KR102645036B1 - Composition for diagnosing anti-cancer medicine resistance and kit comprising the same - Google Patents
Composition for diagnosing anti-cancer medicine resistance and kit comprising the same Download PDFInfo
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- KR102645036B1 KR102645036B1 KR1020190130926A KR20190130926A KR102645036B1 KR 102645036 B1 KR102645036 B1 KR 102645036B1 KR 1020190130926 A KR1020190130926 A KR 1020190130926A KR 20190130926 A KR20190130926 A KR 20190130926A KR 102645036 B1 KR102645036 B1 KR 102645036B1
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Abstract
본 발명은 항암제 내성 진단을 위한 조성물 및 키트에 관한 것으로, 본 발명의 조성물, 키트 및 방법은 항암제의 치료 반응성을 효과적으로 예측할 수 있으며, 암 환자에 대한 선택적, 개별적 항암제 치료가 가능하게 한다.The present invention relates to a composition and kit for diagnosing anticancer drug resistance. The composition, kit, and method of the present invention can effectively predict treatment responsiveness to an anticancer drug and enable selective and individualized anticancer drug treatment for cancer patients.
Description
본 발명은 항암제 내성 진단용 조성물 및 이를 포함하는 키트에 관한 것이다.The present invention relates to a composition for diagnosing anticancer drug resistance and a kit containing the same.
항암화학요법은 일반적으로 인체에 독성 부작용을 유발하고 경제적인면에서도 비용이 많이 드는 고가의 치료이다. 특히 실제 항암제 치료에 의해 유의한 생존율의 향상은 극히 소수의 환자에서만 관찰되기 때문에 최근에는 환자의 개별치료(Personalized therapy)적 관점에서 항암제에 반응하는 환자군을 선별해 내려는 노력이 진행중이다. Chemotherapy is an expensive treatment that generally causes toxic side effects in the human body and is economically expensive. In particular, because significant improvement in survival rate due to actual anticancer drug treatment is observed only in a very small number of patients, recent efforts are underway to select patient groups that respond to anticancer drugs from the perspective of individualized therapy.
예를 들어, 유방암 환자의 예후인자들을 이용한 상용화된 키트인 Mammaprint나 OncotypeDx는 조기유방암 환자 중 항암화학요법이 필요한 나쁜 예후를 가진 환자군을 선별하려는 연구의 대표적인 결과이다.For example, Mammaprint or OncotypeDx, commercialized kits using prognostic factors for breast cancer patients, are representative results of research to select patients with poor prognosis who require chemotherapy among patients with early breast cancer.
최근에는 보다 빠른 시기에 수술전항암화학요법의 유효성을 확인할 수 있는 항암제 사용 직후의 변화 물질(acquired resistance related marker)이나 종양에 내재 되어 있는 항암제 반응/내성 관련 물질(intrinsic resistance related marker)을 발굴하기 위한 다양한 시도가 이루어지고 있으며, 이러한 연구들은 대부분 수술 전 항암화학요법 플랫폼(plarform)에서 이루어지고 있다.Recently, discoveries have been made to identify substances that change immediately after the use of anticancer drugs (acquired resistance related markers) or substances related to anticancer drug response/resistance inherent in the tumor (intrinsic resistance related markers) that can confirm the effectiveness of preoperative chemotherapy at an earlier stage. Various attempts are being made for this purpose, and most of these studies are being conducted on a preoperative chemotherapy platform.
이에, 암의 치료에 있어서, 항암제의 치료 반응성 등을 예측하는데 이용할 수 있는 새로운 표적에 대한 개발이 필요한 실정이고, 이에 대한 연구가 이루어지고 있으나 아직 미미한 수준이다.Accordingly, in the treatment of cancer, there is a need to develop new targets that can be used to predict treatment responsiveness of anticancer drugs, and although research on this is being conducted, it is still at a minimal level.
본 발명은 항암제 내성 진단을 위한 조성물 및 키트을 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a composition and kit for diagnosing anticancer drug resistance.
본 발명은 항암제 내성 진단을 위한 정보제공방법을 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a method for providing information for diagnosing anticancer drug resistance.
본 발명은 항암제 내성 억제제 후보물질의 스크리닝 방법을 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a screening method for candidate anticancer drug resistance inhibitors.
본 발명은 항암제 내성 억제용 약학적 조성물을 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a pharmaceutical composition for suppressing anticancer drug resistance.
1. NMI(N-Myc interator) mRNA 또는 그 단백질에 특이적으로 결합하는 물질을 포함하는 항암제 내성 진단용 조성물.1. A composition for diagnosing anticancer drug resistance containing a substance that specifically binds to NMI (N-Myc interator) mRNA or its protein.
2. 위 1에 있어서, 상기 물질은 항체, 압타머, DNA, RNA, 단백질, 폴리펩티드로 이루어진 군에서 선택되는 적어도 하나인, 조성물.2. The composition of 1 above, wherein the substance is at least one selected from the group consisting of antibodies, aptamers, DNA, RNA, proteins, and polypeptides.
3. 위 1에 있어서, 상기 항암제는 도세탁셀(doxetaxel), 파클리탁셀(paclitaxel), 독소루비신(doxorubicin), 시클로포스파미드(cyclophosphamide) 및 타목시펜(tamoxifen)으로 이루어진 군에서 선택되는 것인, 조성물.3. The composition of 1 above, wherein the anticancer agent is selected from the group consisting of doxetaxel, paclitaxel, doxorubicin, cyclophosphamide, and tamoxifen.
4. 위 1 내지 3 중 어느 한 항의 조성물을 포함하는 항암제 내성 진단용 키트.4. A kit for diagnosing anticancer drug resistance containing the composition of any one of items 1 to 3 above.
5. 진단 대상으로부터 분리된 시료 내의 NMI(N-Myc interator) mRNA 또는 그 단백질의 발현 수준을 측정하는 단계를 포함하는 항암제 내성 진단을 위한 정보제공방법.5. A method of providing information for the diagnosis of anticancer drug resistance, including the step of measuring the expression level of NMI (N-Myc interator) mRNA or its protein in a sample isolated from a diagnostic subject.
6. 위 5에 있어서, 상기 진단 대상은 유방암 환자인, 방법.6. The method of 5 above, wherein the diagnosis subject is a breast cancer patient.
7. 위 5에 있어서, 상기 시료는 조직, 세포, 혈액, 혈청, 혈장, 타액 또는 뇨로 이루어진 군으로부터 선택되는 것인, 방법.7. The method of 5 above, wherein the sample is selected from the group consisting of tissue, cells, blood, serum, plasma, saliva, or urine.
8. 위 5에 있어서, 상기 항암제는 도세탁셀(doxetaxel), 파클리탁셀(paclitaxel), 독소루비신(doxorubicin), 시클로포스파미드(cyclophosphamide) 및 타목시펜(tamoxifen)으로 이루어진 군에서 선택되는 것인, 방법.8. The method of 5 above, wherein the anticancer agent is selected from the group consisting of doxetaxel, paclitaxel, doxorubicin, cyclophosphamide, and tamoxifen.
9. 진단 대상으로부터 분리된 시료 내의 NMI(N-Myc interator) mRNA 또는 그 단백질의 발현을 감소시키는 물질을 선별하는 단계를 포함하는 항암제 내성 억제제 후보물질의 스크리닝 방법.9. A screening method for an anticancer drug resistance inhibitor candidate comprising the step of selecting a substance that reduces the expression of NMI (N-Myc interator) mRNA or its protein in a sample isolated from a diagnostic subject.
10. 위 9에 있어서, 상기 진단 대상은 유방암 환자인, 방법.10. The method of item 9 above, wherein the diagnosis subject is a breast cancer patient.
11. 위 9에 있어서, 상기 시료는 조직, 세포, 혈액, 혈청, 혈장, 타액 또는 뇨로 이루어진 군으로부터 선택되는 것인, 방법.11. The method of item 9 above, wherein the sample is selected from the group consisting of tissue, cells, blood, serum, plasma, saliva, or urine.
12. 위 9에 있어서, 상기 항암제는 도세탁셀(doxetaxel), 파클리탁셀(paclitaxel), 독소루비신(doxorubicin), 시클로포스파미드(cyclophosphamide) 및 타목시펜(tamoxifen)으로 이루어진 군에서 선택되는 것인, 방법.12. The method of item 9 above, wherein the anticancer agent is selected from the group consisting of doxetaxel, paclitaxel, doxorubicin, cyclophosphamide, and tamoxifen.
13. NMI(N-Myc interator) mRNA 또는 그 단백질의 발현을 감소시키는 물질을 포함하는 항암제 내성 억제용 약학적 조성물.13. A pharmaceutical composition for suppressing anticancer drug resistance containing a substance that reduces the expression of NMI (N-Myc interator) mRNA or its protein.
14. 위 13에 있어서, 상기 물질은 저분자량 약물, 유전자 약물, 단백질 약물, 추출물, 핵산, 올리고뉴클레오티드, 단백질, 펩타이드, 항체, RNA, DNA, PNA, 압타머, 화학약품, 효소, 아미노산, 당, 지질로 이루어진 군에서 선택된 적어도 하나인, 조성물.14. In item 13 above, the substances include low molecular weight drugs, gene drugs, protein drugs, extracts, nucleic acids, oligonucleotides, proteins, peptides, antibodies, RNA, DNA, PNA, aptamers, chemicals, enzymes, amino acids, and sugars. , a composition that is at least one selected from the group consisting of lipids.
15. 위 13에 있어서, 상기 물질은 NRF2(Nuclear factor erythroid 2-related factor 2) 억제제인, 조성물.15. The composition of item 13 above, wherein the substance is a Nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor.
