KR100932520B1 - Anticancer agent composition - Google Patents
Anticancer agent composition Download PDFInfo
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- KR100932520B1 KR100932520B1 KR1020020067291A KR20020067291A KR100932520B1 KR 100932520 B1 KR100932520 B1 KR 100932520B1 KR 1020020067291 A KR1020020067291 A KR 1020020067291A KR 20020067291 A KR20020067291 A KR 20020067291A KR 100932520 B1 KR100932520 B1 KR 100932520B1
- Authority
- KR
- South Korea
- Prior art keywords
- anticancer
- citric acid
- cancer
- composition
- arginine
- Prior art date
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Abstract
본 발명은 ⒜ 구연산 및 ⒝ 구연산 및 L-아르기닌 중에서 선택된 활성 성분을 약제학적으로 유효한 양으로 약제학적으로 허용되는 담체 또는 희석제와 함께 함유함을 특징으로 하는 항암제 조성물에 관한 것이다.The present invention relates to an anticancer composition comprising an active ingredient selected from ⒜ citric acid and ⒝ citric acid and L-arginine together with a pharmaceutically acceptable carrier or diluent.
항암제, 구연산, L-아르기닌, 세포사멸Anticancer drugs, citric acid, L-arginine, apoptosis
Description
도 1은 활성 성분으로서 구연산을 함유한 본 발명의 항암제 조성물이 사람 난소 아데노암종 SKOV-3에 미치는 영향을 MTT 검정을 통한 세포 생존율로 나타낸 것이다.Figure 1 shows the effect of the anticancer composition of the present invention containing citric acid as an active ingredient on human ovarian adenocarcinoma SKOV-3 by cell viability through the MTT assay.
도 2는 활성 성분으로서 구연산을 함유한 본 발명의 항암제 조성물이 사람 난소 아데노암종 OVCAR-3에 미치는 영향을 MTT 검정을 통한 세포 생존율로 나타낸 것이다.Figure 2 shows the effect of the anticancer composition of the present invention containing citric acid as an active ingredient on human ovarian adenocarcinoma OVCAR-3 in cell viability through the MTT assay.
도 3은 활성 성분으로서 구연산 및 L-아르기닌을 함유한 본 발명의 항암제 조성물이 사람 난소 아데노암종 SKOV-3에 미치는 영향을 MTT 검정을 통한 세포 생존율로 나타낸 것이다.Figure 3 shows the effect of the anticancer composition of the present invention containing citric acid and L-arginine as active ingredients on human ovarian adenocarcinoma SKOV-3 by cell viability through the MTT assay.
도 4는 활성 성분으로서 구연산 및 L-아르기닌을 함유한 본 발명의 항암제 조성물이 사람 뇌 교모세포종 U87에 미치는 영향을 MTT 검정을 통한 세포 생존율로 나타낸 것이다.Figure 4 shows the effect of the anticancer composition of the present invention containing citric acid and L-arginine as active ingredients on human brain glioblastoma U87 by cell viability through the MTT assay.
도 5는 L-아르기닌 및 L-아스파르트산을 함유한 조성물이 사람 난소 아데노암종 SK0V-3에 미치는 영향을 MTT 검정을 통한 세포 생존율로 나타낸 것이다.Figure 5 shows the effect of the composition containing L-arginine and L-aspartic acid on human ovarian adenocarcinoma SK0V-3 as cell viability through the MTT assay.
도 6은 L-아르기닌을 함유한 조성물이 사람 난소 아데노암종 SK0V-3에 미치는 영향을 MTT 검정을 통한 세포 생존율로 나타낸 것이다.Figure 6 shows the effect of the composition containing L- arginine on human ovarian adenocarcinoma SK0V-3 in cell viability through the MTT assay.
본 발명은 구연산(Citric acid)을 단독으로 함유하거나 또는 구연산 및 L-아르기닌(L-Arginine)을 함유함을 특징으로 하는 항암제 조성물에 관한 것이다. 보다 자세하게는, ⒜ 구연산 및 ⒝ 구연산 및 L-아르기닌 중 선택된 활성 성분을 약제학적으로 유효한 양과 이를 약제학적으로 허용되는 담체 또는 희석제와 함께 함유하여 여러 종류의 암을 치료하는데 유용한 항암제 조성물에 관한 것이다.The present invention relates to an anticancer composition comprising citric acid alone or containing citric acid and L-arginine. More specifically, the present invention relates to an anticancer agent composition useful for treating various types of cancers by containing a pharmaceutically effective amount of selected active ingredients of ⒜ citric acid and ⒝ citric acid and L-arginine together with a pharmaceutically acceptable carrier or diluent.
화학요법의 발전으로 암환자의 생존율 및 치유율은 개선되고 있으나 항암제의 강한 독성으로 인해 정상 세포에 심각한 손상을 입는 것이 큰 문제점이 되고 있다. 이러한 항암제의 부작용을 막기 위해 암세포의 증식만을 특이적으로 억제할 수 있는 물질이 요구되고 있으며, 이에 따라 현재 많은 항암제가 개발되어 있다. 이러한 항암제로는 국제특허공개 WO 96/40142호, WO 97/40142호, WO 97/13771호, WO 95/23141호 등에 기술된 화합물들이 있다. 그러나, 이러한 화합물들은 암세포의 증식만을 특이적으로 억제할 수 있지만 화학적으로 합성된 것이기 때문에 인체내에서 많은 부작용을 유발할 수 있다.Advances in chemotherapy have improved the survival and healing rates of cancer patients, but serious damage to normal cells has been a major problem due to the strong toxicity of anticancer drugs. In order to prevent the side effects of these anticancer drugs, a substance that can specifically inhibit the proliferation of cancer cells is required. Accordingly, many anticancer drugs have been developed. Such anticancer agents include compounds described in WO 96/40142, WO 97/40142, WO 97/13771, WO 95/23141 and the like. However, these compounds can specifically inhibit the proliferation of cancer cells, but because they are chemically synthesized, they can cause many side effects in the human body.
따라서, 부작용을 줄이면서 우수한 항암효과를 나타낼 수 있는 항암제를 개발하고자 하였고, 이 때문에 현재 천연성분으로 된 항암제가 많이 개발되고 있다.Therefore, it was intended to develop an anticancer agent that can exhibit an excellent anticancer effect while reducing side effects, and for this reason, many anticancer agents with natural ingredients are currently being developed.
