Biodistribution and Hepatic Metabolism of Galactosylated $^{111}In-Antibody-Chelator$ Conjugates: Comparison with $^{111}In-Antibody-Chelator$ Conjugates

곽동석,정규식,하정희,안병철,이규보,백창흠,이재태,Kwak, Dong-Suk,Jeong, Kyu-Sik,Ha, Jeoung-Hee,Ahn, Byeong-Cheol,Lee, Kyu-Bo,Paik, Chang-H.,Lee, Jae-Tae The Korea Society of Nuclear Medicine 2003 핵의학 분자영상 Vol.37 No.5

목적: 종양의 진단과 치료에 널리 이용되고 있는 단클론항체를 수용체에 결합하는 수송체로 이용할 수 있는지에 대한 가능성 여부를 평가하기 위하여, 간의 asialoglycoprotein 수용체에 결합할 수 있는 갈락토즈접합 단클론항체를 $^{111}In$로 표지하여 체내에서의 분포와 간을 중심으로 한 체내대사를 분석하였고, 그 결과를 갈락토즈를 접합하지 않은 $^{111}In$ 표지 항체와 비교하였다. 재료 및 방법: 인체 림프 구성백혈병 세포에 대한 T101 단일클론항체를 cyclic DTPA dianhydrate(DTPA) 나 2-p-isothiocy-anatobenzyl-6-methyl-DTPA(IB4M) 로 접합하고 갈락토즈를 붙인후 $^{111}In$으로 표지하였다. 생쥐와 흰쥐에서 갈락토즈를 접합한 화합물과 접합하지 않은 화합물의 체내분포와 간대사를 비교분석하였다. 결과: $^{111}In$ 표지 T101항체와 갈락토즈 접합체는 투여량의 대부분이 10분 이내에 간에 섭취되었다. DTPA 접합자를 사용한 경우 IB4M 접합자를 사용한 경우보다 간에 오랫동안 저류되어 주사 후 44시간 간 섭취율이 각각 55%와 20% 였다. 이 기간동안의 DTPA화합물의 방사성 대사산물은 24%가 소변으로 17%가 대변으로 배설되어 유사하였으나 IB4M 화합물은 68%가 대변으로 8%가 소변으로 배설되어 배설경로에 차이가 있었다. 1B4M화합물을 주사후 3시간의 담즙과 간 현탁액을 HPLC로 분석한 결과 IgG와 저류시간(Rt)이 같은 첫 절정에 35%,유리 $^{111}In$과 유사한 절정의 Rt에 65%가 관찰되어 대사산물이 빠르게 답즙으로 배출됨을 알 수 있었고, DTPA 화합물 주사후 3시간 대사산물은 90%가 $^{111}In-DTPA$와 유사한 Rt의 절정을 보였다. 그러나 대변의 $^{111}In$ 의 축적량은 낮아 DTPA 접합화합물은 담도를 통한 빠른 배설이 일어나지 않음을 알 수 있었다. 결론: 단일클론항체에 갈락토즈를 접합한 경우보통의 항체에 비하여 간 섭취가 많고, 간에서의 대사가 촉진된다. 이 경우 사용되는 접합자의 선택에 따라서 대사산물의 성분이 달라지고 간에서의 제거도 차이가 있다. 이러한 대사의 차이점은 향후 종양세포나 조직의 탐색에 이용할 방사능 표지 항체의 제조에 응용될 수 있을 것이다. Purpose: To evaluate the use of monoclonal antibody (MoAb) as a carrier of the receptor-binding ligand the receptor mediated uptake into liver and subsequent metabolism of $^{111}In-labeled$ galactosylated MoAb-chelator conjugates were investigated and compared with those of $^{111}In$ labeled MoAb. Materials and Methods : T101 MoAb, $IgG_2$ against human lymphocytic leukemic cell, conjugated with cyclic DTPA dianhydride (DTPA) or 2-p-isothiocyanatobenzyl-6-methyl-DTPA (1B4M) was galactosylated with 2-imino-2-methoxyethyl-1-thio-${\beta}$-D-galactose and then radiolabeled with $^{111}In$. Biodistribution and metabolism study was peformed with two $^{111}In-conjugates$ in mice and rats. Results: $^{111}In-labeled$ T101 and its galactosylated conjugates were taken to the liver by the time, mostly within 10 min. However DTPA conjugate was retained longer in the liver than the 1B4M conjugate (55% vs 20% of injected dose at 44 hr). During this time, the radiornetabolite of DTPA conjugate was excreted similarly into urine (24%) and feces (17%). The radiometabolite of 1B4M was excreted primarily into feces (68%) rather than urine (8%). Size exclusion HPLC analysis of the bile and supernatant of liver homogenate showed two peaks the first (35%) with the retention time (Rt) identical to IgG and the second (65%) with Rt similar to free $^{111}In$ at 3 hr post-injection for the 1B4M conjugate, indicating that the metabolite is rapidly excreted through the biliary system. in contrast to DTPA conjugate, the small $^{111}In-DTPA-like$ metabolite was the major radioindium component (90%) in the liver homogenate as early as 3 hour post-injection, but the cumulative radioindium activity in feces was only 17% at 44 hour, indicating that the metabolite from DTPA conjugate does not clear readily through the biliary tract. Conclusion: The galactosylation of the MoAb conjugates resulted in higher hepatocyte uptake and enhanced metabolism, compared to those without galactosylation. Metabolism of the MoAb-conjugates is different between compounds radiolabled with different chelators due to different characteristics of radiometabolites generated in the liver.