16. 위 13에 있어서, 상기 항암제는 도세탁셀(doxetaxel), 파클리탁셀(paclitaxel), 독소루비신(doxorubicin), 시클로포스파미드(cyclophosphamide) 및 타목시펜(tamoxifen)으로 이루어진 군에서 선택되는 것인, 조성물.16. The composition of item 13 above, wherein the anticancer agent is selected from the group consisting of doxetaxel, paclitaxel, doxorubicin, cyclophosphamide, and tamoxifen.
본 발명은 항암제 내성 진단을 위한 조성물 및 키트에 관한 것으로, 본 발명의 조성물, 키트 및 방법은 항암제의 치료 반응성을 효과적으로 예측할 수 있으며, 암 환자에 대한 선택적, 개별적 항암제 치료가 가능하게 한다.The present invention relates to a composition and kit for diagnosing anticancer drug resistance. The composition, kit, and method of the present invention can effectively predict treatment responsiveness to an anticancer drug and enable selective and individualized anticancer drug treatment for cancer patients.
도 1A는 완전 관해(complete response)와 비관해(non-complete response) 환자군에서 NMI 발현을 IHC score로 확인한 도이고, 도 1B는 항암제 내성이 있는 유방암 환자의 암 조직의 면역조직화학염색 결과로서, 갈색 부분이 NMI 발현을 나타내는 것이다.
도 2는 NMI 발현 억제에 따른 약물 반응도를 확인한 도이다.
도 3은 NMI 발현 억제에 따른 타목시펜(tamoxifen) 반응도를 나타낸 도이다.
도 4는 NMI 발현 억제에 따른 spheroids 형성 능력을 확인한 도이다.
도 5는 ML385(NRF2 억제제)에 의한 NMI 발현 억제 효능을 확인한 도이다.Figure 1A is a diagram confirming the expression of NMI by IHC score in the complete response and non-complete response patient groups, and Figure 1B is the result of immunohistochemical staining of cancer tissue of a breast cancer patient with anticancer drug resistance. The brown area indicates NMI expression.
Figure 2 is a diagram confirming drug responsiveness according to inhibition of NMI expression.
Figure 3 is a diagram showing tamoxifen responsiveness according to inhibition of NMI expression.
Figure 4 is a diagram confirming the ability to form spheroids due to inhibition of NMI expression.
Figure 5 is a diagram confirming the efficacy of inhibiting NMI expression by ML385 (NRF2 inhibitor).
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 NMI(N-myc interactor) mRNA 또는 그 단백질에 특이적으로 결합하는 물질을 포함하는 항암제 내성 진단용 조성물을 제공한다.The present invention provides a composition for diagnosing anticancer drug resistance containing a substance that specifically binds to NMI (N-myc interactor) mRNA or its protein.
NMI는 진단 대상 유래 시료에 존재하는 것으로서, 그 mRNA 또는 단백질 서열은 NCBI genbank 등에 공지된 서열을 활용할 수 있다. 예를 들어, 인간의 경우 NMI mRNA는 서열번호 1의 서열, 단백질은 서열번호 2의 서열일 수 있다. 서열은 이에 한정되지 않고, 진단 대상이 되는 개체 종의 서열을 사용할 수 있다.NMI is present in a sample derived from a diagnostic target, and its mRNA or protein sequence can be a known sequence in NCBI genbank, etc. For example, in the case of humans, NMI mRNA may have the sequence of SEQ ID NO: 1, and the protein may have the sequence of SEQ ID NO: 2. The sequence is not limited to this, and the sequence of the individual species to be diagnosed can be used.
상기 진단 대상은 현재 암을 보유하고 있거나, 암을 보유한 경험이 있는 동물, 암의 보유가 의심되는 동물, 그 외 항암제 내성 진단을 위한 정보를 제공받고자 하는 동물 등으로서, 상기 동물은 인간을 포함한 포유류일 수 있다.The diagnostic subjects include animals that currently have cancer or have had cancer, animals that are suspected of having cancer, and other animals for which information for anticancer drug resistance diagnosis is requested. The animals include mammals, including humans. It can be.
상기 암은 유방암, 간암, 폐암, 방광암, 위암, 자궁암, 대장암, 결장암, 혈액암, 난소암, 전립선암, 이자암, 지라암, 고환암, 흉선암, 뇌암, 식도암, 신장암, 담도암, 난소암, 신장암, 갑상선암 또는 피부암 중 선택되는 적어도 하나일 수 있고, 바람직하게는 유방암일 수 있으나, 이에 제한되는 것은 아니다.The above cancers include breast cancer, liver cancer, lung cancer, bladder cancer, stomach cancer, uterine cancer, colon cancer, colon cancer, blood cancer, ovarian cancer, prostate cancer, pancreas cancer, spleen cancer, testicular cancer, thymus cancer, brain cancer, esophagus cancer, kidney cancer, biliary tract cancer, It may be at least one selected from ovarian cancer, kidney cancer, thyroid cancer, or skin cancer, and preferably breast cancer, but is not limited thereto.
상기 시료는 진단 대상으로부터 분리된 것으로서, 그 예로는 조직, 세포, 혈액, 혈청, 혈장, 타액 또는 뇨일수 있고, 구체적으로는 진단 대상으로부터 분리된 암 조직일 수 있으나, 이에 제한되는 것은 아니다.The sample is separated from the diagnostic object, and may be, for example, tissue, cells, blood, serum, plasma, saliva, or urine. Specifically, it may be cancer tissue separated from the diagnostic object, but is not limited thereto.
상기 물질은 진단 대상으로부터 분리된 시료에서 상기 NMI mRNA 또는 그 단백질을 검출하는 물질일 수 잇다.The substance may be a substance that detects the NMI mRNA or its protein in a sample isolated from a diagnostic subject.
상기 물질은 NMI mRNA 또는 그 단백질을 검출할 수 있다면 제한되지 않으나, 예를 들면 항체, 압타머, DNA, 단백질, 폴리펩티드로 이루어진 군에서 선택되는 하나일 수 있다.The substance is not limited as long as it can detect NMI mRNA or its protein, but may be, for example, one selected from the group consisting of antibodies, aptamers, DNA, proteins, and polypeptides.
본원에서, "항체"란 항원성 부위에 특이적인 단백질 분자를 의미한다. 본원의 목적상, 항체는 상기 마커 단백질인 NMI에 특이적으로 결합하는 항체를 의미하며, 모노클로날 항체, 폴리클로날 항체 및 재조합 항체를 모두 포함할 수 있다.As used herein, “antibody” refers to a protein molecule specific for an antigenic site. For the purposes of the present application, an antibody refers to an antibody that specifically binds to NMI, the marker protein, and may include all monoclonal antibodies, polyclonal antibodies, and recombinant antibodies.
상기 모노클로날 항체는 당해 분야에 널리 공지된 하이브리도마 방법, 또는 파지 항체 라이브러리기술을 이용하여 제조될 수 있으나, 이에 제한되지 않을 수 있다.The monoclonal antibody may be produced using a hybridoma method or phage antibody library technology well known in the art, but may not be limited thereto.
상기 폴리클로날 항체는 상기한 단백질 항원을 동물에 주사하고 동물로부터 채혈하여 항체를 포함하는 혈청을 수득하는 것을 포함하는, 당해 분야에 널리 공지된 방법에 의해 생산할 수 있다. 이러한 폴리클로날 항체는 염소, 토끼, 양, 원숭이, 말, 돼지, 소, 개 등의 임의의 동물 종 숙주로부터 제조 가능하나, 이에 제한되지 않을 수 있다.The polyclonal antibody can be produced by a method well known in the art, which includes injecting the protein antigen into an animal and collecting blood from the animal to obtain serum containing the antibody. These polyclonal antibodies can be produced from any animal species host such as goat, rabbit, sheep, monkey, horse, pig, cow, dog, etc., but may not be limited thereto.
또한, 본원의 항체에는 키메라 항체, 인간화 항체, 인간항체 등의 특수항체도 포함될 수 있다.In addition, the antibodies herein may also include special antibodies such as chimeric antibodies, humanized antibodies, and human antibodies.
상기 "펩티드"는 표적 물질에 대한 결합력 높은 장점이 있으며, 열/화학 처리시에도 변성이 일어나지 않는다. 또한 분자 크기가 작기 때문에 다른 단백질에 붙여서 융합 단백질로의 이용이 가능하다. 구체적으로 고분자 단백질 체인에 붙여서 이용이 가능하므로 진단 키트 및 약물전달 물질로 이용될 수 있다.The “peptide” has the advantage of high binding capacity to the target substance and does not undergo denaturation even during heat/chemical treatment. Additionally, because the molecule size is small, it can be used as a fusion protein by attaching it to another protein. Specifically, it can be used by attaching it to a polymer protein chain, so it can be used as a diagnostic kit and drug delivery material.
상기 "앱타머(aptamer)"란, 그 자체로 안정된 삼차 구조를 가지면서 표적 분자에 높은 친화성과 특이성으로 결합할 수 있는 특징을 가진 특별한 종류의 단일가닥 핵산(DNA, RNA 또는 변형핵산)으로 구성된 폴리뉴클레오티드의 일종을 의미한다. 상술한 바와 같이, 앱타머는 항체와 동일하게 항원성 물질에 특이적으로 결합할 수 있으면서도, 단백질보다 안정성이 높고, 구조가 간단하며, 합성이 용이한 폴리뉴클레오티드로 구성되어 있으므로, 항체를 대체하여 사용될 수 있다.The "aptamer" refers to a special type of single-stranded nucleic acid (DNA, RNA or modified nucleic acid) that has a stable tertiary structure and is capable of binding to a target molecule with high affinity and specificity. It refers to a type of polynucleotide. As mentioned above, aptamers can specifically bind to antigenic substances in the same way as antibodies, but are composed of polynucleotides that are more stable than proteins, have a simpler structure, and are easier to synthesize, so they can be used as a replacement for antibodies. You can.
