학적으로 허용가능한 염 60∼40 중량%를 유효성분으로 함유함을 특징으로 한다.In addition, R 1 , R 2 , R 3 are each independently methyl or ethyl, characterized in that 40-60% by weight of N-acetyl phytosphingosine or a pharmaceutically acceptable salt thereof represented by Formula (I) It is characterized in that it contains 60 to 40% by weight of dimethyl phytosphingosine represented by the general formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient.

이하 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.

따라서 본 발명에서는 세라마이드 축적을 유도할 수 있는 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신을 함께 처리함으로써, 체내 세라마이드 축적 효과를 극대화하고, 이를 통하여 정상세포에 영향을 주지 않는 양의 약물처리로써 방사선 치료 효과를 증진시킬 수 있음을 확인하였다.Therefore, in the present invention, by treating together with N-acetyl phytosphingosine and dimethyl phytosphingosine, which can induce the accumulation of ceramide, maximize the ceramide accumulation effect in the body, through which the amount of drug treatment that does not affect the normal cells through the radiation treatment effect It was confirmed that it can be enhanced.

본 발명에서는 방사선 치료의 주된 대상이 되는 폐암, 유방암, 자궁암 세포주를 대상으로 방사선 조사시 유발되는 생존률 감소가 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신의 병용처리에 의해 증가된다는 사실과, 이것이 방사선에 의해 유도되는 세포사멸에 상승적인 작용을 나타내는 결과임을 확인하였다.In the present invention, the fact that the reduction in survival caused by irradiation in lung, breast, and uterine cancer cell lines, which are the main targets of radiation therapy, is increased by the combination of N-acetyl phytosphingosine and dimethyl phytosphingosine, which is induced by radiation. It was confirmed that the result shows a synergistic effect on the cell death.

본 발명의 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신 복합체는 그대로 또는 약학적으로 허용가능한 염의 형태로 의약품으로 사용할 수 있다. 상기 염으로는 약학적으로 허용되는 것이면 특별히 한정되지 않으며, 예를 들어 염산, 황산, 질산, 인산, 불화수소산, 브롬화수소산, 포름산 아세트산, 타르타르산, 젖산, 시트르산, 푸마르산, 말레산, 숙신산, 메탄술폰산, 벤젠술폰산, 톨루엔술폰산,나프탈렌술폰산염 또는 산부가염 등을 사용할 수 있다.The N-acetyl phytosphingosine and dimethyl phytosphingosine complex of the present invention can be used as a medicine as it is or in the form of a pharmaceutically acceptable salt. The salt is not particularly limited as long as it is pharmaceutically acceptable. For example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid , Benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid salt or acid addition salt and the like can be used.

본 발명의 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신 복합체를 방사선 치료 증진제의 약제학적 조성물로 제제화할 경우, 유효 성분에 악영향을 미치지 않는 한, 필요에 따라 의약에 사용되는 각종 보조제, 예컨대 담체나 기타 첨가제, 예컨대 안정제, 완화제, 유화제 등을 사용할 수 있다.When formulating the N-acetyl phytosphingosine and dimethyl phytosphingosine complex of the present invention into a pharmaceutical composition of a radiotherapy enhancer, as long as it does not adversely affect the active ingredient, various auxiliaries used in medicine, such as carriers or other additives, For example, stabilizers, emollients, emulsifiers and the like can be used.

또한, 본 발명의 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신 복합체를 비경구, 경구 등으로 투여할 수 있으며, 주사제, 산제, 과립제, 정제 등을 포함한 약제학적 제제에 적합한 어떠한 제형으로도 할 수 있다.In addition, the N-acetyl phytosphingosine and dimethyl phytosphingosine complex of the present invention may be administered parenterally, orally, and may be in any formulation suitable for pharmaceutical preparations including injections, powders, granules, tablets, and the like.

