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급성백혈병환자에서 다제약제내성 유전자(MDR1)의 과표현(P-glycoprotein)및 치료예측

Other Titles
 Overexpression of multidrug resistant gene(P-glycoprotein) and therapeutic outcome in acute leukemia 
Issue Date
1991
Description
의학과/박사
Abstract
[한글] 급성백혈병은 진단후 1차 관해유도 약물치료에 의해 60∼80%에서 완전관해가 유도되나 1년 내에 50%의 환자에서 재발하며, 이들에게 재차 관해유도 치료가 시도되어도 관해율은 30∼50%에 불과하다. 그리고 1차 관해유도치료에 불응성인경우 2차 약제로 관해유도 약 물요법이 시행되나 그 성적 역시 저조하여 백혈병 환자의 5년 무병생존율은 25% 정도다. 이같이 백혈병 치료실패율이 높은 원인중 항암약제내성이 중요 인자이며, 약제내성중에서도 특히 다제약제내성 유전자(multidrug resistant gene; MDRI)의 활성화에 의해 서로 교차내성이 없는 4가지 약제에 내성을 나타내는 다제약제내성이 중요한 원인이다. 본 연구에서는 백혈병환자에서 MDRI 유전자의 다제약제내성이 표현되는 과정중 DNA와 m RNA는 dot blot 분석으로, 최종산물인 P-glycoprotein은 면역조직화학적염색법(immunohis tochemical staining method)으로 유전자의 증폭(amplification) 혹은 과표현(overexpres sion) 여부를 관찰하여 다제약제내성의 존재를 증폭 혹은 과표현 과정중 용이하게 진단할 수 있는 방법을 조사하고, 아울러 다제약제내성의 발현도를 백혈병 각 질병상태별로 조사하였다. 그리고 다제약제내성의 환자 치료결과 예측 및 치료약제 선택기준으로서의 임 상적 유용성을 조사하기 위하여 다제약제내성 발현여부와 치료결과와의 상관성 및 다제약 제내성 발현여부와 생체외 약제감수성 검사에 의한 약제내성과의 상관성을 조사하여 다음과 같은 결과를 얻었다. 1. 다제약제내성은 DNA에서는 0%(O/26), mRNA에서는 7.7%(2/26), P-glycoprotein에서는 55.4%(41/74) 관찰되었다. 2. P-glycoprotein 과표현은 원발성백혈병 진단시 33.3%, 재발시 78.6%, 치료불응성시 88.9%에서 관찰되어 약제에 노출시 발현빈도는 증가하였다(p<0.01). 3. 속발성 백혈병은 원발성 백혈병에 비해 P-glycoprotein 과표현 빈도가 높은 경향이었다(p=0.18). 4. 진단시 P-glycoprotein을 과표현하는 경우 관해유도율이 낮은 경향이었다(p=0.11). 5. P-glycoprotein을 이용한 관해유도실패 예측도는 수용할만 하였으나(84%), 관해유도 예측도는 낮았다(54%). 6. P-glycoprotein 과표현시 adriamycin, vincristine에 대한 약제내성 발현빈도가 P-glycoprotein을 과표현하지 않는 경우보다 높았다(p= 0.04). 7. P-glycoprotein을 이용한 adriamycin, vincristine에 대한 약제내성 예측도는 수용할만 하였으나(각각 75%, 81%), 약제 감수성 예측도는 낮았다(각각 57%, 43%). 8. P-glycoprotein을 과표현시 verapamil 병용에 의한 다제약제내성의 변화는 adriamycin에서 33.3%, vincristine에서 16.7%였다. 이상의 결과로 면역조직화학적염색에 의한 P-glycoprotein 과표현 여부 관찰이 다제약 재내성 존재확인의 간편한 검사방법이며, 이를 치료결과 예측의 유용한 기준으로 사용할 수 있을 것으로 생각된다. 그리고 다제약제내성이외의 약제내성 기전을 고려하여 생체외 약제 감수성 검사를 병행, 적절한 약제선택을 함으로써 급성백혈병의 치료효과를 증가시킬 수 있을 것으로 기대된다. Overexpression of multidrug resistant gene(P-glycoprotein) and therapeutic outcome in acute leukemia Hyun Cheol Chung Department of Medical Science, The Graduate School, Yonsei University (Directed by Professor Jee Sook Hahn) The complete remission rate of the first induction chemotherapy is 60∼80% in acute leukemia. Most patients who achieve complete remission will ultimately relapse within the first year and are much less responsive to the therapy with a brief second remission in a minority. Acquisition of drug resistance in cellular level is the major cause of treatment failure. Therefore, the identification of the mechanisms of drug resistance is an important goal of current treatment. One mechanism that has been extensively studied in vitro is a multidrug resistance(MDR) mediated by P-glycoprotein which is the product of the MDRI gene, but there is a little information on it's clinical application. In order to find out a suitable method for detecting MDR, and furthermore, to see if the detection of MDR can be used in predicting treatment results, here, the existence of MDR1 amplification/overexpression in DNA, RNA and P-glycoprotein level was studied. P-glycoprotein overexpression by immunohistochemical staining method was more sensitive(55.4%) than DNA amplification(0.0%) and mRNA overexpression(7.7%) in detecting MDR in acute leukemic patients. The incidence of P-glycoprotein overexpression was higher in relapsed(78.6% ) and in refractory patients(88.9%) than in initial state(33.3%). There was a tendency of low complete remission rate in patients with primary P-glycoprotein overexpression. The incidence of acquired P-glycoprotein overexpression was 71.4%. When comparing the correlation between the P-glycoprotein overexpression and the clinical results, the predictability for the treatment failure in P-glycoprotein overexpressing patients was acceptable(86%), but the predictability for the remission in P-glycoprotein non-expressing patients was low(54%). These Predictability