상기 mRNA에 특이적으로 결합하는 물질은 센스 및 안티센스 프라이머, 또는 프로브일 수 있으나, 이에 제한되는 것은 아니다.Substances that specifically bind to the mRNA may be sense and antisense primers, or probes, but are not limited thereto.
본 발명에서 '프라이머'란 DNA 합성의 기시점이 되는 짧은 유전자 서열로써, 진단, DNA 시퀀싱 등에 이용할 목적으로 합성된 올리고뉴클레오티드를 의미한다. 상기 프라이머들은 통상적으로 15 내지 30 염기쌍의 길이로 합성하여 사용할 수 있으나, 사용 목적에 따라 달라질 수 있으며, 공지된 방법으로 메틸화, 캡화 등으로 변형시킬 수 있다.In the present invention, 'primer' refers to a short gene sequence that serves as the starting point for DNA synthesis and an oligonucleotide synthesized for use in diagnosis, DNA sequencing, etc. The primers can generally be synthesized and used in a length of 15 to 30 base pairs, but may vary depending on the purpose of use, and can be modified by methylation, capping, etc. by known methods.
본 발명에서 "프로브"란 효소 화학적인 분리정제 또는 합성과정을 거쳐 제작된 수 염기 내지 수백 염기길이의 mRNA와 특이적으로 결합할 수 있는 핵산을 의미한다. 방사성 동위원소나 효소 등을 표지하여 mRNA의 존재 유무를 확인할 수 있으며, 공지된 방법으로 디자인하고 변형시켜 사용할 수 있다.In the present invention, “probe” refers to a nucleic acid that can specifically bind to mRNA of a few bases to several hundred bases in length, produced through enzyme-chemical separation purification or synthesis. The presence or absence of mRNA can be confirmed by labeling it with a radioactive isotope or enzyme, and it can be designed, modified and used by known methods.
상기 NMI를 코딩하는 유전자의 뉴클레오티드 서열, 상기 뉴클레오티드 서열에 상보적인 서열 또는 상기 뉴클레오티드의 단편에 특이적으로 결합하는 프로브 또는 프라이머는 NMI를 코딩하는 유전자의 뉴클레오티드 서열이 알려져 있으므로, 당업자는 상기 서열을 바탕으로 상기 프라이머 또는 프로브를 당해 기술분야의 통상적인 방법에 따라 디자인할 수 있다.Since the nucleotide sequence of the gene encoding the NMI is known, a probe or primer that specifically binds to the nucleotide sequence of the gene encoding the NMI, a sequence complementary to the nucleotide sequence, or a fragment of the nucleotide sequence, those skilled in the art will use the sequence as the basis. The primer or probe can be designed according to conventional methods in the art.
상기 항암제는 암을 치료하는 효과가 있는 약물이면 제한없이 이용가능하며, 알킬화제(alkylating agents), 대사길항제(antimetabolites, 항대사제), 항암성 항생물질(antitumor antibiotics), 안트라사이클린(anthracyclines), 식물 알칼로이드, 토포아이소머라아제 저해제(topoisomerase inhibitors), 단일클론 항체(monoclonal antibodies), 항종양 호르몬제, 방추체 억제제(mitotic spindle inhibitor)를 포함할 수 있고, 구체적으로는 도세탁셀(doxetaxel), 파클리탁셀(paclitaxel), 독소루비신(doxorubicin), 시클로포스파미드(cyclophosphamide) 및 타목시펜(tamoxifen)으로 이루어진 군에서 선택되는 것일 수 있다.The anticancer drugs can be used without limitation as long as they are effective in treating cancer, and include alkylating agents, antimetabolites, antitumor antibiotics, anthracyclines, and plant alkaloids. , topoisomerase inhibitors, monoclonal antibodies, anti-tumor hormones, and mitotic spindle inhibitors, specifically doxetaxel and paclitaxel. , doxorubicin, cyclophosphamide, and tamoxifen.
본 발명의 조성물은 항암제 투약이 대상 환자에서 암의 치료에 유용할 수 있는지의 여부를 투약 전에 예측하는데 사용하기 위한 물질로서, 진단 대상으로부터 분리된 시료에 처리하여 시료 내의 NMI mRNA 또는 단백질의 발현 수준을 측정하여 항암제에 대한 반응성을 예측하는데 사용될 수 있다.The composition of the present invention is a substance used to predict before administration whether anticancer drug administration may be useful in the treatment of cancer in a target patient, and is treated with a sample isolated from a diagnostic target to determine the expression level of NMI mRNA or protein in the sample. can be used to predict reactivity to anticancer drugs by measuring .
예를 들어, 항암제 내성 의심환자의 시료 내의 NMI mRNA 또는 그 단백질의 발현량과 항암제 투여 후 완전 관해(complete response) 환자의 발현량을 비교하여 의심환자의 NMI 발현량이 완전 관해 환자의 NMI 발현량에 비해 높은 경우 완전 관해 환자에 비해 항암제 내성이 있다고 판단할 수 있다. For example, by comparing the expression level of NMI mRNA or its protein in the sample of a patient suspected of anticancer drug resistance with the expression level of a patient in complete response after anticancer drug administration, the NMI expression level in the suspected patient is compared to the NMI expression level in the complete response patient. If it is high, it can be judged to be resistant to anticancer drugs compared to patients in complete remission.
본 발명은 상기 조성물을 포함하는 항암제 내성 진단용 키트를 제공한다.The present invention provides a kit for diagnosing anticancer drug resistance comprising the composition.
상기 키트는 NMI mRNA 또는 그 단백질에 특이적으로 결합하는 물질을 포함할 뿐만 아니라, 그 키트가 이용하는 NMI mRNA 또는 그 단백질 발현량을 측정하는 분석방법에 적합한 하나 이상의 다른 구성 성분 조성물, 용액 또는 장치를 포함할 수 있다.The kit not only contains a material that specifically binds to NMI mRNA or its protein, but also includes one or more other components, compositions, solutions, or devices suitable for the analytical method for measuring the expression level of NMI mRNA or its protein used in the kit. It can be included.
상기 키트는 NMI mRNA 또는 단백질의 발현량을 측정하기 위한 키트일 경우, RT-PCR을 수행하기 위해 필요한 필수 요소를 포함하는 키트일 수 있다. RT-PCR 키트는 마커 유전자의 mRNA에 대한 특이적인 각각의 프라이머 쌍 이외에도 테스트 튜브 또는 다른 적절한 컨테이너, 반응 완충액, 데옥시리보뉴클레오티드(dNTPs), Taq-폴리머라제 및 역전사효소와 같은 효소, DNase, RNase 억제제, DEPC-수(dEPC water), 멸균수 등을 포함할 수 있다. 또한, 정량 대조군으로 사용되는 유전자에 특이적인 프라이머 쌍을 포함할 수 있다.If the kit is for measuring the expression level of NMI mRNA or protein, it may be a kit containing the essential elements necessary to perform RT-PCR. In addition to each pair of primers specific for the mRNA of the marker gene, the RT-PCR kit also contains test tubes or other suitable containers, reaction buffer, deoxyribonucleotides (dNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNase, and RNase. It may include inhibitors, DEPC-water (dEPC water), sterilized water, etc. Additionally, it may include a pair of primers specific to the gene used as a quantitative control.
상기 키트는 NMI를 코딩하는 유전자의 뉴클레오티드 서열, 상기 뉴클레오티드 서열에 상보적인 서열, 상기 뉴클레오티드의 단편 또는 상기 뉴클레오티드 서열에 의해 코딩되는 단백질에 특이적으로 결합하는 물질의 면역학적 검출을 위하여 기질, 적합한 완충용액, 발색 효소 또는 형광물질로 표지된 2차 항체, 발색 기질을 포함할 수 있다. 상기 기질은 니트로셀룰로오스 막, 폴리비닐 수지로 합성된 96 웰 플레이트, 폴리스티렌 수지로 합성된 96 웰 플레이트 및 유리 슬라이드 글라스 등이 이용될 수 있고, 발색효소는 퍼옥시다아제(peroxidase), 알칼라인 포스파타아제(alkaline phosphatase)가 사용될 수 있고, 형광물질은 FITC, RITC 등이 사용될 수 있고, 발색 기질은 2,2'-아지노-비스(3-에틸벤조티아졸린-6-설폰산)(ABTS) 또는 o-페닐렌디아민(OPD), 테트라메틸 벤지딘(TMB) 등이 사용될 수 있다.The kit includes a substrate, a suitable buffer, and a suitable buffer for the immunological detection of a substance that specifically binds to the nucleotide sequence of the gene encoding NMI, a sequence complementary to the nucleotide sequence, a fragment of the nucleotide, or a protein encoded by the nucleotide sequence. It may include a solution, a secondary antibody labeled with a chromogenic enzyme or a fluorescent substance, and a chromogenic substrate. The substrate may be a nitrocellulose membrane, a 96-well plate synthesized from polyvinyl resin, a 96-well plate synthesized from polystyrene resin, and a glass slide glass, and the coloring enzyme may be peroxidase, alkaline phosphatase ( alkaline phosphatase) can be used, the fluorescent substance can be FITC, RITC, etc., and the chromogenic substrate is 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) or o- Phenylenediamine (OPD), tetramethyl benzidine (TMB), etc. may be used.
상기 키트는 NMI mRNA의 발현량을 측정할 수 있는 항암제 내성 진단용 마이크로어레이(microarray)일 수 있다. 상기 마이크로어레이는 상기 지표인자를 이용하여 당해 기술분야에 공지된 방법에 따라 당업자가 용이하게 제조할 수 있으며, 일 구체예에 따르면 상기 SIRT1, SIRT3 또는 SIRT6 단백질을 코딩하는 유전자의 mRNA 또는 그의 단편에 해당하는 서열의 cDNA가 프로브로서 기판에 부착되어 있는 마이크로어레이일 수 있다.The kit may be a microarray for diagnosing anticancer drug resistance that can measure the expression level of NMI mRNA. The microarray can be easily prepared by a person skilled in the art according to methods known in the art using the indicator factors, and according to one embodiment, the mRNA of the gene encoding the SIRT1, SIRT3 or SIRT6 protein or a fragment thereof It may be a microarray in which cDNA of the corresponding sequence is attached to a substrate as a probe.