본 발명자들도 천연성분으로 된 항암제를 개발하기 위하여 연구한 결과, 구 연산이 암세포의 미토콘드리아에 작용하여 미토콘드리아를 깨뜨린다는 것을 발견하였고, 또한 구연산을 종래 항암효과가 알려진 L-아르기닌과 혼합할 경우 항암효과가 높아진다는 것을 발견하였다. 이에 본 발명자들은 구연산을 단독으로 함유하거나 또는 구연산 및 L-아르기닌을 함유하는 항암제 조성물을 제조하여 암세포에 처리한 결과, 세포사멸(apoptosis)을 유도하여 암세포를 사멸시키는 효과가 높다는 것을 확인하였다.The present inventors have also studied to develop a natural anticancer drug, and found that citric acid acts on the mitochondria of cancer cells and breaks the mitochondria, and when citric acid is mixed with L-arginine, which is known for its anticancer effects, The effect was found to be high. Accordingly, the inventors of the present invention prepared an anticancer composition containing citric acid alone or containing citric acid and L-arginine and treating the cancer cells. As a result, it was confirmed that the effect of killing cancer cells by inducing apoptosis was high.
따라서, 본 발명은 ⒜ 구연산 및 ⒝ 구연산 및 L-아르기닌 중에서 선택된 활성 성분을 약제학적으로 유효한 양으로 약제학적으로 허용되는 담체 또는 희석제와 함께 함유함을 특징으로 하는 항암제 조성물을 제공한다.Accordingly, the present invention provides an anticancer composition comprising an active ingredient selected from ⒜ citric acid and ⒝ citric acid and L-arginine together with a pharmaceutically acceptable carrier or diluent.
본 발명에서 사용된 용어 "약제학적으로 유효한 양"이라 함은 본 발명의 조성물이 적용되는 암에 대해 개선 또는 치료효과를 나타내는 활성 성분의 양을 의미한다.As used herein, the term "pharmaceutically effective amount" means an amount of the active ingredient which has an improvement or therapeutic effect on the cancer to which the composition of the present invention is applied.
용어 "약제학적으로 허용되는 담체 또는 희석제"는 신체의 한 기관 또는 부분으로부터 신체의 다른 기관 또는 부분으로 활성 성분을 수송하는 역할을 하는 것으로 제약 분야에서 통상 사용되는 액체 또는 고체 충진제, 희석제, 부형제 또는 용매와 같은 약제학적으로 허용되는 물질, 조성물 또는 비히클을 의미한다.The term "pharmaceutically acceptable carrier or diluent" refers to the transport of the active ingredient from one organ or part of the body to another organ or part of the body and is a liquid or solid filler, diluent, excipient or By pharmaceutically acceptable substance, composition or vehicle such as solvent.
본 발명의 항암제 조성물은 ⒜ 구연산 및 ⒝ 구연산 및 L-아르기닌 중에서 선택된 활성 성분을 약제학적으로 유효한 양으로 약제학적으로 허용되는 담체 또는 희석제와 함께 함유하는 것을 특징으로 한다. The anticancer agent composition of the present invention is characterized by containing an active ingredient selected from ⒜ citric acid and ⒝ citric acid and L-arginine together with a pharmaceutically acceptable carrier or diluent.
한 양태로서, 본 발명의 항암제 조성물은 활성 성분으로서 0.3 내지 2중량%의 구연산, 바람직하게는 0.5 내지 1중량%의 구연산을 약제학적으로 유효한 양으로 약제학적으로 허용되는 담체 또는 희석제와 함께 함유함을 특징으로 하는 항암제 조성물을 제공한다.In one embodiment, the anticancer composition of the present invention contains 0.3 to 2% by weight of citric acid, preferably 0.5 to 1% by weight of citric acid, in a pharmaceutically effective amount together with a pharmaceutically acceptable carrier or diluent as an active ingredient. It provides an anticancer agent characterized in that.
다른 양태로서, 본 발명의 항암제 조성물은 활성 성분으로서 0.02 내지 0.4중량%의 구연산 및 0.08 내지 1.6중량%의 L-아르기닌, 바람직하게는 0.1 내지 0.3중량%의 구연산 및 0.4 내지 1.2중량%의 L-아르기닌을 약제학적으로 유효한 양으로 약제학적으로 허용되는 담체 또는 희석제와 함께 함유하는 것을 특징으로 하는 항암제 조성물을 제공하며, 이는 본 발명의 항암제 조성물 중 활성 성분의 전체 함량이 0.1 내지 2중량%, 바람직하게는 0.5 내지 1.5중량%인 것을 특징으로 한다.In another embodiment, the anticancer composition of the present invention comprises 0.02 to 0.4 wt% citric acid and 0.08 to 1.6 wt% L-arginine, preferably 0.1 to 0.3 wt% citric acid and 0.4 to 1.2 wt% L- as active ingredients. It provides an anticancer composition comprising arginine together with a pharmaceutically acceptable carrier or diluent in a pharmaceutically effective amount, wherein the total content of the active ingredient in the anticancer agent composition of the present invention is 0.1 to 2% by weight, preferably It is characterized in that 0.5 to 1.5% by weight.
또한, 본 발명의 항암제 조성물은 pH를 6 내지 8로 조절하기 위해 수산화나트륨, 수산화칼륨, 인산나트륨 및 인산칼륨 등의 염기를 사용할 수 있다.In addition, the anticancer agent composition of the present invention may use a base such as sodium hydroxide, potassium hydroxide, sodium phosphate and potassium phosphate to adjust the pH to 6-8.
이하, 본 발명의 항암제 조성물이 적용될 수 있는 많은 종류의 암 가운데 대표적으로 상피성 난소암을 대상으로 설명하고자 한다. 그러나, 당업자라면 본원에 예시적으로 기재된 상피성 난소암에 대한 본 발명의 항암제 조성물 효과를 보고 다른 유형의 암에 대해서도 동일하게 적용할 수 있음을 인식할 것이다.Hereinafter, a description will be given of epithelial ovarian cancer representatively among the many types of cancer to which the anticancer agent composition of the present invention can be applied. However, one of ordinary skill in the art will recognize the effects of the anticancer agent compositions of the present invention on epithelial ovarian cancer described herein by way of example, and recognize that the same applies to other types of cancer.