과백혈구증가증을 동반한 급성 백혈병의 임상적 고찰

이영학(Young Hahk Lee),현동우(Dong Woo Hyun),김정균(Jung Gyun Kim),배선근(Sun Kun Bae),곽동석(Dong Suk Kwak),손상균(Sang Kyun Sohn),이재태(Jae Tae Lee),이규보(Kyu Bo Lee) 대한내과학회 1997 대한내과학회지 Vol.52 No.4

N/A Objectives: It is well known that Acute Leukemic patients with Hyperleukocytosis (ALH, leukocyte count≥100,000/μL) have poor prognosis. This is indebted in fatal complications arising from cerebral and pulmonary leukostasis. To investigate the factors influence on the prognosis of these patients, we have analyzed age, sex, laboratory findings and complications and their relationship to remission rate. Methods: Retrospective evaluation was done from January 1985 to March 1994 on fifty-four patients with ALH. We excluded secondary leukemias transformed from chronic myelogeneous leukemia, relapsed acute leukemia and myelodysplastic syndrome in this study. The prognostic factors associated with early death were also evaluated. Results: 1) Hyperuricemia and incidence of central nervous system and respiratory symptoms were higher in acute myelogeneous leukemia (AML) with hyperleu-kocytosis than in acute lymphocytic leukemia (ALL), 2) Twenty-two of fifty-four patients had complete remission by remission induction chemotherapy. Re- mission rate was 41%, median duration of remission was 26 weeks and 1 year survival rate was 11%. 3) There were no differences in remission rate between male and female and higher WBC group (WBC≥200,000/pL) and lower WBC group (WBC 100,000~200,000/u L). 4) The group with better performance status (ECOG score1-2), younger (age below 40) and higher hemoglobin level (Hb>10g/dL) had higher remission rate. The group of AML and with hepatomegaly had lower remission rate than the group of ALL and without hepatomegly. 5) Early death rate of AML was higher than that of All. Infection was the most common cause of early death in both AML and ALL. 6) Early death rate between the two groups managed with and without leukapheresis was not different. Conclusions: This result reveals that acute leukemia with hyperleukocytosis is grave disease, especially the patients with poor performance status (ECOG score : 3-4), older age above 40 and severe anemia (Hb<10g/dL) have poor prognosis, The group of AML and with hepatomegaly showed worse prognosis than the group of ALL and without hepatomegaly.