또한, 본원의 키트는 마커 성분에 특이적으로 결합하는 항체, 기질과의 반응에 의해서 발색하는 표지체가 접합된 2차 항체 접합체(conjugate), 상기 표지체와 발색 반응할 발색 기질 용액, 세척액 및 효소반응 정지용액 등을 포함할 수 있으며, 사용되는 시약 성분을 포함하는 다수의 별도 패키징 또는 컴파트먼트로 제작될 수 있으나, 이에 제한되지 않을 수 있다.In addition, the kit of the present application includes an antibody that specifically binds to the marker component, a secondary antibody conjugate conjugated with a label that develops color by reaction with the substrate, a color-generating substrate solution to react color with the label, a washing solution, and an enzyme. It may contain a reaction stopping solution, etc., and may be manufactured into a number of separate packaging or compartments containing the reagent components used, but may not be limited thereto.
본원의 키트는 환자 시료 내 NMI mRNA 또는 그 단백질의 발현 수준을 측정할 수 있는 제제뿐만 아니라, 발현 수준 분석에 적합한 한 종류 이상의 조성물, 용액 또는 장치를 포함할 수 있다. 예를 들어, 상기 키트는 항체의 면역학적 검출을 위하여 기질, 적당한 완충용액, 검출 라벨로 표지된 2차 항체, 및 발색 기질 등을 포함할 수 있으나, 이에 제한되지 않을 수 있다.The kit herein may include not only an agent capable of measuring the expression level of NMI mRNA or its protein in a patient sample, but also one or more types of compositions, solutions, or devices suitable for expression level analysis. For example, the kit may include a substrate, an appropriate buffer solution, a secondary antibody labeled with a detection label, and a chromogenic substrate for immunological detection of an antibody, but may not be limited thereto.
구체적인 일례로, 상기 키트는 ELISA 키트, 샌드위치 ELISA등 다양한 ELISA 방법을 구현하기 위하여, ELISA를 수행하기 위해 필요한 필수 요소를 포함하는 것을 특징으로 하는 키트일 수 있다. 이러한 ELISA 키트는 상기 단백질들에 대한 특이적인 항체를 포함한다. 항체는 NMI에 대한 특이성 및 친화성이 높고 다른 단백질에 교차 반응성이 거의 없는 항체로, 모노클로날 항체, 폴리클로날 항체 또는 재조합 항체일 수 있다. 또한 ELISA 키트는 대조군 단백질에 특이적인 항체를 포함할 수 있다. 그 외 ELISA 키트는 결합된 항체를 검출할 수 있는 시약, 예를 들면, 표지된 2차 항체, 발색단(chromopores), 효소 및 그의 기질 또는 항체와 결합할 수 있는 다른 물질 등을 포함할 수 있으나, 이에 제한되지 않을 수 있다.As a specific example, the kit may be a kit characterized by including essential elements required to perform ELISA in order to implement various ELISA methods such as ELISA kit and sandwich ELISA. These ELISA kits contain specific antibodies against the above proteins. The antibody is an antibody with high specificity and affinity for NMI and little cross-reactivity to other proteins, and may be a monoclonal antibody, polyclonal antibody, or recombinant antibody. Additionally, ELISA kits may include antibodies specific for control proteins. Other ELISA kits may include reagents capable of detecting bound antibodies, such as labeled secondary antibodies, chromophores, enzymes and their substrates, or other substances capable of binding to antibodies. It may not be limited to this.
이 외에도, 상기 키트는 웨스턴 블롯, 면역침전분석법, 보체 고정 분석법, 유세포분석, 또는 단백질 칩 등을 구현하기 위한 키트일 수 있으며, 각 분석 방법에 적합한 부가적인 구성을 추가로 포함할 수 있다. 이 분석 방법들을 통하여, 항원-항체 복합체 형성량을 비교함으로써 항암제 내성을 진단할 수 있다.In addition, the kit may be a kit for implementing Western blot, immunoprecipitation analysis, complement fixation analysis, flow cytometry, or protein chip, and may further include additional components suitable for each analysis method. Through these analysis methods, anticancer drug resistance can be diagnosed by comparing the amount of antigen-antibody complex formation.
진단 대상으로부터 분리된 시료 내의 NMI(N-Myc interator) mRNA 또는 그 단백질의 발현 수준을 측정하는 단계를 포함하는 항암제 내성 진단을 위한 정보제공방법을 제공한다.Provides an information provision method for diagnosing anticancer drug resistance, including the step of measuring the expression level of NMI (N-Myc interator) mRNA or its protein in a sample isolated from a diagnostic subject.
상기 측정은 NMI mRNA 또는 그 단백질을 검출하는 물질을 상기 시료에 처리하여 수행되는 것일 수 있다.The measurement may be performed by treating the sample with a substance that detects NMI mRNA or its protein.
상기 NMI mRNA 또는 그 단백질을 검출하는 물질은 앞서 예시한 범위 내의 것일 수 있다.The substance that detects the NMI mRNA or its protein may be within the range exemplified above.
상기 시료, 진단 대상 및 항암제는 전술한 바와 같다.The sample, diagnostic object, and anticancer agent are as described above.
상기 NMI mRNA 또는 그 단백질의 발현 수준을 측정하는 방법으로서 NMI를 코딩하는 유전자의 전사물질인 mRNA의 시료 내 농도 또는 상기 NMI 단백질의 시료 내 농도를 측정하는 방법을 택할 수 있으나, 이에 제한되지 아니하고, 본 발명의 기술분야에서 통상적으로 사용되는 방법을 택하여 수행할 수 있다.As a method of measuring the expression level of the NMI mRNA or its protein, a method of measuring the concentration in the sample of mRNA, which is a transcript of the gene encoding NMI, or the concentration of the NMI protein in the sample may be selected, but is not limited to this, It can be performed by selecting a method commonly used in the technical field of the present invention.
상기 mRNA의 시료 내 농도를 측정하는 방법으로서 역전사효소 중합효소반응(RT-PCR), 경쟁적 역전사효소 중합효소반응(Competitive RT-PCR), 실시간 역전사효소 중합효소반응(Real-time RT-PCR), RNase 보호 분석법(RPA; RNase protection assay), 노던 블롯팅 (Northern blotting) 및 DNA 칩 등이 있으나, 이에 제한되는 것은 아니다.Methods for measuring the concentration of the mRNA in the sample include reverse transcriptase polymerase reaction (RT-PCR), competitive reverse transcriptase polymerase reaction (Competitive RT-PCR), real-time reverse transcriptase polymerase reaction (Real-time RT-PCR), Examples include, but are not limited to, RNase protection assay (RPA), Northern blotting, and DNA chip.
상기 단백질의 시료 내 농도를 측정하는 방법으로서 상기 단백질에 대하여 특이적으로 결합하는 항체를 이용하여 단백질의 양을 확인할 수 있다. 이를 위한 분석 방법으로는 면역탁본검사, 샌드위치 측정법(sandwich assay), ELISA(enzyme linked immunosorbent assay), 방사선면역분석(RIA: Radioimmunoassay), 방사 면역 확산법(radioimmunodiffusion), 오우크테로니(Ouchterlony) 면역 확산법, 로케트(rocket) 면역전기영동, 조직면역 염색(immunohistochemistry), 면역침전 분석법(Immunoprecipitation Assay), 보체 고정 분석법(Complement Fixation Assay), FACS(fluorescence-activated cell sorting), 웨스턴 블롯팅, 유체 세포 측정법(flow cytometry), 효소기질발색법, 항원-항체 응집법 및 단백질 칩(protein chip) 등이 있고, 바람직하게는 ELISA(enzyme linked immunosorbent assay)를 이용할 수 있으나, 이에 제한되는 것은 아니다.As a method of measuring the concentration of the protein in a sample, the amount of the protein can be confirmed using an antibody that specifically binds to the protein. Analysis methods for this include immunorubbing test, sandwich assay, ELISA (enzyme linked immunosorbent assay), radioimmunoassay (RIA), radioimmunodiffusion, and Ouchterlony immunodiffusion method. , rocket immunoelectrophoresis, immunohistochemistry, immunoprecipitation assay, complement fixation assay, fluorescence-activated cell sorting (FACS), Western blotting, fluid cytometry ( flow cytometry, enzyme substrate color development method, antigen-antibody agglutination method, and protein chip, etc. Preferably, ELISA (enzyme linked immunosorbent assay) can be used, but is not limited thereto.
본 발명의 정보제공방법은 상기 발현 수준을 대조 개체의 발현 수준과 비교하는 단계를 더 포함할 수 있다.The information provision method of the present invention may further include comparing the expression level with that of a control subject.
본 발명의 정보제공방법은 상기 방법에 따라 항암제 내성 의심환자의 시료 내의 NMI mRNA 또는 그 단백질의 발현량과 항암제 투여 후 완전 관해(complete response) 환자의 발현량을 비교하여 의심환자의 NMI 발현량이 완전 관해 환자의 NMI 발현량에 비해 높은 경우 완전 관해 환자에 비해 항암제 내성이 있다고 판단할 수 있는 정보를 제공할 수 있다. 또한, 상기 NMI mRNA 또는 그 단백질의 발현량이 완전 관해 환자의 발현량과 비교하여 비슷하거나 낮게 측정되는 경우 항암제 내성이 없다고 판단할 수 있는 정보를 제공할 수 있다.The information provision method of the present invention compares the expression level of NMI mRNA or its protein in the sample of a patient suspected of anticancer drug resistance with the expression level of a patient in complete response after anticancer drug administration according to the above method, and the NMI expression level in the suspected patient shows complete response. If it is higher than the patient's NMI expression level, it can provide information that can be used to determine that the patient has anticancer drug resistance compared to patients in complete remission. In addition, if the expression level of the NMI mRNA or its protein is measured to be similar or lower than that of a patient in complete remission, information can be provided to determine that there is no anticancer drug resistance.