상피성 난소암은 난소암중 가장 흔한 유형일 뿐만 아니라 부인과의학에서 악성에 의한 주된 사망 원인이다. 상피성 난소암 환자의 치사율이 가장 높게 나타나는 이유는 상피성 난소암의 잠행성 진행으로 인해 암이 상당히 진행된 단계에서 환자가 진단되는 것이 대부분이기 때문이다(Ozols, R. F., Semin. Oncol., vol. 22, pp61-66, (1995)). 비록 종양을 수술로 제거하거나 적극적인 화학요법으로 난소암을 치료하지만 난소암 환자의 생존율은 약물 내성으로 인하여 단지 20 내지 30%에 불과하다.Epithelial ovarian cancer is the most common type of ovarian cancer as well as the leading cause of malignancy in gynecology. The highest mortality rates in patients with epithelial ovarian cancer are due to the fact that most patients are diagnosed at an advanced stage of cancer due to the latent progression of epithelial ovarian cancer (Ozols, RF, Semin. Oncol., Vol. 22, pp 61-66, (1995)). Although ovarian cancer is treated by surgical removal of the tumor or by aggressive chemotherapy, survival of ovarian cancer patients is only 20-30% due to drug resistance.
현재까지도 상피성 난소암의 위험 요소와 원인에 관하여 잘 알려져 있지 않다. 그러나 많은 연구들은 배란의 빈도와 상피성 난소암의 발전 사이에 밀접한 관계가 있음을 공통적으로 보여주고 있는데, 이러한 관계는 상피성 난소암의 발생률이 젊은 여성과 나이든 여성(이른 초경과 늦은 폐경기), 미혼 및 미출산 여성에서 증가한다는 것으로 알 수 있다(Franceshi et al., Int. J. Cancer, vol. 49, pp57-60, (1991); Taylor et al., Cancer, vol. 12, p1207-, (1959); Fraumeni et al., J. Natl. Cancer Inst., vol. 42, p455-, (1969); Dorn et al., Public Health Monogr. 56, PHS Publication No. 590, (1959); Weiss et al., J. Natl. Cancer Inst., vol. 58, p913-, (1977); Nergri et al., Int. J. Cancer, vol. 49, pp50-56, (1991)). 따라서, 경구용 피임약은 상피성 난소암의 발전에 대해 방어 효과를 나타내는 것으로 일반적으로 알려져 있다(Stanford, J.L., Contraception 43, pp543-556, (1991); Negri et al., Int. J. Cancer, vol. 49, pp50-56, (1991); Franceshi et al., Int. J. Cancer, vol. 49, pp61-65, (1991)). 상피성 난소암의 발병을 설명하는 유력한 학설은 배란 동안 난소 상피 표면이 반복적으로 분열하고 회복하기 때문이라는 것이다(Fathalla, M.F., Lancet., vol. 2, p163-, (1971)). 상피 표면이 회복되는 과정에 변형된 상피 세포는 자발적으로 돌연변이되고, 종양 억제 유전자가 불활성화되며 발암물질에 의해 종양 유전자(oncogene)가 활성화되기 쉽다.To date, little is known about the risk factors and causes of epithelial ovarian cancer. However, many studies have shown that there is a common relationship between the frequency of ovulation and the development of epithelial ovarian cancer, which suggests that young and older women (early menopause and late menopause), Increase in unmarried and unborn women (Franceshi et al., Int. J. Cancer, vol. 49, pp57-60, (1991); Taylor et al., Cancer, vol. 12, p1207-, (1959); Fraumeni et al., J. Natl. Cancer Inst., Vol. 42, p455-, (1969); Dorn et al., Public Health Monogr. 56, PHS Publication No. 590, (1959); Weiss et al., J. Natl. Cancer Inst., vol. 58, p913-, (1977); Nergri et al., Int. J. Cancer, vol. 49, pp 50-56, (1991)). Therefore, oral contraceptives are generally known to have a protective effect against the development of epithelial ovarian cancer (Stanford, JL, Contraception 43, pp543-556, (1991); Negri et al., Int. J. Cancer, vol. 49, pp 50-56, (1991); Franceshi et al., Int. J. Cancer, vol. 49, pp 61-65, (1991)). A potent theory explaining the development of epithelial ovarian cancer is that the ovarian epithelial surface repeatedly divides and recovers during ovulation (Fathalla, M.F., Lancet., Vol. 2, p163-, (1971)). In the process of restoring the epithelial surface, the modified epithelial cells are spontaneously mutated, the tumor suppressor genes are inactivated, and the oncogenes are likely to be activated by carcinogens.
한편, 알려진 정액의 기능 및 항암효과로서, 사람 정액은 림프구의 세포독성으로 인한 성교 후 정자의 면역학적 손상을 정액의 정장(seminal plasma)성분이 보호한다고 알려져 있으며(Stities et al., Nature, vol. 253, pp727-729, (1975); James et al., Immunol., vol. 6, pp61-70, (1985)), 체액성 면역의 발달과 생체내 종양 성장을 억제시킬 수 있다고 보고되어 있다(Anderson et al., Immunol., vol. 128, pp535-539, (1985); Michaelis et al., Anticancer Drugs, vol. 11, pp369-376, (2000)). 또한 자궁경부 상피성 암종세포에서 메탈로프로테이나제(metalloproteinase; MMP)-2 및 MMP-9의 mRNA가 생성되는 것에 영향을 미치므로 성행위시 정액으로 인해 자궁경부암의 진행에 영향을 미칠 수 있다고 알려져 있다(Jeremias et al., Am. J. Obstet. Gynecol., vol. 181, pp591-595, (1999)). 최근에는 소의 정액 성분 중 리보뉴클레아제(BS-RNase)가 사람 림프구와 사람 종양세포에 노출되는 시간과 농도에 따라 세포사멸을 유도하는 능력이 있다고 밝혀졌다. BN-RNase는 화학치료 약물에 대한 내성적인 신경아(neuroblastoma; NB)세포에 대하여 높은 효능을 나타내는 물질이다(Cinatl et al., Anticancer Res., vol. 20, pp853-859, (2000); Cinatl et al., Int. J. Oncol., vol 15, pp1001-1009, (1999)).On the other hand, as a known semen function and anticancer effect, human semen is known to protect the seminal plasma components of sperm after sexual intercourse due to cytotoxicity of lymphocytes (Stities et al., Nature, vol. 253, pp727-729, (1975); James et al., Immunol., Vol. 6, pp61-70, (1985)), have been reported to inhibit the development of humoral immunity and tumor growth in vivo. (Anderson et al., Immunol., Vol. 128, pp 535-539, (1985); Michaelis et al., Anticancer Drugs, vol. 11, pp 369-376, (2000)). In addition, it affects the production of metalloproteinase (MMP) -2 and MMP-9 mRNAs in cervical epithelial carcinoma cells, which may affect the progression of cervical cancer due to semen during sexual activity. (Jeremias et al., Am. J. Obstet. Gynecol., Vol. 181, pp 591-595, (1999)). Recently, ribonuclease (BS-RNase) among bovine semen has been shown to be capable of inducing apoptosis depending on the time and concentration of exposure to human lymphocytes and human tumor cells. BN-RNase is a substance that shows high efficacy against neuroblastoma (NB) cells resistant to chemotherapeutic drugs (Cinatl et al., Anticancer Res., Vol. 20, pp853-859, (2000); Cinatl et. al., Int. J. Oncol., vol 15, pp 1001-1009, (1999)).