총담관낭종의 99mTc - DISIDA 간담도 스캔

이규보(Kyu Bo Lee),이재태(Jae Tae Lee),정병천(Byung Cheon Chung),최정일(Chung Il Choi),곽동석(Dong Suk Kwak),전석길(Seok Kil Zeon),김정균(Jeong Gyun Kim),배선근(Sun Kun Bae),이형우(Hyung Woo Lee) 대한핵의학회 1993 핵의학 분자영상 Vol.27 No.1

N/A In order to evaluate the scintigraphic features of choledochal cyst and these diagnostic value, authors investigated the findings of fourteen patients with choledochal cyst undergone hepatobiliary scan with Tc-99m-DISIDA before surgery. Five cases demonstrated the decreased hepatic uptake at 5-minute image of which four cases revealed severe jaundice. Seven cases demonstrated visualization of the cystic dilated common bile duct within 1 hour after injection. Two cases showed the cyst activity between 1 and 12 hour, but the cyst activity was not visible in five cases. Nonvisualization of the gall bladder was noted in ten cases, while four cases demonstrated visualization of the gall bladder within 1 hour. The time of visualization of gut activity was variably delayed. The intestinal activity was found in three cases within 1 hour and appeared in three cases between 1 and 2 hours and eight cases showed no visible gut activity. In four cases, intrahepatic ductal prominence was visible on the scintigram. Seven cases showed early and persistent accumulation of tracer in the common bile duct. Three cases showed persistent photon-deficient area in the gall bladder region. Two cases showed early photon-deficient area around gall bladder region with progressive accumulation of tracer in the same region. Two cases showed no evidence of activity in the biliary tract but noted late excretion into the sma11 intestine. We concluded that hepatobiliary scan using Tc-99m-DISIDA is a noninvasive test useful in the eva1uation and the diagnosis of choledochal cyst.

심근관류 스캔중에 나타난 Thallium - 201의 심장외 국소적 섭취

이규보(Kyu Bo Lee),이재태(Jae Tae Lee),정병천(Byung Cheon Chung),최정일(Chung Il Choi),곽동석(Dong Suk Kwak),박무근(Moo Keun Park) 대한핵의학회 1992 핵의학 분자영상 Vol.26 No.1

N/A Myocardial perfusion imaging with 201T1-chloride following exercise or vasodilator-induced hyperemia has been effective in detecting the presence of coronary artery disease. An increased lung uptake of thallium has been reported as a sensitive marker of severe and extensive coronary artery disease and associated with poor prognosis. Thallium has also been noted to concentrate in a variety of malignant lesions. We report 5 cases of extracardiac uptake of thallium during myocardial perfusion scan with pharmacologic vasodilation. Accumulation of thallium was found in the lesions of a breast cancer, a lung cancer, a Castleman's disease and 2 cases of thymoma. We believe that the presence of focal extracardiac uptake of thallium during myocardial perfusion scan should suggest the need for further clinical evaluation to detect the tumor and must differentiate the increased lung uptake of thallium due to left ventricular dysfunction in coronary artery disease.

정상인 심근의 Thallium - 201 섭취 및 제거 : Adenosine , Dipyridamole Dobutamine 정맥주사와 운동부하시의 비교

이규보(Kyu Bo Lee),이재태(Jae Tae Lee),정병천(Byung Chun Chung),채성철(Shung Chull Chae),곽동석(Dong Suk Kwak),최정일(Jung Il Choi),정진홍(Chin Hong Chung) 대한핵의학회 1993 핵의학 분자영상 Vol.27 No.1