진단 대상으로부터 분리된 시료 내의 NMI(N-Myc interator) mRNA 또는 그 단백질의 발현을 감소시키는 물질을 선별하는 단계를 포함하는 항암제 내성 억제제 후보물질의 스크리닝 방법을 제공한다.Provided is a screening method for a candidate anticancer drug resistance inhibitor, including the step of selecting a substance that reduces the expression of NMI (N-Myc interator) mRNA or its protein in a sample isolated from a diagnostic subject.
상기 방법은 피검물질을 개체에 처리하여 그 mRNA 또는 그 단백질의 발현 수준이 감소한다면 항암제 내성이 억제되는 것이므로, 그러한 피검물질을 항암제 내성 억제제 후보물질로 선별할 수 있다.In the above method, anticancer drug resistance is suppressed if the expression level of the mRNA or protein is reduced by treating the test material to the subject, and such test material can be selected as a candidate for an anticancer drug resistance inhibitor.
또한, 상기 방법은 항암제 내성을 지닌 개체로부터 분리된 시료에 피검물질을 처리하여, 처리 전후 NMI mRNA 또는 단백질의 발현 정도를 비교할 수도 있고, 여러 개체 중 일부 개체에 피검물질을 처리하여 비교군과 상기 발현 수준을 비교할 수도 있다.In addition, the method can be used to treat samples isolated from individuals with anticancer drug resistance with a test substance and compare the expression level of NMI mRNA or protein before and after treatment, or to treat some of several individuals with the test substance to compare the comparison group and the above. Expression levels can also be compared.
상기 피검물질은 새롭게 합성된 또는 공지된 물질로 항암제 내성의 억제에 효과를 나타낼 것으로 기대되는 물질을 제한 없이 포함할 수 있고, 본 발명의 mRNA 또는 단백질의 발현량에 영향을 미치는지 여부를 검사하기 위하여 스크리닝에서 이용되는 미지의 물질을 의미한다. 상기 피검물질은 화학물질, 뉴클레오타이드, 안티센스-RNA, shRNA(short hairpin RNA), siRNA(small interference RNA) 및 천연물 추출물을 포함하나, 이에 한정되는 것은 아니다.The test substance may be a newly synthesized or known substance and may include without limitation substances expected to be effective in suppressing anticancer drug resistance, and to test whether it affects the expression level of the mRNA or protein of the present invention. Refers to an unknown substance used in screening. The test substances include, but are not limited to, chemicals, nucleotides, antisense-RNA, shRNA (short hairpin RNA), siRNA (small interference RNA), and natural product extracts.
본 발명의 일 실시예에 있어서, 상기 NMI mRNA 또는 그 단백질의 발현 수준을 감소시키는 물질은 siRNA 또는 shRNA일 수 있다. 예를 들어, 진단 대상이 인간인 경우, 서열번호 3 및 4의 siNMI를 사용할 수 있고, 서열번호 5의 shNMI 또는 서열번호 6의 shNMI를 사용할 수 있다. 서열을 이에 제한되지 않고, 진단 대상이 되는 개체 종의 siNMI 또는 shNMI를 사용할 수 있다.In one embodiment of the present invention, the substance that reduces the expression level of NMI mRNA or its protein may be siRNA or shRNA. For example, when the diagnostic subject is a human, siNMI of SEQ ID NO: 3 and 4 can be used, shNMI of SEQ ID NO: 5, or shNMI of SEQ ID NO: 6 can be used. The sequence is not limited to this, and siNMI or shNMI of the individual species being diagnosed can be used.
이외, 진단대상, 시료, 항암제는 전술한 바와 같다.In addition, diagnostic objects, samples, and anticancer agents are the same as described above.
본 발명은 NMI(N-Myc interator) mRNA 또는 그 단백질의 발현을 감소시키는 물질을 포함하는 항암제 내성 억제용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for suppressing anticancer drug resistance containing a substance that reduces the expression of NMI (N-Myc interator) mRNA or its protein.
상기 NMI mRNA 또는 그 단백질의 발현 수준을 감소시키는 물질은 저분자량 약물, 유전자 약물, 단백질 약물, 추출물, 핵산, 올리고뉴클레오티드, 단백질, 펩타이드, 항체, RNA, DNA, PNA, 압타머, 화학약품, 효소, 아미노산, 당, 지질, 화합물(천연화합물 및/또는 합성화합물) 및 이들을 구성하는 요소로 이루어진 군에서 선택된 적어도 하나일 수 있으나, NMI를 코딩하는 유전자의 mRNA 또는 상기 유전자가 코딩하는 단백질의 발현을 감소시키는 효능을 가진 물질이라면 특별히 제한되지 아니한다.Substances that reduce the expression level of the NMI mRNA or its protein include low molecular weight drugs, gene drugs, protein drugs, extracts, nucleic acids, oligonucleotides, proteins, peptides, antibodies, RNA, DNA, PNA, aptamers, chemicals, and enzymes. It may be at least one selected from the group consisting of amino acids, sugars, lipids, compounds (natural compounds and/or synthetic compounds), and elements constituting them, but the expression of the mRNA of the gene encoding NMI or the protein encoded by the gene There is no particular limitation as long as it is a substance that has a reducing effect.
상기 물질은 NRF2(Nuclear factor erythroid 2-related factor 2) 억제제일 수 있다. NRF2 유전자의 mRNA에 상보적으로 결합하는 안티센스 뉴클레오타이드, siRNA 또는 shRNA일 수 있고, NRF2 단백질에 특이적으로 결합하는 화합물, 펩티드, 펩티드 미메틱스(peptide mimetics), 앱타머, 항체 또는 천연물일 수 있으나, 이에 제한되지 않는다.The substance may be a nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor. It may be an antisense nucleotide, siRNA, or shRNA that binds complementary to the mRNA of the NRF2 gene, or it may be a compound, peptide, peptide mimetics, aptamer, antibody, or natural product that specifically binds to the NRF2 protein. , but is not limited to this.
예를 들어, 상기 NRF2 억제제는 ML385(CAS No 846557-71-9)일 수 있다. 본 발명의 일 실시예에 따라 NMI 과발현 세포주에 ML385를 처리하면, NMI 발현이 억제됨을 알 수 있다.For example, the NRF2 inhibitor may be ML385 (CAS No 846557-71-9). It can be seen that when NMI overexpressing cell line is treated with ML385 according to an embodiment of the present invention, NMI expression is suppressed.
본 발명의 약학적 조성물은 항암제와 병용하여 투여될 수 있다. 이 경우, 항암제 내성 억제 효과와 항암제에 의한 치료 효과를 동시에 얻을 수 있어 항암화학요법의 효과를 극대화할 수 있다.The pharmaceutical composition of the present invention can be administered in combination with an anticancer agent. In this case, the effect of suppressing anticancer drug resistance and the treatment effect of the anticancer drug can be obtained at the same time, thereby maximizing the effect of the anticancer chemotherapy.
상기 조성물은 약학적으로 허용가능한 담체를 추가로 포함할 수 있으며, 담체와 함께 제제화될 수 있다. 본 발명에서 용어, "약학적으로 허용가능한 담체"란 생물체를 자극하지 않고 투여 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 말한다. 액상 용액으로 제제화되는 조성물에 있어서 허용되는 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로오스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.The composition may further include a pharmaceutically acceptable carrier and may be formulated together with the carrier. As used herein, the term “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not irritate living organisms and does not inhibit the biological activity and properties of the administered compound. Acceptable pharmaceutical carriers for compositions formulated as liquid solutions include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and One or more of these ingredients can be mixed and used, and other common additives such as antioxidants, buffers, and bacteriostatic agents can be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
본 발명의 조성물은 상기 NMI mRNA 또는 그 단백질의 발현을 감소시키는 물질을 유효성분으로 포함하는 어떠한 제형으로도 적용가능하며, 경구용 또는 비경구용 제형으로 제조할 수 있다. 본 발명의 약학적 제형은 구강(oral), 직장(rectal), 비강(nasal), 국소(topical; 볼 및 혀 밑을 포함), 피하, 질(vaginal) 또는 비경구(parenteral; 근육 내, 피하 및 정맥내를 포함) 투여에 적당한 것 또는 흡입(inhalation) 또는 주입(insufflation)에 의한 투여에 적당한 형태를 포함한다.The composition of the present invention can be applied in any formulation containing a substance that reduces the expression of NMI mRNA or its protein as an active ingredient, and can be prepared as an oral or parenteral formulation. The pharmaceutical formulation of the present invention may be administered orally, rectally, nasally, topically (including cheeks and under the tongue), subcutaneously, vaginally, or parenterally (intramuscularly, subcutaneously). and forms suitable for administration (including intravenous) or forms suitable for administration by inhalation or insufflation.