또한, 생태학적 연구를 통한 정액의 항암효과를 조르고브(Gjorgov)는 다양한 사례-대조 연구를 실시하여 사람 정액의 감소된 노출과 유방암 발생사이의 상호관계를 조사하였다. 예를 들면, 차단피임방법(콘돔)을 사용한 여성과 비차단 피임방 법(피임약, 자궁내장치(Intra Uterine Device; IUD), 리듬 또는 난관 결찰)을 사용한 여성을 대상으로 유방암 발생 위험도를 비교한 결과, 차단피임방법(콘돔)을 사용한 여성이 유방암 발생 위험도가 5.2배 더 높다는 결과를 얻을 수 있었다(Gjorgov et al., Folia Med., vol. 40, pp17-23, (1998)).In addition, the ecological study of anti-cancer effects of semen, Gjorgov conducted a variety of case-control studies to investigate the correlation between reduced exposure of human semen and the development of breast cancer. For example, we compared the risk of breast cancer in women who used blocking contraceptive methods (condoms) and women who used non-blocking contraceptive methods (contraceptives, intra Uterine Device (IUD), rhythm or fallopian ligation). As a result, women who used the contraceptive contraceptive method (condom) had a 5.2 times higher risk of developing breast cancer (Gjorgov et al., Folia Med., Vol. 40, pp 17-23, (1998)).
상기 제시된 항암효과를 나타내는 정액의 주요성분은 알부민(albumin), 락토페린(lactoferrin), 전달요소(transferring factors), 면역글로불린, 산 포스파타제(acid phosphatase), L-카르니틴(L-carnitine), L-아르기닌, L-히스티딘(L-Histidine), 구연산(citric acid), 프락토즈(fructose), 마그네슘(magnesium), 아연(zinc), 프로스타글란딘(prostaglandin) 및 글리세로포스포콜린(glycerophosphocholine) 등이다.The main components of semen exhibiting the anticancer effects shown above include albumin, lactoferrin, transferring factors, immunoglobulins, acid phosphatase, L-carnitine, and L-arginine. , L-Histidine, citric acid, fructose, fructose, magnesium, zinc, prostaglandin and glycerophosphocholine.
상술한 바와 같이, 상피성 난소암 및 정액의 항암효과에 관한 종래 지식으로부터 본 발명자들은 상피성 난소암에 있어서, 배란기간동안 사람 정액에 대한 감소된 노출이 상피성 난소암 진행에 병인학적 위험요소 중 하나가 될 것이라고 판단하였다. 따라서, 사람 정액 성분들이 악성형질전환된 상피 세포를 제거하는데 기여할 수 있을 것이다.As mentioned above, from the prior knowledge of the anticancer effects of epithelial ovarian cancer and semen, the present inventors have found that in epithelial ovarian cancer, reduced exposure to human semen during ovulation is a pathological risk factor for the progression of epithelial ovarian cancer. I decided it would be one of Thus, human semen components may contribute to the removal of malignant transformed epithelial cells.
이와 관련하여, 본 발명자들은 생체 외(in vitro)에서 암세포에 영향을 미치는 사람 정액 성분을 연구한 결과, 사람 정액 성분 중 구연산이 암세포의 미토콘드리아에 작용하여 미토콘드리아를 깨뜨린다는 것을 발견하였고 또한 이를 종래 암치료에서 세포독성 T세포와 자연살해세포의 항암작용을 항진시켜 종양과 암세포의 성장, 전이 등을 지연시킨다고 알려진 L-아르기닌과 구연산을 혼합할 경우 항암효과 가 높아진다는 것을 발견하였다. 이에 본 발명자들은 구연산을 단독으로 함유하거나 또는 구연산 및 L-아르기닌을 함유하는 항암제 조성물을 제조하여 사람 난소 아데노암종인 SKOV-3, 사람 난소 아데노암종인 OVCAR-3 및 사람 뇌 교모세포종인 U87에 처리한 결과, 세포사멸을 유도하여 암세포를 사멸시키는 효과가 높다는 것을 확인하였다. 즉, 이러한 항암효과를 SKOV-3, OVCAR-3 및 U87의 암세포주를 대상으로 확인한 결과, 구연산을 단독으로 함유하거나 또는 구연산 및 L-아르기닌을 함유하는 본 발명의 항암제 조성물이 세포사멸을 유도하여 암세포의 세포 생존율을 감소시키는 효과를 나타내었고(도 1, 도 2, 도 3 및 도 4 참조), 비교 실험으로서 항암효과가 공지된 성분인 L-아르기닌 및 L-아스파르트산(L-Aspartic acid)을 혼합한 조성물 또는 L-아르기닌을 함유한 조성물을 상기 암세포주에 처리한 결과, 암세포의 세포 생존율을 효과적으로 감소시키지 못했다(도 5 및 도 6 참조).In this regard, the present inventors studied human semen components affecting cancer cells in vitro, and found that citric acid in human semen components acts on the mitochondria of cancer cells and breaks down the mitochondria. In the treatment, it was found that the combination of L-arginine and citric acid, which is known to delay the growth and metastasis of tumors and cancer cells by enhancing the anticancer activity of cytotoxic T cells and natural killer cells, increased the anticancer effect. Accordingly, the present inventors have prepared an anticancer composition containing citric acid alone or citric acid and L-arginine and treated it with human ovarian adenocarcinoma SKOV-3, human ovarian adenocarcinoma OVCAR-3 and human brain glioblastoma U87. As a result, it was confirmed that the effect of inducing apoptosis and killing cancer cells is high. That is, as a result of confirming the cancer cell lines of SKOV-3, OVCAR-3 and U87, such anti-cancer effects, the anticancer composition of the present invention containing citric acid alone or citric acid and L-arginine induces cell death It showed the effect of reducing the cell viability of cancer cells (see Fig. 1, 2, 3 and 4), L- arginine and L-Aspartic acid (L-Aspartic acid), a known component of the anti-cancer effect as a comparative experiment As a result of treating the cancer cell line with a composition or a composition containing L-arginine, the cell viability of cancer cells was not effectively reduced (see FIGS. 5 and 6).
