卵巣がんにおける薬剤耐性の分子生物学的解析および耐性のin vitro評価方法に関する研究 (<シンポジウム>1. 卵巣がん化学療法の基礎と臨床)

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Acquisition of multidrug resistance (MDR) phenotype in ovarian cancers is the main obstacle in successful improvement of the treatment strategies. Currently, putative two MDR pathways have been proposed. First is membrane associated drug efflux pump such as MDR-1 and MRP or LRP(Type 1 MDR factor). Second is anti-apoptosis proteins such as p53, Bcl-2 and survivin (Type 2 MDR factor). In addition to these factors, we have studied DNA repair enzyme ERCC-1, microsatellite instability (MI) and c-erbB-2 amplification (Type 3 MDR factors) in 62 (stage I, II, III, IV=18, 9, 20, 15) ovarian cancer cases. Also plasma free telomere fragments are monitored before and after chemotherapy to test its diagnostic potential for early detection of MDR phenotype. The expression of type 1, 2, 3 MDR factors are equally seen in serous, mucinous, endometrioid and clear cell cancers. The MDR-1 and LRP were more frequently seen in advanced stages (III+IV) than early stases (I+II). Survival analysis by the Cox proportional hazard model showed over expression of mutant p53 (RR=3.3, p<0.006), survivin(RR=6.2, p<0.008) and amplification of c-erbB-2 (RR=2.0, p<0.01) were stage-independent risk factors. On the other hand, the progression free intervals (PFI) were affected by MDR-1 (RR=5.6, p<0.02) and LRP (RR=16.8, p<0.004). Expression of MDR-1 and LRP positively correlated with later development of MDR phenotype whereas type 2 has no impact on the MDR. Type 3 factors all positively correlated with the MDR phenotype after recurrence (ERCC-1 : RR=2, p<0.001, MI : RR=1.5, p<0.05, c-erbB-2 : RR=2.0, p<0.002). Chronology of MDR related factor expression was tested longitudinally in primary, early metastatic and late recurrent lesions of the same patients (n=19). The analysis showed frequency of MDR-1 expression, MI and c-erbB-2 amplification have been increased in late recurrent lesions whereas LRP and survivin have already been expressed in the primary lesions. These observation indicate that drug efflux pumps are related with recurrence and resistance but MDR-1 and MRP are associated with acquired resistance but LRP with primary resistance. The p53 and survivin are strong negative indicator for survival but have little impact on recurrence. ERCC-1, MI and c-erbB-2 do have relationship with recurrence and resistance. Lastly free telomere fragments are successfully detected in the peripheral blood and the positive predictive value for discriminating chemotherapy responders front non-responders was 0.83 whereas serum tumor markers had that of 0.52. This is the first report of chronology in MDR and MDR-related genes expressions in ovarian cancer. The distinct association of each MDR-related factors with clinical parameters indicates independent roles of these factors and thus potential use of the factors as target for molecular treatments of ovarian cancer.
社団法人日本産科婦人科学会の論文
1999-08-01

卵巣がんにおける薬剤耐性の分子生物学的解析および耐性のin vitro評価方法に関する研究 (<シンポジウム>1. 卵巣がん化学療法の基礎と臨床)

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