본 발명의 조성물은 약학적으로 유효한 양으로 투여한다. 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The composition of the present invention is administered in a pharmaceutically effective amount. The effective dosage level depends on factors including the type and severity of the patient's disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the field of medicine. can be decided. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
본 발명의 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 매우 다양하며, 적정한 투여량은 예를 들면 환자의 체내에 축적된 약물의 양 및/또는 사용되는 상기 NMI mRNA 또는 그 단백질의 발현을 감소시키는 물질의 구체적 효능 정도에 따라 달라질 수 있다. 일반적으로 인비보 동물모델 및 인비트로에서 효과적인 것으로 측정된 EC50을 기초로 계산될 수 있으며, 예를 들면 체중 1kg당 0.01 μg 내지 1 g 일 수 있으며, 일별, 주별, 월별 또는 연별의 단위 기간으로, 단위 기간 당 일회 내지 수회 나누어 투여될 수 있으며, 또는 인퓨전 펌프를 이용하여 장기간 연속적으로 투여될 수 있다. 반복투여 횟수는 약물이 체내 머무는 시간, 체내 약물 농도 등을 고려하여 결정된다. 질환 치료 경과에 따라 치료가 된 후라도, 재발을 위해 조성물이 투여될 수 있다.The dosage of the composition of the present invention varies widely depending on the patient's weight, age, gender, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. The appropriate dosage is, for example, the patient's It may vary depending on the amount of drug accumulated in the body and/or the specific efficacy of the substance used to reduce the expression of the NMI mRNA or its protein. In general, it can be calculated based on the EC50 measured to be effective in in vivo animal models and in vitro, for example, it may be 0.01 μg to 1 g per kg of body weight, and in unit periods of daily, weekly, monthly or yearly, It can be administered once or several times per unit period, or it can be administered continuously for a long period of time using an infusion pump. The number of repeated doses is determined by considering the time the drug stays in the body and the concentration of the drug in the body. Even after treatment, depending on the course of disease treatment, the composition may be administered for recurrence.
본 발명의 조성물은 항암제 내성 치료와 관련하여 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 또는 유효성분의 용해성 및/또는 흡수성을 유지/증가시키는 화합물을 추가로 함유할 수 있다. 또한 선택적으로, 화학치료제, 항염증제, 항바이러스제 및/또는 면역조절제 등을 추가로 포함할 수 있다.The composition of the present invention may additionally contain one or more active ingredients that exhibit the same or similar functions in relation to the treatment of anticancer drug resistance, or a compound that maintains/increases the solubility and/or absorption of the active ingredient. Additionally, optionally, it may further include a chemotherapy agent, an anti-inflammatory agent, an antiviral agent, and/or an immunomodulatory agent.
또한, 본 발명의 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말의 형태일 수 있다.Additionally, the compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Dosage forms may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, or sterile powders.
이하, 본 발명을 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다.Hereinafter, the present invention will be described in detail with reference to examples.
실험재료experiment material
1. 세포 배양(cell culture)1. Cell culture
유방암 세포주 MCF7, MCF7/PR (MCF7-paclitaxel 저항성 세포주), MCF7/ADR (MCF7-adriamycin 저항성 세포주), MCF7/TAMR (MCF7-tamoxifen 저항성 세포주), MDA-MB-231, BT20, MDA-MB-468 세포주는 모두 DMEM medium+10% FBS (소태아혈청, Gibco) + 1% PS (Penicillin streptomycin, Gibco) 조성에서 37℃ (5% CO2) 인큐베이터에서 배양하였다.Breast cancer cell lines MCF7, MCF7/PR (MCF7-paclitaxel resistant cell line), MCF7/ADR (MCF7-adriamycin resistant cell line), MCF7/TAMR (MCF7-tamoxifen resistant cell line), MDA-MB-231, BT20, MDA-MB-468 All cell lines were cultured in DMEM medium + 10% FBS (fetal bovine serum, Gibco) + 1% PS (Penicillin streptomycin, Gibco) in an incubator at 37°C (5% CO 2 ).
2. siRNA를 이용한 NMI 유전자 억제(siRNA transfection)2. NMI gene suppression using siRNA (siRNA transfection)
NMI 유전자 knock-down을 위하여 siNMI(서열번호 3 및 4)와 siControl (바이오니아, 한국)을 구매하고, 제조업체의 설명서에 따라 RNAimax (thermofisher)를 이용하여 각각의 siRNA를 다양한 유방암 세포주 (MCF7, MCF7/PR, MCF7/ADR, MCF7/TAMR, MDA-MB-231, BT20, MDA-MB-468)에 형질주입(transfection)하였고 NMI 유전자의 발현이 억제되는 것을 RT-PCR 및 western blot으로 확인하였다.For NMI gene knock-down, siNMI (SEQ ID NO: 3 and 4) and siControl (Bioneer, Korea) were purchased, and each siRNA was used in various breast cancer cell lines (MCF7, MCF7/MCF7) using RNAimax (thermofisher) according to the manufacturer's instructions. PR, MCF7/ADR, MCF7/TAMR, MDA-MB-231, BT20, MDA-MB-468) were transfected, and the inhibition of NMI gene expression was confirmed by RT-PCR and western blot.
3. NMI 억제 안정 세포주 (stable cell line) 수립3. Establishment of NMI-inhibiting stable cell line
NMI 과발현 안정 세포주를 수립하기 위하여 pLOC(Precision LentiORF control vector, lentiviral control vector(Dhrmacon))와 NMI vector(lentivirus-based vector, NMI 증폭에 사용된 sequencing primer Forward 5'CTCCATAGAAGACACCGAC-3'(서열번호 7), Reverse 5-'CATATAGACAAACGCACAC3' (서열번호 8))), NMI 억제 안정 세포주를 수립하기 위하여 shcontrol(GIPZ non-silencing shRNA control)과 shNMI(서열번호 5 또는 6)를 Dharmacon에서 구입하여 HEK293T 세포주에 각각의 vector를 이용하여 lentiviral 형질주입 하였고, 형질주입 후 24시간, 48시간 각각의 세포 배양액을 모아 타겟하는 세포주에 형질도입(transduction)하여 Blasticidin (과발현 세포주 - Hs578T) 혹은 puromycin selection (억제 세포주 - BT20, MDA-MB-231)을 통해 NMI 과발현, 억제 및 대조군 안정 세포주를 수립하였다.To establish a stable cell line overexpressing NMI, pLOC (Precision LentiORF control vector, lentiviral control vector (Dhrmacon)) and NMI vector (lentivirus-based vector, sequencing primer used for NMI amplification Forward 5'CTCCATAGAAGACACCGAC-3' (SEQ ID NO. 7) , Reverse 5-'CATATAGACAAACGCACAC3' (SEQ ID NO: 8))), To establish an NMI-silencing stable cell line, shcontrol (GIPZ non-silencing shRNA control) and shNMI (SEQ ID NO: 5 or 6) were purchased from Dharmacon and added to the HEK293T cell line, respectively. lentiviral transfection was performed using the vector, and 24 and 48 hours after transfection, each cell culture was collected and transduced into the target cell line, followed by Blasticidin (overexpression cell line - Hs578T) or puromycin selection (suppressor cell line - BT20, NMI overexpression, inhibition and control stable cell lines were established through MDA-MB-231).
실험방법 및 결과Experiment method and results
1. 유방암 환자에서 항암제 반응 및 비반응 환자 NMI 발현 차이 확인1. Confirmation of differences in NMI expression in breast cancer patients responding to anticancer drugs and non-responding patients
유방암 환자에서 선행 항암화학요법 (neoadjuvant chemotherapy)을 받은 환자군에서 항암화학요법 완전 관해군 (n=54, 완전히 종양세포가 없어진 군락을 의미, CR)과 항암화학요법 비관해군 (n=56, nCR)의 NMI 발현 차이를 확인하기 위하여, NMI의 발현 score를 H-score 기반 (Ishibashi H et.al, 2003)하여 scoring하였다(표 1). 선행 항암화학요법은 Docetaxel, Adriamycin, Cyclophosphamide를 모두 시행 받은 환자를 대상하여 수행하였다. NMI 항체는 Novus (cat. NBP1-90374) 제품을 이용하여 면역조직화학염색을 수행하였다.Among breast cancer patients who received neoadjuvant chemotherapy, there were a chemotherapy complete response group (n=54, meaning a group in which tumor cells completely disappeared, CR) and a chemotherapy non-remission group (n=56, nCR). In order to confirm the difference in NMI expression, the expression score of NMI was scored based on H-score (Ishibashi H et.al, 2003) (Table 1). Neoadjuvant chemotherapy was performed on patients who received Docetaxel, Adriamycin, and Cyclophosphamide. Immunohistochemical staining was performed using the NMI antibody from Novus (cat. NBP1-90374).
그 결과는 도 1에 나타내었으며, 완전 관해(CR)군과 비관해(nCR)군 간의 IHC score는 0.855:1.275로 확인되었다(p=0.012).The results are shown in Figure 1, and the IHC score between the complete response (CR) group and the non-remission (nCR) group was confirmed to be 0.855:1.275 ( p =0.012).
2. NMI 발현 억제에 따른 약물 반응도 확인2. Confirmation of drug response according to inhibition of NMI expression
NMI 발현 억제 세포주(MCF7/PR, MDA-MB-231, BT20, MDA-MB-468)를 96-well plate에 3,000 cells/well로 cell seeding 하고 24시간 후 각각의 약물 (docetaxel = 20nM, paclitaxel = 20nM, Adriamycin = 500nM, cyclophosphamide = 4mM)를 처리하였고, 약물 처리 후 48시간째 세포 생존률(%)을 측정하였다. 세포 생존률은 cellTiter-Glo luminescent cell viability assay (Promega) kit로 측정하였고, 발광도는 GloMax luminometer (Promega)로 측정하였다.Cell lines suppressing NMI expression (MCF7/PR, MDA-MB-231, BT20, MDA-MB-468) were seeded at 3,000 cells/well in a 96-well plate, and 24 hours later, each drug (docetaxel = 20nM, paclitaxel = 20nM, Adriamycin = 500nM, cyclophosphamide = 4mM), and cell viability (%) was measured 48 hours after drug treatment. Cell viability was measured using the cellTiter-Glo luminescent cell viability assay (Promega) kit, and luminescence was measured using the GloMax luminometer (Promega).