Adenosine 부하 99mTc-MIBI 심근 관류스캔도중 나타나는 ST 절 하강과 관상동맥 질환의 중증도와의 관계

이규보(Kyu Bo Lee),이재태(Jae Tae Lee),손상균,채성철,전재은,박의현,정병천(Byung Cheon Chung),최정일(Chung Il Choi),곽동석(Dong Suk Kwak),강승완(Seung Wan Kang),우언조(Eon Jo Woo),김정균(Jeong Gyun Kim),배선근(Sun Kun Bae),조정아(Jung Ah Cho) 대한핵의학회 1994 핵의학 분자영상 Vol.28 No.2

N/A Pharmacologic coronary vasodilation in conjunct.ion with myocardial perfusion scintigraphy has become an alternative to dynamic exercise test for the diagnosis and risk stratification of coronary arter y disease, especially in patients who are unable to perform adequate exercise. Dipyridamole and adenosine have been used for pharmacologic stress t,esting with myocardial perfusion imaging. Adenosine is a potent, coronary vasodilator with rapid onset of action, short half Iife, near maximal coronary vasodilation and less serious side effects. ST segment depression has been reported in about 7-15% of patients with coronary artery disease receiving dipyridamole in conjunction with myocar dial perfusion imaging. The exact cause and clinical significance are not known. In order to evaluate ihe relationship between adenosine-induced ST segment depression dur- ing Tc-MIBI myocardial perfusion scin(igraphy and the severity of coronary artery disease, we performed 99mTc-MIBI imaging after int#ravenous infusion of adenosine in 120 patients with susper,t.ed coronary artery disease. Of t.he 120 patients, 28 also performed coronary angiography. There were 24 patients with ST segment depression during 99mTc-5/IIBI scintigraphy and 96 patients without ST segment depression. Adenosine was infused intravenously at. a dose of 0.14mg/kg per minute for 6minutes and 99mTc-MIB1 was injected at 3 miinute. We then compared the hemodynamic changes, side effects, scintigraphic and angiographic findings. Heart, rate increased 90 +- 19 beats/minute in t.he group with ST depression compared with 80+16 beats/rninute in the group without ST depression(p<0.05). Baseline systolic blood pressure was significantly higher in the group with ST depression(152 +- 27 mmHg) than in the group without ST depression(140 +- 21mmHg, p<0.05). Double product, at baseline(10.90 +- 2.77 versus 9.55 +- 2.34beats/minutexmmHg) and during adenosine infusion(12.72 +- 3.89 versus 10.83+2.98 beats/minutexmrnHg) were significant,ly higher in t.he group with ST de pression(p<0.05). The incidenoe of anginal chest pain was also significantly higher in the group with ST depression(75 versus 29%, p<0.0001). The 99mTc-MIBI images were abnormal in 23(96%) patients wit.h ST segment depression and 66(69%) patients without ST segment depression(p<0.05). In patients with ST segment depression, there were more reversible per- fusion defects than in patients without ST segment depression(83 versus 55%, p<0.05). The number of abnormal segments were significantly higher in the group with ST depression(3.05 +- 2.01 versus 1.51 +- 1.45, p<0.005). In patients with ST segment depression, there were more segments of reversible perfusion defects than in patients without segment depression(2.15 +- 2. 11 versus 0.89 +- 1.24, p<0.05). There were no differences in the angiographic severity by ves sel(p, NS). We concluded that ST segment depression during 99mTc-MIBI myocardial perfusion scintigraphy with intravenous adenosine is related to the severity of coronary artery disease.

기관지천식 환자에서 혈청 IgG 와 IgG 아형 측정

박해심,곽연식,김희연,한동석,이수걸,남동호,이재욱,김선신 대한알레르기학회 1999 천식 및 알레르기 Vol.19 No.6

Background and objective : IgG subclass deficiency has been reported in patients with bronchial asthma and is associated with recurrent respiratory tract infections. This study was done to identify prevalence of IgG subclass deficiency and to evaluate the possible difference between atopic and non-atopic asthmatics. Subjects and methods : We measured serum levels of IgG and IgG subclass in 35 asthmatic patients and 50 healthy controls using nephelometry. Reference values of each IgG subclass was defined as cumulative percentile between 2.5% to 97.5% of controls. Results : Total IgG, IgG1 and IgG2 of asthmatics were significantly lower than for those of controls(p$lt;0.05, respectively). In atopic asthmatics, compared with non-atopic asthmatics, IgG4 level was significantly higher (p$lt;0.05). The frequency of IgG subclass levels below the reference value was eight (22.9%) of 35 asthmatics. Conclusion : IgG, IgG1 and IgG2 were significantly lower in asthmatic patients. Some patients had IgG subclass levels below reference value. Further studies will be needed to evaluate their clinical significance.