N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신 복합체의 두 성분의 병용 투여시 함량비는, N-아세틸 파이토스핑고신 5∼95 중량%, 다이메틸 파이토스핑고신 95∼5 중량% 비이고, 바람직하게는 N-아세틸 파이토스핑고신 30∼70 중량%, 다이메틸 파이토스핑고신 70∼30 중량%비이고, 더욱 바람직하게는 N-아세틸 파이토스핑고신 40∼60 중량%, 다이메틸 파이토스핑고신 60∼40 중량%비이다. 약제학적 제형에 있어서 상기 복합체의 함유량은 제형에 따라 광범위하게 변할 수 있으며, 통상적인 방법에 따른다.The combined content ratio of the two components of N-acetyl phytosphingosine and dimethyl phytosphingosine complex is 5 to 95% by weight of N-acetyl phytosphingosine and 95 to 5% by weight of dimethyl phytosphingosine, and preferably 30 to N-acetyl phytosphingosine. It is 70 weight%, dimethyl phytosphingosine 70-30 weight% ratio, More preferably, it is 40-60 weight% of N-acetyl phytosphingosine, and 60-40 weight% dimethyl phytosphingosine ratio. The content of the complex in pharmaceutical formulations can vary widely depending on the formulation and is in accordance with conventional methods.

이하, N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신 조성물의 제조및 약리학적 작용에 대하여 제조실시예 및 실시예를 통하여 더욱 상세히 설명한다.Hereinafter, the preparation and pharmacological action of N-acetyl phytosphingosine and dimethyl phytosphingosine composition will be described in more detail with reference to Preparation Examples and Examples.

(제조실시예)(Production Example)

본 발명에 사용한 N-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신은 (주) 두산에서 제공받은 것으로 사용하였다.N-acetyl phytosphingosine and dimethyl phytosphingosine used in the present invention were used as provided by Doosan Corporation.

1) N-아세틸 파이토스핑고신의 농도 결정1) Determination of N-Acetyl Phytosphingosine Concentration

암세포의 방사선 민감 효과에 대한 실험을 하기 위한 파이토스핑고신 혹은 그 유도체의 농도를 결정하기 위해, 다양한 농도 (1, 3, 5, 10uM)로 폐암세포주인 LLC(Lewis lung carcinoma) 세포(2 x105개)에 처리한 후, 24시간과 48시간 후에 각각의 암세포 생존률을 트립판 블루 염색법으로 측정하였다. 그 결과 도 1에서와 같이, 폐암 세포의 생존률은 각각의 파이토스핑고신 의해 농도 의존적으로 감소하는 경향을 보였다.To determine the phytosphingosine or concentration of a derivative thereof for the experiments on the radiation-sensitive effects of the cancer cells, various concentrations (1, 3, 5, 10uM ) in lung cancer cell line, LLC (Lewis lung carcinoma) cells (2 x10 5 pieces) After treatment with, each cancer cell viability after 24 hours and 48 hours was measured by trypan blue staining. As a result, as shown in Figure 1, the survival rate of lung cancer cells showed a tendency to decrease in concentration dependent by each phytosphingosine.

본 실험에서는 방사선 민감작용 증대에 관한 실험을 목적하였으므로 세포 자체에 대한 살상효과는 배제한 농도, 즉, 90%이상의 생존을 나타내는 농도로 고정하여 실험하였다.In this experiment, the purpose of the experiment was to increase the radiosensitivity effect. Therefore, the experiment was fixed at a concentration that excludes the killing effect on the cell itself, that is, a concentration indicating survival of more than 90%.

2) 다이메틸파이토스핑고신 농도 결정2) Determination of dimethyl phytosphingosine concentration

암세포의 방사선 민감 효과에 대한 실험을 하기 위한 다이메틸파이토스핑고신 농도를 결정하기 위해, 다양한 농도 (1, 3, 5, 10uM)로 폐암세포주인 LLC세포(2 x105개)에 처리하고 24시간 후에 각각의 암세포 생존률을 트립판 블루 염색법으로 측정하였다. 그 결과 도 2에서와 같이, 폐암 세포의 생존률은 다이메틸파이토스핑고신에 의해 농도 의존적으로 감소하는 경향을 보였다.To determine the dimethylphytosphingosine concentration for experiments on the radiation-sensitive effects of cancer cells, the cells were treated with various concentrations (1, 3, 5, 10 uM) of LLC cells (2 x 10 5 cells) at 24 hours after each treatment. Cancer cell viability was measured by trypan blue staining. As a result, as shown in Figure 2, the survival rate of lung cancer cells showed a tendency to decrease in a concentration-dependent manner by dimethyl phytosphingosine.

마찬가지로 다이메틸파이토스핑고신 사용농도는 세포의 생존에 거의 영향을 미치지 않은 농도, 즉, 90% 이상의 생존을 나타내는 농도로 사용하였다.Likewise, the dimethyl phytosphingosine concentration was used at a concentration that had little effect on the survival of the cells, that is, at least 90% survival.