were similar to the predictability for drug resistance by comparing the correlation between the P-glycoprotein overexpression and in vitro cytotoxic assay results; the predictability for drug resistance to adriamycin in P-glycoprotein overexpressing patients was acceptable(75%), but the predictability of drug sensitivity in P-glycoprotein non-expressing patients was low(57%). Combination of verapamil and cytotoxic drug reversed MDR in 33.3% for adriamycin and 16.7% for vincristine in P-glycoprotein overexpressing patients. These results suggest the P-glycoprotein by immunohistochemical staining method could be a useful method for predicting treatment results. However, the low predictability for the remission in P-glycoprotein non-expressing patients, suggested by some other drug resistance mechanisms, can be overcome by combination with in vitro cytotoxic assay, This fact might contribute to the better treatment results in acute leukemia by optimization of drug selection.
[영문] The complete remission rate of the first induction chemotherapy is 60∼80% in acute leukemia. Most patients who achieve complete remission will ultimately relapse within the first year and are much less responsive to the therapy with a brief second remission in a minority. Acquisition of drug resistance in cellular level is the major cause of treatment failure. Therefore, the identification of the mechanisms of drug resistance is an important goal of current treatment. One mechanism that has been extensively studied in vitro is a multidrug resistance(MDR) mediated by P-glycoprotein which is the product of the MDRI gene, but there is a little information on it's clinical application. In order to find out a suitable method for detecting MDR, and furthermore, to see if the detection of MDR can be used in predicting treatment results, here, the existence of MDR1 amplification/overexpression in DNA, RNA and P-glycoprotein level was studied. P-glycoprotein overexpression by immunohistochemical staining method was more sensitive(55.4%) than DNA amplification(0.0%) and mRNA overexpression(7.7%) in detecting MDR in acute leukemic patients. The incidence of P-glycoprotein overexpression was higher in relapsed(78.6% ) and in refractory patients(88.9%) than in initial state(33.3%). There was a tendency of low complete remission rate in patients with primary P-glycoprotein overexpression. The incidence of acquired P-glycoprotein overexpression was 71.4%. When comparing the correlation between the P-glycoprotein overexpression and the clinical results, the predictability for the treatment failure in P-glycoprotein overexpressing patients was acceptable(86%), but the predictability for the remission in P-glycoprotein non-expressing patients was low(54%). These Predictability were similar to the predictability for drug resistance by comparing the correlation between the P-glycoprotein overexpression and in vitro cytotoxic assay results; the predictability for drug resistance to adriamycin in P-glycoprotein overexpressing patients was acceptable(75%), but the predictability of drug sensitivity in P-glycoprotein non-expressing patients was low(57%). Combination of verapamil and cytotoxic drug reversed MDR in 33.3% for adriamycin and 16.7% for vincristine in P-glycoprotein overexpressing patients. These results suggest the P-glycoprotein by immunohistochemical staining method could be a useful method for predicting treatment results. However, the low predictability for the remission in P-glycoprotein non-expressing patients, suggested by some other drug resistance mechanisms, can be overcome by combination with in vitro cytotoxic assay, This fact might contribute to the better treatment results in acute leukemia by optimization of drug selection.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/117000
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2. 학위논문 > 1. College of Medicine > 박사
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