부비강미분화암종 3예

김용대,곽동석,이형중,신재흔,배창훈,송시연 영남대학교 의과대학 2004 Yeungnam University Journal of Medicine Vol.21 No.1

Sinonasal Undifferentiated Carcinoma (SNUC) is a very rare, highly aggressive malignant tumor of the nasal cavity and paranasal sinuses. SNUC tends to present with advanced-stage disease, often with intracranial invasion. It requires an aggressive multimodality therapy that includes surgical resection. A cure rate of less than 20% is generally reported in the literature, with most patients dying within 1 year of onset of the disease. Three patients diagnosed as SNUC were treated at the Yeungnam University Medical Center between the years 2000 and 2003 were analyzed retrospectively. All patients presented with the disease very advanced. The three cases were given chemotherapy or chemotherapy with radiotherapy. Two patients died of the disease, surviving only 6 and 11 months following treatment, respectively. We did a follow-up on just the one remaining case with incomplete controlled disease for 27 months. The overall prognosis of SNUC is very poor. We consider that more intensive multimodality therapies are recommended for all patients with SNUC.

급성 림프구성 백혈병의 구제항암화학요법 후 골수부전기에 발생한 Trichosporon beigelii 폐렴 1례

정진태,백진호,김동환,곽동석,박소향,손상균,서장수,이규보 大韓血液學會 2000 大韓血液學會誌 Vol.35 No.2

다약제내성 발현 암세포에서 99mTc-sestamibi와 99mTc-tetrofosmin 섭취의 비교

유정아,정신영,서명랑,곽동석,안병철,이규보,이재태 대한핵의학회 2003 핵의학 분자영상 Vol.37 No.3

목적 : 다약제내성이 유발된 암세포에서 ^99mTc-sestamibi와 ^99mTc-tetrofosmin의 암세포 내 섭취정도를 비교하고 다약제내성 극복제로 잘 알려진 verapamil 과 cyclosporin A 처리에 의한 두 방사성 의약품의 암세포 내 섭취정도를 비교해 보았다. 재료 및 방법 : Doxorubicin으로 다약제내성이 유발된 HCT15/CL02 대장암 세포와 doxorubicin과 vincristine으로 다약제내성을 유발시킨 K562(Adr)과 K562(Vcr) 백혈병 세포를 사용하였다. 다약제내성의 발현은 RT-PCR로 증명하였으며, vetapamil은 1, 10, 50, 100, 200 ㎛의 농도로, cyclosporin A는 0.1, 1, 10, 50, 100 ㎛의 농도로 각각 사용하였다. MIBI와 tetrofosmin의 암세포내 섭취는 37℃에서 1 × 10_6 cell/㎖ 농도의 단일세포 부유상태에서 1, 15, 30, 45, 60분 간격으로 배양하여 각 시간대별로 상층액과 침전물을 분리하여 각각의 방사능을 감마 계수기로 측정하였다. 결과 : 다약제내성이 발현된 암세포에서는 모세포에 비하여 MIBI와 tetrofosmin의 섭취가 감소되었다. 두 방사성약품의 섭취정도는 HCT15/CL02세포와 K562(Adr)세포에서는 유의한 차이가 없었으나, K562(Vcr)세포에서는 MIBI가 tetrofosmin보다 다소 높았다. Verapamil과 cyclosporin A를 처리하였을 때 MIBI와 tetrofosmin의 섭취율은 기저치보다 모두 증가하였고, verapamil에 의한 MIBI와 tetrofosmin의 섭취율(30분)을 기저치(30분)와 비교해 본 결과 HCT15/CL02세포에서 (100㎛)는 각각 11.9배와 6.8배, K562(Adr)세포에서(50 ㎛)는 각각 14.3배와 8배, K562(Vcr)세포에서(10㎛)는 각각 7배와 5.7배 증가하였다. Cyclosporin A에 의한 MIBI와 tetrofosmin의 섭취율(30분)을 기저치(30분)와 비교해 본 결과 HCT15/CL02세포에서(50 ㎛)는 각각 10배와 2.4배, K562(Adr)세포에서(50 ㎛)는 각각 44배와 13배, K562(Vcr)세포에서(10㎛)는 각각 18.8배와 11.8배 증가하여, MIBI의 섭취율이 tetrofosmin보다 1.2배에서 4배정도 높게 나타났다. 