(실시예)(Example)

상기 제조실시예에서 결정된 파이토스핑고신과 다이메틸파이토스핑고신이 유도하는 암세포의 방사선 민감도의 변화는 다음과 같이 측정하였다.The change in radiation sensitivity of phytosphingosine and dimethyl phytosphingosine-induced cancer cells determined in the preparation example was measured as follows.

(실시예 1) N-아세틸 파이토스핑고신과 다이메틸파이토스핑고신의 처리에 의 한 암세포의 방사선 민감작용Example 1 Radiation Sensitization of Cancer Cells by Treatment of N-Acetyl Phytosphingosine and Dimethyl Phytosphingosine

N-아세틸 파이토스핑고신과 다이메틸파이토스핑고신 처리시 암세포의 방사선 민감 작용을 측정하기 위하여, 폐암 세포에 방사선(0, 3Gy)만 조사한 경우와 방사선(0, 3Gy)과 함께 각각의 약물을 단독 혹은 병용처리 한 다음 생존률을 클론형성 능력을 통해 비교하였다.In order to measure the radiation sensitivity of cancer cells during treatment with N-acetyl phytosphingosine and dimethyl phytosphingosine, lung cancer cells were irradiated only with radiation (0, 3Gy) and each drug alone or in combination with radiation (0, 3Gy). The survival rates were then compared via clonal capacity.

도 3으로부터 알 수 있는 바와 같이, 방사선만 조사한 경우 0Gy에서 100%, 3Gy에서 76.1%의 클론생성능을 보였다. 방사선과 함께 N-아세틸 파이토스핑고신 또는 다이메틸파이토스핑고신을 단독 처리한 경우에는 방사선 단독 조사군보다 생존율이 감소하는 경향이 나타나긴 했으나, 유의적이진 않았으며, 거의 비슷한 형태의 그래프로 나타났다. 그러나 방사선 조사와 함께 N-아세틸 파이토스핑고신과 다이메틸파이토스핑고신 복합처리했을 경우에는, 암세포의 생존률이 현저하게 감소하여, 3Gy에서 24.5%로 방사선 민감작용이 유의적으로 나타났다.As can be seen from Figure 3, the radiation alone showed 100% cloning performance at 0Gy, 76.1% cloning performance in 3Gy. Treatment with N-acetyl phytosphingosine or dimethyl phytosphingosine in combination with radiation showed a tendency to decrease survival rate compared with the radiation alone group, but it was not significant, and the graphs were almost similar. However, when N-acetyl phytosphingosine and dimethyl phytosphingosine were combined with irradiation, the survival rate of cancer cells was significantly decreased, and radiation sensitivity was significantly increased at 24.5% at 3Gy.

(실시예 2) 방사선 조사 후 세포사멸 증가 작용Example 2 Apoptosis Increase Effect After Irradiation

LLC 세포에, 방사선만 조사했을 때, 또는 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신만을 처리했을 때, N-아세틸 파이토스핑고신/다이메틸파이토스핑고신을 함께 사전 처리하고(24시간 전), 방사선을 조사했을 때의 세포사멸의 양적인 분석을 위하여, FACS 분석을 행하였다. 방사선만 조사(3Gy)한 경우, N-아세틸 파이토스핑고신/다이메틸파이토스핑고신(각각 3uM)만을 함께 처리한 경우, 방사선 조사(3Gy) 24시간 전에 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신(각각 3uM)을 함께 처리한 경우에 있어서, 암세포(1x105개)에서 진행된 세포 사멸 정도를 TUNEL분석을 통하여 비교해 보았다. 각 조건하의 세포들을 방사선 조사 24시간 후에 원심분리하여 세척한 후, 사이토스핀을 이용하여 슬라이드에 세포들을 부착시켜 고정시켰다. 고정된 세포를 TdT (Terminal deoxynucleotidyl 전이효소)와 반응시키고, HRP(horse-radish peroxidase)와 반응시켜 DAB으로 발색하여 현미경으로 관찰하였다. 이 때 세포사멸을 일으킨 세포는 갈색으로 염색되는 것에 비해, 그 이외의 세포들은 파란색으로 염색되므로, 이 수를 세어 백분율로 환산 후, 세포 사멸 정도를 비교하였다.When the LLC cells were irradiated only or treated with N-acetyl phytosphingosine / dimethyl phytosphingosine only, the cells when N-acetyl phytosphingosine / dimethyl phytosphingosine were pretreated together (24 hours ago) and irradiated For quantitative analysis of killing, FACS analysis was performed. When only radiation (3Gy) was treated with only N-acetyl phytosphingosine / dimethylphytosphingosine (3uM each), together with N-acetyl phytosphingosine / dimethyl phytosphingosine (3uM each) 24 hours prior to irradiation (3Gy) In one case, the degree of cell death in cancer cells (1 × 10 5 cells) was compared by TUNEL analysis. Cells under each condition were washed by centrifugation 24 hours after irradiation, and then fixed by attaching cells to slides using cytospin. The immobilized cells were reacted with TdT (Terminal deoxynucleotidyl transferase), reacted with horse-radish peroxidase (HRP), developed with DAB, and observed under a microscope. At this time, the cells that caused apoptosis were stained in brown, whereas the other cells were stained in blue, so this number was counted as a percentage, and the degree of cell death was compared.