그 결과 NMI 발현 억제 세포주에서 4가지 항암제(DTX, PTX, ADR, CPM)에 대한 약물 반응도가 증가함을 확인하였다(도 2).As a result, it was confirmed that drug responsiveness to four anticancer drugs (DTX, PTX, ADR, CPM) increased in NMI expression suppressed cell lines (Figure 2).
3. NMI 발현에 따른 타목시펜(tamoxife) 반응도 확인3. Confirmation of tamoxifen response according to NMI expression
타목시펜에 대한 반응성 측정은 ER (estrogen receptor, 에스트로겐 수용체) 양성 세포주 (MCF7, MCF7/PR, MCF7/ADR)를 이용하였다. ER 양성 세포주를 96-well plate에 3,000 cells/well로 cell seeding하고 24시간 후 타목시펜 (12.5μM, 25μM)을 처리하였고, 타목시펜 처리 후 48시간째 세포 생존률을 측정하였다.Responsiveness to tamoxifen was measured using ER (estrogen receptor) positive cell lines (MCF7, MCF7/PR, MCF7/ADR). ER-positive cell lines were seeded at 3,000 cells/well in a 96-well plate and treated with tamoxifen (12.5 μM, 25 μM) 24 hours later, and cell survival rate was measured 48 hours after tamoxifen treatment.
도 3A를 참조하면, MCF7 세포주에서 독소루비신 및 파클리탁셀 저항성이 생기면, NMI 발현이 증가하였다. 도 3B를 참조하면, NMI 억제시 타목시펜에 대한 반응성이 증가됨을 알 수 있다.Referring to Figure 3A, when doxorubicin and paclitaxel resistance developed in the MCF7 cell line, NMI expression increased. Referring to Figure 3B, it can be seen that responsiveness to tamoxifen increases when NMI is inhibited.
4. NMI 발현에 따른 3차원 구상체 형성 능력 평가(3D spheroids formation assay)4. Evaluation of 3D spheroid formation ability according to NMI expression (3D spheroids formation assay)
일반적으로 약물에 대하여 저항성이 획득되면 3차원 구상체 형성 능력(3D spheroids formation ability)이 촉진된다. NMI 발현 억제 시 3차원 구상체 형성 능력의 차이를 확인하고자, siRNA를 사용하여 NMI의 발현을 억제시키고, siControl과 siNMI 세포의 3차원 구상체 형성을 위해 low-attached 96-well plate에 1,000 cells/well 세포를 seeding 하고, bFGF (20nM), EGF (20nM), 1XB27 보충물이 함유된 구상체 분석 배지에서 7-10일 배양하였다. 이후, 100㎛ 이상 사이즈의 3차원 구상체의 개수를 세어 도표화 하였다.In general, when resistance to a drug is acquired, 3D spheroids formation ability is promoted. To confirm the difference in the ability to form 3D spheroids when NMI expression is suppressed, the expression of NMI was suppressed using siRNA, and 1,000 cells/cell were incubated in a low-attached 96-well plate to form 3D spheroids of siControl and siNMI cells. Well cells were seeded and cultured for 7-10 days in spheroid assay medium containing bFGF (20nM), EGF (20nM), and 1XB27 supplements. Afterwards, the number of three-dimensional spheroids with a size of 100㎛ or more was counted and tabulated.
도 4를 참조하면, NMI의 발현을 억제한 세포주에서 구상체 형성이 현저히 억제되었으므로, NMI 발현 억제가 약물 반응도를 증가시킴을 알 수 있다. 또한, 이는 NMI가 약물 저항성과 관련 있음을 시사한다.Referring to Figure 4, since spheroid formation was significantly suppressed in the cell line in which the expression of NMI was suppressed, it can be seen that suppressing NMI expression increases drug responsiveness. Additionally, this suggests that NMI is associated with drug resistance.
5. ML385에 의한 NMI 억제 효능 확인5. Confirmation of NMI inhibition efficacy by ML385
NRF2와 NMI의 상관관계를 확인하기 위하여 bc-GenExMiner v4.3 (http://bcgenex.centregauducheau.fr/BC-GEM/GEM-Accueil.php?js=1) 사이트에서 두 단백질의 관련성을 확인하였다(도 5A). 총 n = 9414 데이터 샘플에서 NMI와 NRF2는 양의 상관관계(positive correlation, r = 0.30, p < 0.0001)이 있었다. 이를 확인하고자 NMI 발현 억제 안정 세포주(BT20, MDA-MB-231) 및 NMI 과발현 안정 세포주(Hs578T)에서 RT-PCR 방법을 통해 확인하였다(도 5B).In order to confirm the correlation between NRF2 and NMI, the relationship between the two proteins was confirmed on the bc-GenExMiner v4.3 ( http://bcgenex.centregauducheau.fr/BC-GEM/GEM-Accueil.php?js=1 ) site. (Figure 5A). In a total of n = 9414 data samples, NMI and NRF2 were positively correlated (r = 0.30, p < 0.0001). To confirm this, it was confirmed by RT-PCR in NMI expression suppressed stable cell lines (BT20, MDA-MB-231) and NMI overexpressed stable cell lines (Hs578T) (Figure 5B).
또한, NRF2 특이 억제제(ML385)를 BT20-shControl 세포와 shNMI 발현 억제 안정 세포주에 25μM, 50μM 를 24시간 동안 처리 후 NMI 발현을 western blot 방법을 통해 확인하였다. 그 결과 NRF2억제제인 ML385에 의해 NMI 발현이 억제됨을 알 수 있다(도 5C).In addition, NRF2-specific inhibitor (ML385) was treated with BT20-shControl cells and stable cell lines suppressing shNMI expression at 25 μM and 50 μM for 24 hours, and NMI expression was confirmed through western blot method. As a result, it can be seen that NMI expression is suppressed by ML385, an NRF2 inhibitor (Figure 5C).
<110> SEOUL NATIONAL UNIVERSITY HOSPITAL <120> Composition for diagnosing anti-cancer medicine resistance and kit comprising the same <130> 19P10048 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 1229 <212> RNA <213> Homo sapiens <400> 1 gtttcaggcg ctgctgtttt ccgggaaggg caggcgcgct gggccttggg gagctgcgct 60 cggcgggcgg acgcggggga tcatggaagc tgataaagat gacacacaac aaattcttaa 120 ggagcattcg ccagatgaat ttataaaaga tgaacaaaat aagggactaa ttgatgaaat 180 tacaaagaaa aatattcaac taaagaagga gatccaaaag cttgaaacgg agttacaaga 240 ggctaccaaa gaattccaga ttaaagagga tattcctgaa acaaagatga aattcttatc 300 agttgaaact cctgagaatg acagccagtt gtcaaatatc tcctgttcgt ttcaagtgag 360 ctcgaaagtt ccttatgaga tacaaaaagg acaagcactt atcacctttg aaaaagaaga 420 agttgctcaa aatgtggtaa gcatgagtaa acatcatgta cagataaaag atgtaaatct 480 ggaggttacg gccaagccag ttccattaaa ttcaggagtc agattccagg tttatgtaga 540 agtttctaaa atgaaaatca atgttactga aattcctgac acattgcgtg aagatcaaat 600 gagagacaaa ctagagctga gcttttcaaa gtcccgaaat ggaggcggag aggtggaccg 660 cgtggactat gacagacagt ccgggagtgc agtcatcacg tttgtggaga ttggagtggc 720 tgacaagatt ttgaaaaaga aagaataccc tctttatata aatcaaacct gccatagagt 780 tactgtttct ccatacacag aaatacactt gaaaaagtat cagatatttt caggaacatc 840 taagaggaca gtgcttctga caggaatgga aggcattcaa atggatgaag aaattgtgga 900 ggatttaatt aacattcact ttcaacgggc aaagaatgga ggtggagaag tagatgtggt 960 caagtgttct ctaggtcaac ctcacatagc atactttgaa gaatagactt aacagaatca 1020 tgaaaactat agctttttaa cccggattac tgtaaatgtt tgacaaaaat gaatatgctt 1080 ttccttaaaa aatgaaaact ttaattttta ccatccattt atgtttagat acaaaactta 1140 tttccatgtt tctgaatctt ctttgtttca aatggtgctg catgttttca actacaataa 1200 gtgcactgta ataaaaagtt ttgtttata 1229 <210> 2 <211> 307 <212> PRT <213> Homo sapiens <400> 2 Met Glu Ala Asp Lys Asp Asp Thr Gln Gln Ile Leu Lys Glu His Ser 1 5 10 15 Pro Asp Glu Phe Ile Lys Asp Glu Gln Asn Lys Gly Leu Ile Asp Glu 20 25 30 Ile Thr Lys Lys Asn Ile Gln Leu Lys Lys Glu Ile Gln Lys Leu Glu 35 40 45 Thr Glu Leu Gln Glu Ala Thr Lys Glu Phe Gln Ile Lys Glu Asp Ile 50 55 60 Pro Glu Thr Lys Met Lys Phe Leu Ser Val Glu Thr Pro Glu Asn Asp 65 70 75 80 Ser Gln Leu Ser Asn Ile Ser Cys Ser Phe Gln Val Ser Ser Lys Val 85 90 95 Pro Tyr Glu Ile Gln Lys Gly Gln Ala Leu Ile Thr Phe Glu Lys Glu 100 105 110 Glu Val Ala Gln Asn Val Val Ser Met Ser Lys His His Val Gln Ile 115 120 125 Lys Asp Val Asn Leu Glu Val Thr Ala Lys Pro Val Pro Leu Asn Ser 130 135 140 Gly Val Arg Phe Gln Val Tyr Val Glu Val Ser Lys Met Lys Ile Asn 145 150 155 160 Val Thr Glu Ile Pro Asp Thr Leu Arg Glu Asp Gln Met Arg Asp Lys 165 170 175 Leu Glu Leu Ser Phe Ser Lys Ser Arg Asn Gly Gly Gly Glu Val Asp 180 185 190 Arg Val Asp Tyr Asp Arg Gln Ser Gly Ser Ala Val Ile Thr Phe Val 195 200 205 Glu Ile Gly Val Ala Asp Lys Ile Leu Lys Lys Lys Glu Tyr Pro Leu 210 215 220 Tyr Ile Asn Gln Thr Cys His Arg Val Thr Val Ser Pro Tyr Thr Glu 225 230 235 240 Ile His Leu Lys Lys Tyr Gln Ile Phe Ser Gly Thr Ser Lys Arg Thr 245 250 255 Val Leu Leu Thr Gly Met Glu Gly Ile Gln Met Asp Glu Glu Ile Val 260 265 270 Glu Asp Leu Ile Asn Ile His Phe Gln Arg Ala Lys Asn Gly Gly Gly 275 280 285 Glu Val Asp Val Val Lys Cys Ser Leu Gly Gln Pro His Ile Ala Tyr 290 295 300 Phe Glu Glu 305 <210> 3 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Homo