대한핵의학회지 (The Korean Journal of Nuclear Medicine)

대한핵의학회 (The Korean Society of Nuclear Medicine)
권호 표지

분자핵의학 기법을 이용한 다약제내성 진단

Detection of Multidrug Resistance Using Molecular Nuclear Technique

  • 이재태 (경북대학교 의과대학 핵의학교실) ;
  • 안병철 (경북대학교 의과대학 핵의학교실)
  • Lee, Jae-Tae (Department of Nuclear Medicine, School of Medicine, Kyungpook National University) ;
  • Ahn, Byeong-Cheol (Department of Nuclear Medicine, School of Medicine, Kyungpook National University)
  • 발행 : 2004.04.30
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초록

다약제내성이 발현된 암세포에서 세포내의 항암제를 세포외로 배출시키는 기전을 체내에서 비침습적인 방법으로 영상화 할 수 있는 SPECT와 PET는 악성종양의 진단과 평가에 중요한 역할을 할 것으로 판단되나, 아직까지도 Pgp와 MRP의 운반능을 적절하게 평가하는 핵의학적 영상방법을 정립하는데는 극복해야할 문제점들이 많다. 지금까지의 MDR영상에 관한 연구들은 대부분이 $^{99m}Tc$-표지 방사성의약품을 이용한 연구였으나, PET의 임상 응용이 증가함에 따라 보다 특이적이고 쉽게 응용될 수 있는 PET용 방사성 추적자의 개발도 이루어져야 할 것이다. $^{99m}Tc$-MIBI의 암 세포내 일방향(unidirectional) 섭취는 음성인 세포막 전하와 세포내 소립체 기질 전하에 의하여 결정되므로, MIBI의 섭취는 다른 지용성 양전하를 띤 막전위 추적자들과 유사하게 작용한다. $^{99m}Tc$-표지 방사성의약품은 암조직의 혈류 증가나 소립체 용적이나 활성도가 증가하면 섭취가 증가할 수 있어 보다 특이적인 MDR추적제의 개발이 필요한 것이다. 최근 Lorke 등은 약제감수성 및 내성 인체대장암세포인 $HT-29^{par}$ 세포와 $HT-29^{mdrl}$ 세포를 이용한 연구에서, 두세포 모두에서 $^{18}F$-FDG의 섭취가 있었고, MDR이 발현된 세포와 종양에서 $^{18}F$-FDG 섭취가 훨씬 낮았고, MIBI는 MDR이 없는 모세포에서도 매우 낮았음을 보고한 바 있다. 이 세포는 전자현미경검사에서 사립체가 풍부하지 않은 세포였다. 그러므로 이러한 결과로 보아 $^{99m}Tc$-MIBI 영상에서 종양이 보이지 않거나 섭취가 미약하다고 해도 MDR이 발현되었다고 단정할 수는 없게 된다. 즉 MDR의 발현유무를 정확하게 감별할 수 있기 위하여는 저항이 없는 세포에 MIBI가 충분하게 섭취되어야 한다는 것이 필수적인 요건이며, 종양세포 종류에 따라서는 FDG가 MDR의 marker가 될 수 있다는 것이다. Pgp 수송체는 ATP의존성 약제배출 펌프이므로 MDR세포는 에너지가 많이 필요하여, MDR 세포는 당분해율(rate of glycolysis)이 증가되어 있고 HT-29 mdrl 종양세포에서는 포도당 이동과정의 변화로 FDG 섭취가 감소되었다. 또한 Pgp가 점차 증가됨과 함께 plasma membrane transporter인 GLUT-1 level이 감소된다. 이러한 결과는 다약제내성의 영상화가 지금까지의 예상보다 보다 복합적이고 다양하므로 보다 많은 연구가 필요할 것이라는 점을 시사한다. 최근 시도되고 있는 생체광학 영상을 이용한 다약제내성 유전자 및 Pgp 발현 연구는 아직 시작단계이나, 분자 생물학적 영상법의 발전과 함께 MRI 기술등에도 이용될 수 있으므로 향후 많은 연구가 있을 것으로 기대된다.

Although the outcome of cancer patients after cytotoxic chemotherapy is related diverse mechanisms, multidrug resistance (MDR) for chemotherapeutic drugs due to cellular P-glycoprotein (Pgp) or multidrug-resistance associated protein (MRP) is most important factor in the chemotherapy failure to cancer. A large number of pharmacologic compounds, including verapamil, quinidine, tamoxifen, cyclosporin A and quinolone derivatives have been reported to overcome MDR. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are available for the detection of Pgp and MRP-mediated transporter. $^{99m}Tc$-MIBI and other $^{99m}Tc$-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies for tumor imaging, and to visualize blockade of PgP-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with $^{11}C$ have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and $N-[^{11}C]acetyl-leukotriene$ E4 provides an opportunity to study MRP function non-invasively in vivo. SPECT and PET pharmaceuticals have successfully used to evaluate pharmacologic effects of MDR modulators. Imaging of MDR and reversal of MDR with bioluminescence in a living animal is also evaluated for future clinical trial. We have described recent advances in molecular imaging of MDR and reviewed recent publications regarding feasibility of SPECT and PET imaging to study the functionality of MDR transporters in vivo.

키워드

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