결론 : 이러한 결과로 보아 MIBI와 tetrofosmin은 다약제내성의 발현을 평가할 수 있는 방사성의약품으로 판단되며, 다약제내성 극복제의 효능평가에는 MIBI가 tetrofosmin보다 더 우수할 것으로 사료되나, 세포주에 따른 차이가 있을 수 있으므로 보다 많은 세포주에서의 추가적인 연구가 필요할 것이다. Purpose : Cellular uptakes of ^99mTc-sestamibi(MIBI) and ^99mTc-tetrofosmin into cancer cell lines expressing multidrug resistance(MDR) were investigated and compared. The effects of verapamil and cyclosporin A, well-known multidrug resistant reversing agents, on cellular uptake of both tracers were also compared. Materials and Methods : Doxorubicin-resistant HCT15/CL02 human colorectal cell and doxorubicin-resistant K562(Adr) and vincristine-resistant K562(Vcr) human leukemic cells were studied. RT-PCR analysis was used for the detection of mdr1 mRNA expression. MDR-reversal effects with verapamil and cyclosporine A were evaluated at different drug concentrations after incubation with MIBI and tetrofosmin for 1, 15, 30, 45 and 60 min, using single-cell suspensions at 1×10_6 cell/㎖ incubated at 37℃. Radioactivity in supernatants and pellets were measured with gamma well counter. Results : The cellular uptakes of MIBI and tetrofosmin in K562(Adr) and K562(Vcr) were lower than those of parental J562 cell. In HCT15/CL02 cells and K562(Adr) cells, there were no significant difference in cellular uptakes of both tracers, but cellular uptake of MIBI was higher than that of tefrofosmin in K562(Vcr) cells. Coincubation with verapamil resulted in a increase in cellular uptakes of MIBI and tetrofosmin. Verapamil increased cellular uptakes of MIBI and tetrofosmin by HCT15/CL02 cell by 11.9- and 6.8-fold, by K562(Adr) cell by 14.3- and 8-fold and by K562(Vcr) cell by 7- and 5.7-fold in maximum, respectively. Cyclosporin A increased cellular uptakes of MIVi and tetrofosmin by HCT15/CL02 cell by 11.9- and 6.8-fold, by K562(Adr) cell by 14.3- and 8-fold and by K562(Vcr) cell by 7- and 4.7-fold in maximum, respectively. Cyclosporin A increased cellular uptakes of MIBI and tetrofosmin by HCT15/CL02 cell by 10- and 2.4-fold, by K562(Adr) cell 44- and 13-fold and by K562(Vcr) cell by 18.8- and 11.8-fold in maximum, respectively. Conclusion : Taking together, MIBI and tetrofosmin are considered as suitable radiopharmaceuticals for detecting multidrug resistance. However, MIBI seems to be a better tracer than tetrofosmin for evaluation MDR reversal effect of the modulators. Since cellular uptakes of both tracers might differ in different cell types, further experiments regarding differences in cellular uptakes between cell types should be explored.