도 4에 나타낸 바와 같이, 방사선만 조사한 암세포에서는 약 8.3%의 세포사멸이, N-아세틸 파이토스핑고신와 다이메틸파이토스핑고신을 함께 사전 처리한 경우에는 약 80.7%의 세포사멸이 진행된 것이 관찰되었고, 방사선 조사 없이 N-아세틸 파이토스핑고신와 다이메틸파이토스핑고신만을 동시 처리한 암세포는 약 4.4% 정도의 세포사멸정도가 나타났다.As shown in FIG. 4, about 8.3% of apoptosis in radiation-only cancer cells and about 80.7% of apoptosis were observed when N-acetyl phytosphingosine and dimethyl phytosphingosine were pretreated together. Cancer cells treated with acetyl phytosphingosine and dimethyl phytosphingosine at the same time showed about 4.4% cell death.

(실시예 3) 자궁암세포주와 유방암세포주에서의 방사선 민감작용Example 3 Radiation Sensitization in Uterine Cancer Cell Lines and Breast Cancer Cell Lines

자궁암세포와 유방암세포에서 N-아세틸 파이토스핑고신과 다이메틸파이토스핑고신의 방사선 치료 증진효과를 클론 형성 능력을 통하여 조사하여 보았을 때, 자궁암세포(CT26)와 유방암세포(EMT6)에서도 방사선 민감작용이 방사선 민감 증대지수 각각 1.6, 1.9로 방사선 민감작용이 유의적으로 나타났다. 이런 결과로 폐암세포 뿐만 아니라 자궁암세포와 유방암세포에서도 N-아세틸 파이토스핑고신과 다이메틸파이토스핑고신이 효과적으로 방사선 치료 증진 효과를 나타냄을 확인하였다(도 5참조).Radiation-sensitizing index was increased in uterine cancer cells (CT26) and breast cancer cells (EMT6) when investigating the effect of N-acetyl phytosphingosine and dimethyl phytosphingosine on the radiation therapy of uterine cancer cells and breast cancer cells. The radiation sensitivity was significant at 1.6 and 1.9, respectively. As a result, it was confirmed that N-acetyl phytosphingosine and dimethyl phytosphingosine effectively showed radiation treatment enhancement effects in uterine cancer cells and breast cancer cells as well as lung cancer cells (see FIG. 5).

(실시예 4) 동물실험에서의 항암작용 및 방사선 민감작용Example 4 Anticancer Activity and Radiation Sensitization in Animal Experiments

C57BL/6 마우스의 왼쪽 다리에 LLC 세포(1 x 106/마우스)를 이식시킨 후, 총 4개의 그룹, 즉, 대조군, 방사선단독조사군, N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 처리군, N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 및 방사선 조사군으로 구분하였다. 14일 경과 후 그 종양의 크기가 대략 1000mm3정도 되었을 때, N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 처리군과 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 및 방사선 조사군에 N-아세틸 파이토스핑고신 0.5∼2.5mg/kg과 같은 양의 다이메틸파이토스핑고신 0.5∼2.5mg/kg을 함께 복강내 투여하였으며, 24시간 후에 방사선 단독조사군과 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 및 방사선 조사군에60Co 방사선 20 Gy를 종양에 조사시켜 종양의성장속도와 마우스의 생존율을 비교 관찰하였다. 이때 종양의 성장속도는 종양의 크기를 측정하여 (가로 x 세로2)/2로 계산하였다.After implanting LLC cells (1 × 10 6 / mouse) into the left leg of C57BL / 6 mice, a total of four groups, namely, the control group, the radiotherapy group, the N-acetyl phytosphingosine / dimethyl phytosphingosine treatment group, and N- It was divided into acetyl phytosphingosine / dimethyl phytosphingosine and radiation group. After 14 days, when the tumor was about 1000 mm 3 in size, the N-acetyl phytosphingosine / dimethyl phytosphingosine group and the N-acetyl phytosphingosine / dimethyl phytosphingosine group and the irradiation group of N-acetyl phytosphingosine 0.5-2.5 mg / kg The same amount of dimethyl phytosphingosine 0.5 ~ 2.5mg / kg was administered intraperitoneally, and after 24 hours the radiation alone group and N-acetyl phytosphingosine / dimethyl phytosphingosine and radiation group irradiated with 60 Co radiation 20 Gy to the tumor Tumor growth rate and survival rate of the mice were compared. The growth rate of the tumor was calculated by measuring the size of the tumor (width x length 2 ) / 2.

