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소세포폐암에서 Multidrug Resistance-1 유전자의 다형성과 Etoposide-cisplatin 항암화학요법 반응의 관계

The Relationship between MDR1 Polymorphisms and the Response to Etoposide/Cisplatin Combination Chemotherapy in Small Cell Lung Cancer

Tuberculosis and respiratory diseases : TRD = 결핵 및 호흡기 질환, v.58 no.2 = no.241, 2005년, pp.135 - 141  

손지웅 (경북대학교 의과대학 내과학교실) ,  이신엽 (경북대학교 의과대학 내과학교실) ,  이수정 (경북대학병원 암연구센터) ,  전효성 (경북대학병원 암연구센터) ,  이재희 (경북대학교 의과대학 내과학교실) ,  박재형 (경북대학교 의과대학 내과학교실) ,  김은진 (경북대학교 의과대학 내과학교실) ,  강영모 (경북대학교 의과대학 내과학교실) ,  이재태 (경북대학교 의과대학 핵의학교실) ,  차승익 (경북대학교 의과대학 내과학교실) ,  김창호 (경북대학교 의과대학 내과학교실) ,  정태훈 (경북대학교 의과대학 내과학교실) ,  박재용 (경북대학교 의과대학 내과학교실)

초록
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배경 및 목적 : Multidrug Resistance-1 (MDR1) 유전자는 다약제내성에 관여하는 P-glycoprotein을 암호화한다. MDR1 유전자의 다형성은 P-glycoprotein의 발현과 기능의 차이를 일으켜 항암화학요법 반응에 영향을 미칠 수 있을 것이다. 저자들은 소세포폐암 환자에서 MDR1 유전자의 다형성과 일배체형에 따른 항암화학요법에 대한 반응을 조사하였다. 대상 및 방법 : 경북대학병원에서 병리적으로 소세포폐암으로 진단받고 etoposide-cisplatin 항암화학요법을 받은 54명을 대상으로 하였다. 전혈 5cc에서 DNA를 추출하고 PCR-RFLP법을 통해 MDR1 유전자 엑손 21의 2677G>T 다형성과, 엑손 26의 3435C>T 다형성을 조사하고 다형성과 일배체형에 따른 항암화학요법의 반응을 조사하였다. 결 과 : 2677G>T 유전자형에 따른 항암화학요법의 반응은 유의한 차이가 없었다. 3435 CC 유전자형은 3435 CT+TT 형에 비해 치료 반응율이 유의하게 높았다 (P = 0.025). 유전자형 분석 결과와 일치되게 2677G/3435C 일배체형은 다른 일배체형에 비해 치료반응을 보이는 경우가 유의하게 많았다 (P = 0.015). 결 론 : 소세포폐암에서 MDR1 유전자의 2677G>T와 3435C>T 다형성 및 이들 다형성의 일배체형은 etoposide-cisplatin 항암화학요법의 반응을 예측할 수 있는 지표로 사용될 수 있을 것으로 생각된다.

주제어

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제안 방법

  • In the present study, we included 54 SCLC patients who were histologically diagnosed at Kyungpook National University Hospital, Daegu, Korea from January 2002 to June 2003. All these patients underwent complete staging procedures including chest radiograph, CT scan of the thorax and upper abdomen, brain MRI and bone scan. The clinical data for smoking habits, weight loss and Eastern Cooperative Oncology Group performance status (ECOG PS) were collected prospectively.
  • Logistic regression analysis was performed to examine the association between genotypes/haplotypes and chemotherapy response with adjustment for possible confounders [age as a continuous variable, and sex, staging (limited vs extensive stage) and PS (ECOG 0-1 vs ECOG 2) as nominal variables]. Referent and 3 alternative models (codominant, dominant and recessive for the minor allele) were applied in the analyses. When multiple comparisons are made, the corrected P-values (Pcvalues) were also calculated for multiple testing using Bonferroni’s inequality method.
  • For quality control, the genotyping analysis was repeated twice for all the subjects. To confirm the genotyping results, selected PCR-amplified DNA samples (n = 2, respectively, for each genotype) were examined by DNA sequencing.
  • Therefore, we have hypothesized that these two variants of MDR1 gene, and particularly their haplotypes, could influence the response to chemotherapy. To test this hypothesis, we evaluated the association of 2677G>T and 3435C>T polymorphisms and their haplotypes with the response to chemotherapy for SCLC patients treated with a combination chemotherapy of etoposide and cisplatin (EP)

대상 데이터

  • The Patients consisted of 46 men and 8 women, and their average age was 61.6 ± 7.9 years. The clinical staging was limited disease (LD) in 28 patients and extensive disease (ED) in 26 patients.
  • 9 years. The clinical staging was limited disease (LD) in 28 patients and extensive disease (ED) in 26 patients. The ECOG PS was 0-1 in 35 patients and 2 in 19 patients.

데이터처리

  • Chi-square test was used to evaluate the association between clinical variables and chemotherapy response. Hardy-Weinberg equilibrium of alleles at individual loci was tested with a goodness-of-fit x2 test with one degree of freedom to compare the observed genotype frequencies with the expected genotype frequencies among the subjects. Haplotypes and their frequencies were estimated based on the Bayesian algorithm using the Phase program20, which is available at http:// www.

이론/모형

  • Hardy-Weinberg equilibrium of alleles at individual loci was tested with a goodness-of-fit x2 test with one degree of freedom to compare the observed genotype frequencies with the expected genotype frequencies among the subjects. Haplotypes and their frequencies were estimated based on the Bayesian algorithm using the Phase program20, which is available at http:// www.stat.washington. edu/stephens/phase.
  • Genomic DNA was extracted from peripheral blood lymphocytes by proteinase K digestion and phenol/chloroform extraction. The MDR1 2677G>T (Ala893Ser) and 3435C>T (Ile1145Ile) genotypes were determined by PCR-RFLP assay. PCR primers were designed based on the GenBank reference sequence (accession no.
  • Referent and 3 alternative models (codominant, dominant and recessive for the minor allele) were applied in the analyses. When multiple comparisons are made, the corrected P-values (Pcvalues) were also calculated for multiple testing using Bonferroni’s inequality method. All analyses were performed using Statistical Analysis Software for Windows, version 6.
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