sapiens siNMI <400> 3 cuccauacac agaaauaca 19 <210> 4 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Homo sapiens siNMI <400> 4 catatagaca aacgcacac 19 <210> 5 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Homo sapiens shNMI 1 <400> 5 tcttcatcca tttgaatgc 19 <210> 6 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Homo sapiens shNMI 2 <400> 6 ttaatggaac tggcttggc 19 <210> 7 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> NMI Primer_F <400> 7 ctccatagaa gacaccgac 19 <210> 8 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> NMI Primer_R <400> 8 catatagaca aacgcacac 19 <110> SEOUL NATIONAL UNIVERSITY HOSPITAL <120> Composition for diagnosing anti-cancer medicine resistance and kit comprising the same <130> 19P10048 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 1229 <212> RNA <213> Homo sapiens <400> 1 gtttcaggcg ctgctgtttt ccgggaaggg caggcgcgct gggccttggg gagctgcgct 60 cggcgggcgg acgcggggga tcatggaagc tgataaagat gacacacaac aaattcttaa 120 ggagcattcg ccagatgaat ttataaaaga tgaacaaaat aagggactaa ttgatgaaat 180 tacaaagaaa aatattcaac taaagaagga gatccaaaag cttgaaacgg agttacaaga 240 ggctaccaaa gaattccaga ttaaagagga tattcctgaa acaaagatga aattcttatc 300 agttgaaact cctgagaatg acagccagtt gtcaaatatc tcctgttcgt ttcaagtgag 360 ctcgaaagtt ccttatgaga tacaaaaagg acaagcactt atcacctttg aaaaagaaga 420 agttgctcaa aatgtggtaa gcatgagtaa acatcatgta cagataaaag atgtaaatct 480 ggaggttacg gccaagccag ttccattaaa ttcaggagtc agattccagg tttatgtaga 540 agtttctaaa atgaaaatca atgttactga aattcctgac acattgcgtg aagatcaaat 600 gagagacaaa ctagagctga gcttttcaaa gtcccgaaat ggaggcggag aggtggaccg 660 cgtggactat gacagacagt ccgggagtgc agtcatcacg tttgtggaga ttggagtggc 720 tgacaagatt ttgaaaaaga aagaataccc tctttatata aatcaaacct gccatagagt 780 tactgtttct ccatacacag aaatacactt gaaaaagtat cagatatttt caggaacatc 840 taagaggaca gtgcttctga caggaatgga aggcattcaa atggatgaag aaattgtgga 900 ggatttaatt aacattcact ttcaacgggc aaagaatgga ggtggagaag tagatgtggt 960 caagtgttct ctaggtcaac ctcacatagc atactttgaa gaatagactt aacagaatca 1020 tgaaaactat agctttttaa cccggattac tgtaaatgtt tgacaaaaat gaatatgctt 1080 ttccttaaaa aatgaaaact ttaattttta ccatccattt atgtttagat acaaaactta 1140 tttccatgtt tctgaatctt ctttgtttca aatggtgctg catgttttca actacaataa 1200 gtgcactgta ataaaaagtt ttgtttata 1229 <210> 2 <211> 307 <212> PRT <213> Homo sapiens <400> 2 Met Glu Ala Asp Lys Asp Asp Thr Gln Gln Ile Leu Lys Glu His Ser 1 5 10 15 Pro Asp Glu Phe Ile Lys Asp Glu Gln Asn Lys Gly Leu Ile Asp Glu 20 25 30 Ile Thr Lys Lys Asn Ile Gln Leu Lys Lys Glu Ile Gln Lys Leu Glu 35 40 45 Thr Glu Leu Gln Glu Ala Thr Lys Glu Phe Gln Ile Lys Glu Asp Ile 50 55 60 Pro Glu Thr Lys Met Lys Phe Leu Ser Val Glu Thr Pro Glu Asn Asp 65 70 75 80 Ser Gln Leu Ser Asn Ile Ser Cys Ser Phe Gln Val Ser Ser Lys Val 85 90 95 Pro Tyr Glu Ile Gln Lys Gly Gln Ala Leu Ile Thr Phe Glu Lys Glu 100 105 110 Glu Val Ala Gln Asn Val Val Ser Met Ser Lys His His Val Gln Ile 115 120 125 Lys Asp Val Asn Leu Glu Val Thr Ala Lys Pro Val Pro Leu Asn Ser 130 135 140 Gly Val Arg Phe Gln Val Tyr Val Glu Val Ser Lys Met Lys Ile Asn 145 150 155 160 Val Thr Glu Ile Pro Asp Thr Leu Arg Glu Asp Gln Met Arg Asp Lys 165 170 175 Leu Glu Leu Ser Phe Ser Lys Ser Arg Asn Gly Gly Gly Glu Val Asp 180 185 190 Arg Val Asp Tyr Asp Arg Gln Ser Gly Ser Ala Val Ile Thr Phe Val 195 200 205 Glu Ile Gly Val Ala Asp Lys Ile Leu Lys Lys Lys Glu Tyr Pro Leu 210 215 220 Tyr Ile Asn Gln Thr Cys His Arg Val Thr Val Ser Pro Tyr Thr Glu 225 230 235 240 Ile His Leu Lys Lys Tyr Gln Ile Phe Ser Gly Thr Ser Lys Arg Thr 245 250 255 Val Leu Leu Thr Gly Met Glu Gly Ile Gln Met Asp Glu Glu Ile Val 260 265 270 Glu Asp Leu Ile Asn Ile His Phe Gln Arg Ala Lys Asn Gly Gly Gly 275 280 285 Glu Val Asp Val Val Lys Cys Ser Leu Gly Gln Pro His Ile Ala Tyr 290 295 300 Phe Glu Glu 305 <210> 3 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Homo sapiens siNMI <400> 3 cuccauacac agaaauaca 19 <210> 4 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Homo sapiens siNMI <400> 4 catatagaca aacgcacac 19 <210> 5 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Homo sapiens shNMI 1 <400> 5 tcttcatcca tttgaatgc 19 <210> 6 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Homo sapiens shNMI 2 <400> 6 ttaatggaac tggcttggc 19 <210> 7 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> NMI Primer_F <400> 7 ctccatagaa gacaccgac 19 <210> 8 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> NMI Primer_R <400> 8 catatagaca aacgcacac 19
Claims (16)
A composition for diagnosing anticancer drug resistance containing a substance that specifically binds to NMI (N-Myc interator) mRNA or its protein.
The composition according to claim 1, wherein the substance is at least one selected from the group consisting of antibodies, aptamers, DNA, RNA, proteins, and polypeptides.
The composition of claim 1, wherein the anticancer agent is selected from the group consisting of doxetaxel, paclitaxel, doxorubicin, cyclophosphamide, and tamoxifen.
A kit for diagnosing anticancer drug resistance comprising the composition of any one of claims 1 to 3.
A method of providing information for diagnosing anticancer drug resistance, comprising measuring the expression level of NMI (N-Myc interator) mRNA or its protein in a sample isolated from a diagnostic subject.
The method of claim 5, wherein the diagnosis subject is a breast cancer patient.
The method of claim 5, wherein the sample is selected from the group consisting of tissue, cells, blood, serum, plasma, saliva, or urine.
The method of claim 5, wherein the anticancer agent is selected from the group consisting of doxetaxel, paclitaxel, doxorubicin, cyclophosphamide, and tamoxifen.
A screening method for a candidate anticancer drug resistance inhibitor, comprising the step of selecting a substance that reduces the expression of NMI (N-Myc interator) mRNA or its protein in a sample isolated from a diagnostic subject.
The method of claim 9, wherein the diagnosis subject is a breast cancer patient.
The method of claim 9, wherein the sample is selected from the group consisting of tissue, cells, blood, serum, plasma, saliva, or urine.
The method of claim 9, wherein the anticancer agent is selected from the group consisting of doxetaxel, paclitaxel, doxorubicin, cyclophosphamide, and tamoxifen.
A pharmaceutical composition for suppressing anticancer drug resistance containing a substance that reduces the expression of NMI (N-Myc interator) mRNA or its protein.
The method of claim 13, wherein the substances include low molecular weight drugs, genetic drugs, protein drugs, extracts, nucleic acids, oligonucleotides, proteins, peptides, antibodies, RNA, DNA, PNA, aptamers, chemicals, enzymes, amino acids, sugars, and lipids. A composition, which is at least one selected from the group consisting of.
The composition of claim 13, wherein the substance is a Nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor.
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Non-Patent Citations (4)
Title |
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Feng Xu et al, Cell death & disease (2017.), vol 8, e2783, pp 1-11. |
Hawley C Pruitt et al, International Journal of Cancer (2016.), vol 139, pp 491-500. |
Metge Brandon J et al, Scientific Reports (2015.), vol 5, no 11995, pp 1-11. |
Nazmeen Aarifa et al, J Cell Sci Ther (2018.), vol 9, no 4, 1000286, pp 1-4. |
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