또한 종양의 크기가 4000mm3정도 되는데 걸리는 시간을 환산하여 수치화시켰다. 그 결과 LLC세포를 주입한 마우스는 4000mm3되는데 19일이 걸린 반면 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신을 주입한 마우스의 경우 27일로 그 성장속도가 감소함을 알 수 있었고 이는 LLC세포를 주입한 후 방사선을 조사한 마우스와 비슷한 수치를 나타냈으며, N-아세틸 파이토스핑고신/다이메틸파이토스핑고신을 주입한 후 방사선을 조사한 마우스는 53일이 걸려 LLC세포에 방사선을 조사한 마우스보다 약2배 정도의 지연효과가 있음을 확인하였다(표 1 참조, 제 6도 참조). 또한 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신을 주입한 마우스의 생존율도 증가했으며 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신을 주입한 후 방사선을 조사한 마우스는 이보다 더 증가하였다(제 7도 참조). 이로써 동물실험에서도 본 발명의 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신이 방사선 민감효과도 지녔음을 확인할 수 있었다. 그 결과 방사선 단독 조사군과 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 단독 처리군도 대조군에 비해 생존기간이 약간 연장되기는 하였으나, N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 및 방사선 조사군의 경우 확연히 증가된 40% 정도의 생존율이 관찰되었다.In addition, the time required for tumor size to be about 4000mm 3 was converted into numbers. As a result, the mice injected with LLC cells took 19 days to reach 4000 mm 3 , whereas the mice injected with N-acetyl phytosphingosine / dimethyl phytosphingosine decreased their growth rate to 27 days. The results were similar to those of the mice irradiated, and the mice irradiated after the injection of N-acetyl phytosphingosine / dimethyl phytosphingosine took 53 days to have a delay effect approximately twice that of mice irradiated with LLC cells. It was confirmed (see Table 1, FIG. 6). In addition, the survival rate of mice injected with N-acetyl phytosphingosine / dimethyl phytosphingosine was increased, and the mice irradiated after the injection of N-acetyl phytosphingosine / dimethyl phytosphingosine increased even more (see FIG. 7). Accordingly, it was confirmed that the N-acetyl phytosphingosine / dimethyl phytosphingosine of the present invention also had a radiation sensitive effect in animal experiments. As a result, the radiation alone group and the N-acetyl phytosphingosine / dimethyl phytosphingosine-treated group also showed a slightly longer survival compared to the control group, but the N-acetyl phytosphingosine / dimethyl phytosphingosine and radiation group showed a marked increase of 40%. Survival was observed.

방사선 조사후 항목간 종양의 크기 비교Comparison of tumor size between items after irradiation 항목Item 종양의 크기가 4000mm3되는데 걸리는 시간(일)Number of days it takes for the tumor to reach 4000mm 3 LLC세포LLC cell 1919 LLC세포+N-아세틸 파이토스핑고신+다이메틸파이토스핑고신LLC cells + N-acetyl phytosphingosine + dimethyl phytosphingosine 2727 LLC세포+N-아세틸 파이토스핑고신+다이메틸파이토스핑고신+방사선(20Gy)LLC cells + N-acetyl phytosphingosine + dimethyl phytosphingosine + radiation (20 Gy) 5353

(실시예 5) 파이토스핑고신/다이메틸파이토스핑고신에 대한 급성 독성 평가Example 5 Acute Toxicity Assessment of Phytosphingosine / Dimethylphytosphingosine

본 실험에서는 기본적으로 독성을 나타내는 N-아세틸 파이토스핑고신 및 다이메틸파이토스핑고신을 생체내 무독한 용량으로 복합처리함으로써 방사선에 의한 암치료율을 증가시키는 발명이다.In this experiment, N-acetyl phytosphingosine and dimethyl phytosphingosine, which are basically toxic, are combined with a toxic dose in vivo to increase cancer treatment rate by radiation.