상기 결과와 관련하여, 본 발명의 항암제 조성물은 이들로 한정되는 것은 아니지만 다음과 같은 여러 종류의 암을 치료하는데 유용할 수 있다: 방광, 유방, 장, 신장, 간, 폐(소세포폐암 포함), 뇌, 식도, 쓸개, 난소, 췌장, 위, 경부, 갑상선, 전립선 및 피부(편평상피 세포 암종 포함)와 같은 암종; 백혈병, 급성 임파성 백혈병, 급성림프성 백혈병, B-세포 임파종, T-세포 임파종, 호지킨 임파종, 비호지킨 임파종, 모발상 세포 임파종 및 버킷 임파종을 포함한 림프계열의 조혈성 종양; 급성 및 만성 골수성 백혈병, 골수이형성증후군 및 전골수구성백혈병을 포함한 골수계열의 조혈성 종양; 섬유육종 및 횡문근육종을 포함한 간충직 발원의 종양; 성상세포종, 신경모세포증, 신경교종 및 신경초종을 포함한 중추 및 말초 신경계의 종양; 및 흑색종, 정상피종, 기형종, 골육종, 색소건피증, 각화극세포종, 갑상선 여포상암 및 카포시 육종을 포함한 기타 종양.In connection with the above results, the anticancer agent compositions of the present invention may be useful for treating various kinds of cancers including but not limited to: bladder, breast, intestine, kidney, liver, lung (including small cell lung cancer), Carcinomas such as brain, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin (including squamous cell carcinoma); Hematopoietic tumors of the lymphatic system, including leukemia, acute lymphocytic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; Hematopoietic tumors of the myeloid line, including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; Tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannoma; And other tumors including melanoma, normal carcinoma, teratoma, osteosarcoma, pigmentosa, keratinous blastoma, thyroid follicular cancer and Kaposi's sarcoma.
바람직한 양태로서, 본 발명의 항암제 조성물은 폐암, 뇌암, 유방암, 대장암 또는 상피성 난소암의 억제 또는 치료에 유용하며, 특히 바람직하게는 상피성 난소암의 억제 또는 치료에 유용하다.In a preferred embodiment, the anticancer composition of the present invention is useful for the inhibition or treatment of lung cancer, brain cancer, breast cancer, colon cancer or epithelial ovarian cancer, particularly preferably for the inhibition or treatment of epithelial ovarian cancer.
본 발명의 항암제 조성물은 단독으로 사용할 수 있지만, 방사선 요법 또는 화학 요법(세포성장정지 또는 세포독성 물질, 항생물질형 물질, 알킬화제, 항대사성 물질, 호르몬제, 면역제, 인터페론형 물질, 사이클로옥시게나제 억제제(예를 들면, COX-2 억제제), 메탈로매트릭스프로테아제 억제제, 테로머라제 억제제, 티로신 키나제 억제제, 항성장인자수용체 물질, 항-HER 물질, 항-EGFR 물질, 항-혈관생성 물질, 파르네실 트랜스퍼라제 억제제, ras-raf 시그날 전도 경로 억제제, 세포 주기 억제제, 기타 cdk 억제제, 튜불린 결합제, 토포이소머라제 I 억제제, 토포이소머라제 II 억제제 등)과 같은 다른 항암 치료법과 병용하여 사용할 수 있다.The anticancer agent composition of the present invention can be used alone, but radiation therapy or chemotherapy (cell growth arrest or cytotoxic substance, antibiotic-type substance, alkylating agent, anti-metabolic substance, hormone, immune agent, interferon-type substance, cyclooxygena Agent inhibitors (eg, COX-2 inhibitors), metallomatrix protease inhibitors, teromerase inhibitors, tyrosine kinase inhibitors, anti-growth receptor substances, anti-HER substances, anti-EGFR substances, anti-angiogenic substances, Use in combination with other anticancer therapies such as farnesyl transferase inhibitors, ras-raf signal conduction pathway inhibitors, cell cycle inhibitors, other cdk inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like. Can be.
또한, 본 발명의 항암제 조성물은 리포좀 제제내에 임의로 함유된 하나 이상의 화학요법제제(예를 들면, 택산, 택산 유도체, 캡슐화 택산, CPT-11, 캠프토테신 유도체, 안트라사이클린 글리코사이드, 독소루비신, 이다루비신, 에피루비신, 에토포사이드, 나벨바인, 빈블라스틴, 카르보플라틴, 시스플라틴, 에스트라무스틴, 셀레콕시브, 슈겐 SU-5416, 슈겐 SU-6668, 헤르셉틴 등)와 병용하여 투여할 수도 있다.In addition, the anticancer composition of the present invention may include one or more chemotherapeutic agents optionally contained in liposome preparations (e.g., taxanes, taxane derivatives, encapsulated taxanes, CPT-11, camptothecin derivatives, anthracycline glycosides, doxorubicin, idarubicin). Leucine, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, schgen SU-5416, schgen SU-6668, herceptin and the like). have.
이러한 조합물을 일정한 용량으로 제형화하는 경우, 본 발명의 항암제 조성 물은 하기된 용량 범위내에서 사용하고 다른 약제학적 활성 물질은 승인된 용량 범위내에서 사용한다. 또한, 본 발명의 항암제 조성물은 조합 제제가 부적절할 경우 알려진 항암제와 순차적으로 사용할 수 있다.When formulating such combinations at constant doses, the anticancer agent compositions of the present invention are used within the following dosage ranges and other pharmaceutically active substances within the approved dosage ranges. In addition, the anticancer composition of the present invention can be used sequentially with known anticancer agents when the combination formulation is inappropriate.
상기 활성 성분과 약제학적으로 허용되는 담체 또는 희석제를 함유하는 본 발명의 항암제 조성물은 보통 통상적인 방법에 따라 제형화하고 약제학적으로 적합한 형태로 투여한다. 즉, 본 발명의 항암제 조성물은 여러 제형, 예를 들면 정제, 캡슐, 당의정 또는 필름 피막 정제, 액제 또는 현탁제의 경구 형태, 근육내, 정맥내 및/또는 척수강내 및/또는 척수내 주사 또는 주입의 비경구 형태로 제형화하여 투여할 수 있다.Anticancer compositions of the invention containing the active ingredient and a pharmaceutically acceptable carrier or diluent are usually formulated according to conventional methods and administered in a pharmaceutically suitable form. That is, the anticancer composition of the present invention may be administered in various formulations, such as tablets, capsules, dragees or film-encapsulated tablets, oral forms of liquids or suspensions, intramuscular, intravenous and / or intrathecal and / or spinal cord injections or infusions. It may be administered by formulating it in a parenteral form.