이상과 같은 시험예로부터, N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 복합체가 다양한 암 종에서 방사선과 병용 처리 시 방사선 치료의 선량을 낮추면서도 치료 효율적인 측면에서는 고선량 처리 효과를 얻을 수가 있어, 고선량 방사선 치료시 나타나는 부작용인 정상세포의 손상을 현저히 줄일 수 있는 효과가 있으며, 따라서 방사선 치료의 효율을 극대화할 수 있음을 알 수 있다.From the above test examples, the N-acetyl phytosphingosine / dimethyl phytosphingosine complex can obtain a high dose treatment effect in terms of treatment efficiency while lowering the dose of radiation treatment when combined with radiation in various cancers. It can be seen that there is an effect that can significantly reduce the damage of normal cells that appear side effects, thereby maximizing the efficiency of radiation therapy.

본 발명의 효과는 N-아세틸 파이토스핑고신/다이메틸파이토스핑고신 복합체조성물을 사용하여 방사선 치료 효율을 증진시킬 수 있으며, 부작용이 없어 안전하고 효율 높은 방사선 치료 증진제로의 이용이 가능하므로 인체 방사선의 의학적 이용 확대를 유도할 수 있다.The effects of the present invention can improve the radiation treatment efficiency by using the N-acetyl phytosphingosine / dimethyl phytosphingosine complex composition, and since there is no side effect, it can be used as a safe and efficient radiation treatment enhancer, thereby expanding the medical use of human radiation. Can be induced.

Claims (3)

하기 일반식(Ⅰ)로 표시되는 N-아세틸 파이토스핑고신 또는 이의 약제학적으로 허용가능한 염 5∼95 중량%와 하기 일반식(Ⅱ)로 표시되는 다이메틸파이토스핑고신 또는 이의 약제학적으로 허용가능한 염 5∼95 중량%를 유효성분으로서 함유하는 방사선 치료 민감제 조성물.5 to 95% by weight of N-acetyl phytosphingosine or a pharmaceutically acceptable salt thereof represented by the following general formula (I) and dimethyl phytosphingosine or a pharmaceutically acceptable salt thereof represented by the following general formula (II) Radiation therapy containing wt% as an active ingredient Sensitizer composition. (일반식 Ⅰ)(Formula I) (일반식 Ⅱ)(Formula II) 상기 식에서,Where R1,R2, R3는 각각 서로 독립적으로 탄소수 1∼4의 저급알킬 또는 치환된 저급알킬이다.R 1 , R 2 and R 3 are each independently of the other lower alkyl having 1 to 4 carbon atoms or substituted lower alkyl. 제 1항에 있어서, 상기 R1,R2, R3는 각각 서로 독립적으로 메틸 또는 에틸임을 특징으로 하는 방사선 치료 민감제 조성물The method of claim 1, wherein ROne, R2, R3Are each independently methyl or ethyl radiation therapy Sensitizer Composition 제 1항에 있어서, 상기 일반식(Ⅰ)로 표시되는 N-아세틸 파이토스핑고신 또는 이의 약제학적으로 허용가능한 염 40∼60 중량%와 상기 일반식(Ⅱ)로 표시되는 다이메틸파이토스핑고신 또는 이의 약제학적으로 허용가능한 염 60∼40 중량%를 유효성분으로 함유함을 특징으로 하는 방사선 치료 민감제 조성물According to claim 1, N-acetyl phytosphingosine represented by the general formula (I) or a pharmaceutically acceptable salt thereof 40 to 60% by weight and dimethyl phytosphingosine represented by the general formula (II) or pharmaceutically thereof Radiation therapy comprising from 60 to 40% by weight of acceptable salt as an active ingredient Sensitizer Composition
KR10-2002-0027739A 2002-05-20 2002-05-20 Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients KR100459484B1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
KR10-2002-0027739A KR100459484B1 (en) 2002-05-20 2002-05-20 Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients
PCT/KR2003/000406 WO2003097631A1 (en) 2002-05-20 2003-03-03 Radiosensitizer composition containing n-acetylphytosphingosine analogs and n,n-dimethyl-phytosphingosine analogs as the active ingredients
AU2003269871A AU2003269871A1 (en) 2002-05-20 2003-03-03 Radiosensitizer composition containing n-acetylphytosphingosine analogs and n,n-dimethyl-phytosphingosine analogs as the active ingredients

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR10-2002-0027739A KR100459484B1 (en) 2002-05-20 2002-05-20 Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients

Publications (2)

Publication Number Publication Date
KR20020042606A true KR20020042606A (en) 2002-06-05
KR100459484B1 KR100459484B1 (en) 2004-12-03

Family

ID=27726406

Family Applications (1)

Application Number Title Priority Date Filing Date
KR10-2002-0027739A KR100459484B1 (en) 2002-05-20 2002-05-20 Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients

Country Status (3)

Country Link
KR (1) KR100459484B1 (en)
AU (1) AU2003269871A1 (en)
WO (1) WO2003097631A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100532579B1 (en) * 2002-08-14 2005-12-19 주식회사 바이오씨에스 A pharmaceutical composition comprising phytospingosine derivatives for preventing and treating keratosis or skin cancer
KR100736145B1 (en) * 2004-06-01 2007-07-06 주식회사 두산 Monomethylphytosphingosine-Polyethyleneglycol and the composition for anti-cancer containing the same
KR100823146B1 (en) * 2006-12-28 2008-04-22 재단법인 한국원자력의학원 Novel phytosphingosine derivatives and their use for enhancing radiation therapy
WO2013085346A1 (en) * 2011-12-07 2013-06-13 가톨릭대학교 산학협력단 Novel phytosphingosine derivatives, and composition comprising same for preventing and treating inflammatory skin diseases, autoimmune diseases, and hyperkeratosis diseases
WO2016159537A1 (en) * 2015-03-31 2016-10-06 (주)아모레퍼시픽 Phytospingosine derivative and composition containing same
KR20230051965A (en) 2021-10-12 2023-04-19 한국원자력의학원 Composition for Enhancing Efficacy of Radiotherapy of Cancer Comprising Butyrate as Active Ingredient

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060166934A1 (en) * 2002-08-14 2006-07-27 Tae-Yoon Kim Composition comprising phytosphingosine derivatives for apoptosis induction
WO2022158993A1 (en) * 2021-01-25 2022-07-28 Carbocode S.A. Method for the production of d-erythro-sphingosine and analogs thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5583160A (en) * 1989-02-03 1996-12-10 The Biomembrane Institute Methylsphingosine used to treat apoptosis
CA2007507C (en) * 1989-02-03 1998-05-19 Yasuyuki Igarashi Sphingosine and n-methyl-sphingosine as inhibitor of cell growth
DE4025316A1 (en) * 1990-08-09 1992-02-13 Basf Ag New 3,4-epoxy:sphingosine derivs. - for use in tumour and immune therapy and to influence circulation, also as intermediates for ceramide(s) and glycosphingolipid(s)
JPH11269190A (en) * 1998-03-19 1999-10-05 Nissin Food Prod Co Ltd Compound having immunomodulative activity
US7820718B1 (en) * 1999-04-07 2010-10-26 Roger Williams Hospital Combinations of ceramide and chemotherapeutic agents for inducing cell death and uses thereof in treating cancer
KR100371491B1 (en) * 1999-07-27 2003-02-07 주식회사 두산 Cream Composition For Skin Care
KR100457113B1 (en) * 2001-12-27 2004-11-16 한국원자력연구소 Radiosensitizer containing ceramides or derivatives thereof and dimethylsphingosine as the active ingredient