예를 들면, 본 발명의 조성물을 경구용 고형제로 제형화하는 경우, 활성 성분과 함께 희석제(예를 들면, 락토즈, 덱스트로즈, 자당, 셀룰로즈, 옥수수 전분 또는 감자 전분), 활탁제(예를 들면, 실리카, 탈크, 스테아린산, 마그네슘 또는 칼슘 스테아레이트 및/또는 폴리에틸렌 글리콜), 결합제(예를 들면, 전분, 아라빅 검, 젤라틴 메틸셀룰로즈, 카르복시메틸셀룰로즈 또는 폴리비닐 피롤리돈), 붕해제(예를 들면, 전분, 알긴산, 알기네이트 또는 나트륨 전분 글리콜레이트), 포르말 혼합물, 염료, 감미제, 습윤제(예를 들면, 레시틴, 폴리솔베이트, 라우릴설페이트) 및 일반적으로 약제에 사용되는 약물학적 불활성 물질을 함유할 수 있다. 이들 약제는 공지된 방법, 예를 들면 혼합, 과립화, 타정, 당의 또는 필름-피복 공정의 수단에 의해 제조할 수 있다.For example, when the compositions of the present invention are formulated as oral solids, diluents (e.g. lactose, dextrose, sucrose, cellulose, corn starch or potato starch), active agents (e.g. Silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol), binders (e.g., starch, arabic gum, gelatin methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone), disintegrants (E.g., starch, alginic acid, alginate or sodium starch glycolate), formal mixtures, dyes, sweeteners, wetting agents (e.g. lecithin, polysorbates, laurylsulfate) and drugs commonly used in pharmaceuticals It may contain a chemically inert substance. These agents can be prepared by known methods, for example by means of mixing, granulating, tableting, dragging or film-coating processes.
또한, 시럽, 유화액 및 현탁액 등의 경구 투여용 액체 분산액으로 제형화하 는 경우, 활성 성분과 함께 천연 검, 한천, 나트륨 알기네이트, 펙틴, 메틸셀룰로즈, 카르복시메틸셀룰로즈 또는 폴리비닐 알코올을 함유할 수 있다. In addition, when formulated as a liquid dispersion for oral administration such as syrups, emulsions and suspensions, it may contain natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol together with the active ingredient. .
또한, 근육내 주사를 위한 현탁액 또는 용액으로 제형화하는 경우, 활성 성분과 함께 멸균수, 올리브유, 에틸 올레에이트, 글리콜(예를 들면, 프로필렌 글리콜) 및 필요한 경우 적합한 양의 리도카인 하이드로클로라이드를 함유할 수 있다.In addition, when formulated as a suspension or solution for intramuscular injection, it may contain sterile water, olive oil, ethyl oleate, glycol (eg propylene glycol) and, if necessary, a suitable amount of lidocaine hydrochloride with the active ingredient. Can be.
또한, 정맥내 주사 또는 주입용 용액으로 제형화하는 경우, 활성 성분과 함께 멸균수를 함유하거나 바람직하게는 멸균, 수성, 등장성 염수 용액의 형태일 수 있거나 담체 프로필렌 글리콜을 함유할 수 있다.In addition, when formulated as a solution for intravenous injection or infusion, it may contain sterile water with the active ingredient or preferably in the form of a sterile, aqueous, isotonic saline solution or may contain carrier propylene glycol.
본 발명의 항암제 조성물의 치료 유효량은 환자의 연령, 성별, 적용부위, 투여회수, 투여시간, 제형, 보조제의 종류 등에 따라 변할 수 있지만, 주사제의 경우 일반적으로 50 내지 200㎎, 바람직하게는 100 내지 150㎎을 1일 1 내지 5회 투여하고, 경구 투여제의 경우 일반적으로 250 내지 1,000㎎, 바람직하게는 300 내지 500㎎을 1일 1 내지 5회 투여한다.The therapeutically effective amount of the anticancer agent composition of the present invention may vary depending on the age, sex, site of application, frequency of administration, time of administration, dosage form, type of adjuvant, etc., but in the case of injection, it is generally 50 to 200 mg, preferably 100 to 150 mg is administered 1 to 5 times a day, and in the case of oral administration, it is generally administered 250 to 1,000 mg, preferably 300 to 500
본 발명은 하기 실시예 및 실험예로 보다 구체적으로 예시될 것이다. 그러나 이들 실시예 및 실험예는 단지 본 발명의 구현예이며 본 발명의 범위를 한정하는 것이 아니다.
The invention will be more specifically illustrated by the following examples and experimental examples. However, these examples and experimental examples are only embodiments of the present invention and do not limit the scope of the present invention.
<실시예 1><Example 1>
주사제
Injection
구연산(Sigma, U.S.A.) 1중량%1% by weight citric acid (Sigma, U.S.A.)
10N 수산화나트륨 pH7 조정량10N sodium hydroxide pH7 adjustment amount
멸균수 100% 조성량
100% of sterile water
상기 성분들을 제시된 함량으로 배합하여 바이알(100㎎)에 충진하여 제조하였다.
The ingredients were combined in the amounts shown to prepare a vial (100 mg).
<실시예 2><Example 2>
주사제
Injection
구연산(Sigma, U.S.A.) 0.2중량%0.2 wt% citric acid (Sigma, U.S.A.)
L-아르기닌(Ajinomoto, Japan) 0.8중량%0.8% by weight of L-arginine (Ajinomoto, Japan)
10N 수산화나트륨 pH 7 조성량10N
멸균수 100% 조성량
100% of sterile water
상기 성분들을 제시된 함량으로 배합하여 바이알(100㎎)에 충진하여 제조하였다.
The ingredients were combined in the amounts shown to prepare a vial (100 mg).
<실시예 3><Example 3>
정제
refine
구연산(Sigma, U.S.A.) 1중량%1% by weight citric acid (Sigma, U.S.A.)