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100532579B1 (en) * 2002-08-14 2005-12-19 주식회사 바이오씨에스 A pharmaceutical composition comprising phytospingosine derivatives for preventing and treating keratosis or skin cancer
KR100736145B1 (en) * 2004-06-01 2007-07-06 주식회사 두산 Monomethylphytosphingosine-Polyethyleneglycol and the composition for anti-cancer containing the same
KR100823146B1 (en) * 2006-12-28 2008-04-22 재단법인 한국원자력의학원 Novel phytosphingosine derivatives and their use for enhancing radiation therapy
WO2013085346A1 (en) * 2011-12-07 2013-06-13 가톨릭대학교 산학협력단 Novel phytosphingosine derivatives, and composition comprising same for preventing and treating inflammatory skin diseases, autoimmune diseases, and hyperkeratosis diseases
US9868697B2 (en) 2011-12-07 2018-01-16 The Catholic University Of Korea Industry-Academic Cooperation Foundation Phytosphingosine derivatives, and composition comprising same for preventing and treating inflammatory skin diseases, autoimmune diseases, and hyperkeratosis diseases
WO2016159537A1 (en) * 2015-03-31 2016-10-06 (주)아모레퍼시픽 Phytospingosine derivative and composition containing same
KR20160116690A (en) * 2015-03-31 2016-10-10 (주)아모레퍼시픽 Phytosphingosine Derivatives and Composition Comprising Thereof
JP2018510167A (en) * 2015-03-31 2018-04-12 アモーレパシフィック コーポレイションＡｍｏｒｅｐａｃｉｆｉｃ Ｃｏｒｐｏｒａｔｉｏｎ Phytosphingosine derivative and composition containing the same
US10172777B2 (en) 2015-03-31 2019-01-08 Amorepacific Corporation Phytospingosine derivative and composition containing same
KR20230051965A (en) 2021-10-12 2023-04-19 한국원자력의학원 Composition for Enhancing Efficacy of Radiotherapy of Cancer Comprising Butyrate as Active Ingredient

Also Published As

Publication number Publication date
KR100459484B1 (en) 2004-12-03
AU2003269871A1 (en) 2003-12-02
WO2003097631A1 (en) 2003-11-27

Similar Documents

Publication Publication Date Title
EP2061452B1 (en) Anti cancer use of caffeic acid and derivatives
EP0774255B1 (en) Use of ursolic acid for the manufacture of a medicament for suppressing metastasis
CA2228281C (en) Use of l-carnitine and acyl l-carnitines for lowering ceramide levels
AU619022B2 (en) Pharmaceutical compositions for the inhibition of tumor metastasis
AU2016308641A1 (en) Treatment and prevention of muscle loss using L-ornithine in combination with at least one of phenylacetate and phenylbutyrate
US5089517A (en) Neuroprotection by indolactam v and derivatives thereof
KR100459484B1 (en) Radiosensitizer composition containing N-acetylphytosphingosine and dimethylphytosphingosine as the active ingredients
EP0923371B1 (en) Pharmaceutical compositions comprising tyrphostins
EP1491206B1 (en) Use of peptide derivatives for inducing cell differentiation
CN110664807B (en) Pharmaceutical composition with synergistic anti-melanoma efficacy and application thereof
US6011066A (en) Method for treating septic shock
CN116726021A (en) Combined medicine of DRP1 inhibitor and iron death inducer and anti-tumor application thereof
JP4260888B2 (en) Pharmaceutical composition containing S-alkylisothiouronium derivatives
KR100457113B1 (en) Radiosensitizer containing ceramides or derivatives thereof and dimethylsphingosine as the active ingredient
CN113262218B (en) Use of isothiocyanate compounds
JP2018508495A (en) Prodrug and pharmaceutical composition of sunitinib
RU2328306C2 (en) Combined antitumour therapy with substituted derivatives of acryloyldistamicine and inhibitors of protein kinases (serine/threonine kinase)
CN111905102A (en) Use of EZH2 inhibitors for the treatment of gliomas
CN114948951B (en) Use of FK506 or a pharmaceutically acceptable derivative thereof in combination with an iron death inducer or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of cancer
KR100421261B1 (en) Radiosensitizer containing phytosphingosine derivatives as the active ingredient
KR20030071029A (en) Composition useful as anticancer drug and radiosensitizer
CN116036126A (en) Antitumor pharmaceutical composition and application thereof
KR20220043046A (en) Use of sphingosine-1-phosphate receptor agonist
CN115137831A (en) Application of astaxanthin in preparation of anti-angiogenesis drug synergist and drug composition
CN110946858A (en) Use of indolinone derivatives for the treatment of obesity and related diseases

Legal Events

Date Code Title Description
A201 Request for examination
E902 Notification of reason for refusal
E701 Decision to grant or registration of patent right
GRNT Written decision to grant
FPAY Annual fee payment

Payment date: 20121011

Year of fee payment: 9

FPAY Annual fee payment

Payment date: 20130808

Year of fee payment: 10

FPAY Annual fee payment

Payment date: 20140825

Year of fee payment: 11

FPAY Annual fee payment

Payment date: 20150825

Year of fee payment: 18