락토즈 30중량%Lactose 30% by weight
마그네슘 스테아레이트 5중량%Magnesium Stearate 5% by weight
나트륨 전분 글리콜레이트 10중량%10% by weight sodium starch glycolate
10N 수산화나트륨 pH 7 조성량10N
멸균수 100% 조성량
100% of sterile water
상기 성분들을 제시된 함량으로 혼합하여 30 내지 60℃로 유지하면서 1시간 동안 교반한 후, 실온으로 냉각시키고, 통상적인 정제의 제조 방법에 따라 타정하여 조성물 350㎎씩을 함유하는 정제를 제조하였다.
The ingredients were mixed in the indicated contents, stirred for 1 hour while maintaining at 30 to 60 ° C, cooled to room temperature, and compressed into tablets according to a conventional method for preparing tablets to prepare 350 mg of the composition.
<실시예 4><Example 4>
정제
refine
구연산(Sigma, U.S.A.) 0.2중량%0.2 wt% citric acid (Sigma, U.S.A.)
L-아르기닌(Ajinomoto, Japan) 0.8중량%0.8% by weight of L-arginine (Ajinomoto, Japan)
락토즈 30중량%Lactose 30% by weight
마그네슘 스테아레이트 5중량%Magnesium Stearate 5% by weight
나트륨 전분 글리콜레이트 10중량% 10% by weight sodium starch glycolate
10N 수산화나트륨 pH 7 조성량10N
멸균수 100% 조성량
100% of sterile water
상기 성분들을 제시된 함량으로 혼합하여 30 내지 60℃로 유지하면서 1시간 동안 교반한 후, 실온으로 냉각시키고, 통상적인 정제의 제조 방법에 따라 타정하여 조성물 350㎎씩을 함유하는 정제를 제조하였다.
The ingredients were mixed in the indicated contents, stirred for 1 hour while maintaining at 30 to 60 ° C, cooled to room temperature, and compressed into tablets according to a conventional method for preparing tablets to prepare 350 mg of the composition.
<실험예>Experimental Example
본 발명의 항암제 조성물 처리에 따른 세포 생존율의 측정
Measurement of Cell Viability According to Treatment of Anticancer Drug Composition of the Present Invention
본 발명의 항암제 조성물이 암세포의 성장과 생존에 미치는 영향을 조사하기 위해 활성 성분의 함량을 달리하여 제조한 조성물을 암세포주에 처리하여 세포 생존율을 측정하였다. 세포주로는 SKOV-3(사람 난소 아데노암종, ATCC 번호: HTB-77), OVCAR-3(사람 난소 아데노암종, ATCC 번호: HTB-161) 및 U87(사람 뇌 교모세포종, ATCC 번호: HTB-14)을 사용하였다.In order to investigate the effects of the anticancer agent composition of the present invention on the growth and survival of cancer cells, the cell viability was measured by treating the cancer cell line with a composition prepared by varying the content of the active ingredient. Cell lines include SKOV-3 (human ovarian adenocarcinoma, ATCC number: HTB-77), OVCAR-3 (human ovarian adenocarcinoma, ATCC number: HTB-161), and U87 (human brain glioblastoma, ATCC number: HTB-14 ) Was used.
상기 세포를 3×103 세포/웰(well)이 되도록 96-웰 평판에 넣은 다음 12시간 배양하였다. 배양 배지로는 열불활성화 FBS(fetal bovine serum, 소 태반 혈청) 10%(v/v), 스트렙토마이신 100㎍/㎖, 페니실린 100U/㎖ 및 L-글루타민 100㎍/㎖을 첨가한 DMEM(Dulbecco's modified Eagle's medium, Life Technology, Inc., USA)를 사용하였다. 배양한 각각의 세포주에 실시예 1 내지 2와 같은 방법으로 활성 성분 의 함량을 달리하여 제조한 조성물을 처리하고 분류한 후, 이를 37℃에서 이산화탄소 5% 및 산소 95%가 공급되는 상태에서 24시간 동안 배양한 다음 세포 생존율을 측정하였다.The cells were placed in 96-well plates to 3 × 10 3 cells / well and incubated for 12 hours. As culture medium, DMEM (Dulbecco's modified) was added 10% (v / v) of heat-inactivated FBS (fetal bovine serum), 100 μg / ml of streptomycin, 100 U / ml of penicillin and 100 μg / ml of L-glutamine. Eagle's medium, Life Technology, Inc., USA). Each cell line was cultured and treated with a composition prepared by varying the content of the active ingredient in the same manner as in Examples 1 and 2, and then, this was applied for 24 hours at 37 ° C. with 5% carbon dioxide and 95% oxygen. Incubated and then cell viability was measured.
세포 생존율은 공지된 MTT(3-(4,5-디메틸티아졸-2-yl)2,5-디페닐-2H-테트라조리움 브로미딘)검정법으로 측정하였다(Hansen, M.B. et al., J. Immunol. Methods, 172, 203-210 (1989)). 20㎕ MTT 용액[PBS(phosphate buffered saline, 인산염 완충 염수)중 10㎎/㎖인 MTT]을 각각의 웰에 첨가하였고, 평판을 37℃에서 4시간 배양하였다. 배지를 제거한 후, DMSO(dimethyl sufoxide, 디메틸 설폭시드) 200㎕에 포마잔(formazan) 결정을 용해시켜 각각의 웰에 첨가하였다. 이를 10분 동안 실온에서 흔들어 혼합하고, Bio-Rad 모델 3550 마이크로플레이트 리더(Microplate Reader, Richmond, CA.)를 사용하여 540㎚에서 측정하였다. 이때, DMEM-FBS와 MTT가 첨가되고 상기 조성물을 첨가하지 않은 웰을 대조군으로 사용하였다. 실험결과는 도 1, 도 2, 도 3 및 도 4에 나타내었다.Cell viability was measured by known MTT (3- (4,5-dimethylthiazole-2-yl) 2,5-diphenyl-2H-tetrazolium bromidine) assay (Hansen, MB et al., J Immunol.Methods, 172, 203-210 (1989). 20 μl MTT solution [MTT in 10 mg / ml in phosphate buffered saline (PBS)] was added to each well and the plate was incubated at 37 ° C. for 4 hours. After removing the medium, formazan crystals were dissolved in 200 µl of DMSO (dimethyl sufoxide, dimethyl sulfoxide) and added to each well. This was shaken for 10 minutes at room temperature and mixed and measured at 540 nm using a Bio-Rad Model 3550 Microplate Reader (Microplate Reader, Richmond, CA.). At this time, wells without DMEM-FBS and MTT added and the composition was used as a control. Experimental results are shown in FIGS. 1, 2, 3 and 4.
도 1 및 2로부터 알 수 있는 바와 같이, 구연산을 활성 성분으로 함유한 조성물을 처리한 세포주 SKOV-3 및 OVCAR-3의 생존율은 활성 성분인 구연산의 함량을 증가시켜 처리함에 따라 감소하였다. 특히, 구연산의 함량이 0.4중량% 이상인 경우에 생존율이 50%이하로 감소하였고 구연산의 함량이 0.6중량% 이상일 경우 생존율은 20% 이하로 감소하였다.As can be seen from Figures 1 and 2, the viability of cell lines SKOV-3 and OVCAR-3 treated with a composition containing citric acid as an active ingredient decreased with increasing content of citric acid as an active ingredient. In particular, when the content of citric acid is more than 0.4% by weight, the survival rate is reduced to less than 50%, and when the content of citric acid is more than 0.6% by weight the survival rate is reduced to less than 20%.
도 3 및 4로부터 알 수 있는 바와 같이, 구연산 및 L-아르기닌을 활성 성분으로 함유한 조성물을 처리한 세포주 SKOV-3 및 U87의 생존율은 활성 성분인 구연 산 및 L-아르기닌의 함량을 증가시켜 처리함에 따라 감소하였다. 특히, 구연산 및 L-아르기닌의 함량이 0.3중량% 이상인 경우에 생존율이 50% 이하로 감소하였고 구연산 및 L-아르기닌의 함량이 0.8중량% 이상인 경우에 생존율은 20% 이하로 감소하였다.
As can be seen from Figures 3 and 4, the viability of cell lines SKOV-3 and U87 treated with a composition containing citric acid and L-arginine as active ingredients was increased by increasing the contents of the active ingredients citric acid and L-arginine. As it decreases. In particular, when the content of citric acid and L-arginine is 0.3% by weight or more, the survival rate is reduced to 50% or less, and when the content of citric acid and L-arginine is 0.8% by weight or more, the survival rate is reduced to 20% or less.
<비교 실험예>Comparative Experimental Example
L-아르기닌 및 L-아스파라트산을 함유한 조성물 또는 L-아르기닌을 함유한 조성물의 처리에 따른 세포 생존율 측정
Determination of cell viability following treatment of a composition containing L-arginine and L-aspartic acid or a composition containing L-arginine
본 발명의 항암제 조성물을 처리한 암세포의 생존율과 비교를 위해 종래 항암효과가 알려진 성분으로서 L-아르기닌 및 L-아스파르트산(Ajinomoto, Japan)을 함유한 조성물 또는 L-아르기닌을 함유한 조성물을 암세포주에 처리하여 세포 생존율을 측정하였다. 세포주로는 SKOV-3을 사용하였고, 이들 세포의 배양, 상기 조성물을 암세포주에 처리하는 방법 및 세포 생존율 측정은 상기 실험 실시예와 같은 방법으로 실시하였다. 실험결과는 도 5 및 도 6에 나타내었다.For comparison with the survival rate of cancer cells treated with the anticancer agent composition of the present invention, a composition containing L-arginine and L-aspartic acid (Ajinomoto, Japan) or a composition containing L-arginine as a known anticancer effect is a cancer cell line. Cell viability was measured. SKOV-3 was used as the cell line, and the culture of these cells, the method of treating the composition with the cancer cell line, and cell viability were measured in the same manner as in the experimental example. Experimental results are shown in FIGS. 5 and 6.
도 5 및 6으로부터 알 수 있는 바와 같이, 상기 조성물을 처리한 세포주 SKOV-3의 생존율은 L-아르기닌 및 L-아스파르트산을 혼합한 함량 또는 L-아르기닌 함량의 증가에 따라 생존율이 감소하긴 하지만, 생존율은 50% 이상이었다.As can be seen from Figures 5 and 6, the survival rate of the cell line SKOV-3 treated with the composition, although the survival rate decreases with increasing L-arginine and L-aspartic acid content or L-arginine content, Survival was over 50%.
즉, 본 발명의 항암제 조성물을 처리한 암세포의 생존율과 비교하여 볼 때, 상기 비교 실험예의 결과는 효과적인 암세포의 생존율 저하를 나타내지 못했다.That is, when compared with the survival rate of the cancer cells treated with the anticancer agent composition of the present invention, the results of the comparative experimental example did not show a reduction in the effective survival rate of cancer cells.
상술한 바와 같이, 활성 성분으로서 구연산을 단독으로 함유하거나 또는 구연산 및 L-아르기닌을 함유하는 본 발명의 항암제 조성물은 세포사멸을 유도하여 암세포를 사멸시키는 효과를 나타낸다.As described above, the anticancer composition of the present invention containing citric acid as an active ingredient alone or containing citric acid and L-arginine exhibits the effect of inducing cell death and killing cancer cells.
Claims (6)
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KR1020020067291A KR100932520B1 (en) | 2002-10-31 | 2002-10-31 | Anticancer agent composition |
PCT/KR2003/000514 WO2003077899A1 (en) | 2002-03-16 | 2003-03-17 | Anticancer composition |
AU2003215935A AU2003215935A1 (en) | 2002-03-16 | 2003-03-17 | Anticancer composition |
US10/508,268 US7163919B2 (en) | 2002-03-16 | 2003-03-17 | Anticancer composition |
AU2003274800A AU2003274800A1 (en) | 2002-10-31 | 2003-10-31 | Anticancer or antiviral composition |
JP2004548147A JP4603891B2 (en) | 2002-10-31 | 2003-10-31 | Anticancer composition |
CNA2003801024520A CN1708310A (en) | 2002-10-31 | 2003-10-31 | Anticancer or antiviral composition |
US10/510,727 US20070166401A1 (en) | 2002-10-31 | 2003-10-31 | Anticancer or antiviral composition |
AT03759049T ATE401901T1 (en) | 2002-10-31 | 2003-10-31 | ANTICANCER AND ANTIVIRAL COMPOSITION |
PCT/KR2003/002324 WO2004039379A1 (en) | 2002-10-31 | 2003-10-31 | Anticancer or antiviral composition |
EP03759049A EP1565195B1 (en) | 2002-10-31 | 2003-10-31 | Anticancer or antiviral composition |
DE60322415T DE60322415D1 (en) | 2002-10-31 | 2003-10-31 | ANTIQUE AND ANTIVIRAL COMPOSITION |
US12/247,896 US20090226538A1 (en) | 2002-10-31 | 2008-10-08 | Anticancer or antiviral composition |
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