Hinoshita E, Uchiumi T, Taguchi K, Kinukawa N, Tsuneyoshi M, Maehara Y, Sugimachi K, Kuwano M
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Clin Cancer Res. 2000 Jun;6(6):2401-7.
The expression of ATP-binding cassette superfamily transporter genes, such as P-glycoprotein/multidrug resistance (MDR) 1 and MDR protein (MRP) 1, is often up-regulated in various tumor types and is involved in responses to some anticancer chemotherapeutic agents. Five human MRP subfamily members (MRP2-6) with structural similarities to MRP1 have been identified. The relationships between MRP2-6 mRNA levels and drug resistance are not well understood. Data on 45 patients with colorectal cancer were analyzed. Of the ATP-binding cassette superfamily genes, we asked whether mRNA levels of MDR1, MRP1, MRP2, and MRP3 correlated with drug resistance to anticancer agents. For this analysis, we used quantitative reverse transcription-PCR, and the sensitivity to anticancer agents in surgically resected colon carcinomas was determined using the in vitro succinate dehydrogenase inhibition test. MDR1, MRP1, and MRP3 were highly expressed in normal colorectal mucosa, and the relative mRNA levels of MDR1, MRP1, and MRP3 in cancerous tissues compared with noncancerous tissues were decreased or unchanged. By contrast, MRP2 mRNA expression was low in normal colorectal mucosa and specifically increased in cancer regions compared with noncancerous regions. Of the anticancer agents prescribed for patients with colorectal cancers, including doxorubicin, mitomycin C, cisplatin, 5-fluorouracil, etoposide, and a camptothecin derivative, mRNA expression of MRP2 was significantly associated with resistance to cisplatin. MRP2 may be important for resistance to cisplatin treatment in colorectal cancer.
ATP结合盒超家族转运蛋白基因，如P-糖蛋白/多药耐药（MDR）1和多药耐药蛋白（MRP）1，在多种肿瘤类型中表达常常上调，并参与对某些抗癌化疗药物的反应。已鉴定出五个与MRP1结构相似的人类MRP亚家族成员（MRP2 - 6）。MRP2 - 6 mRNA水平与耐药性之间的关系尚未完全清楚。分析了45例结直肠癌患者的数据。对于ATP结合盒超家族基因，我们询问MDR1、MRP1、MRP2和MRP3的mRNA水平是否与对抗癌药物的耐药性相关。为此分析，我们使用了定量逆转录PCR，并通过体外琥珀酸脱氢酶抑制试验测定手术切除的结肠癌对抗癌药物的敏感性。MDR1、MRP1和MRP3在正常结直肠黏膜中高表达，与非癌组织相比，癌组织中MDR1、MRP1和MRP3的相对mRNA水平降低或不变。相比之下，MRP2 mRNA在正常结直肠黏膜中表达较低，与非癌区域相比，在癌区域中特异性增加。在为结直肠癌患者开具的抗癌药物中，包括阿霉素、丝裂霉素C、顺铂、5-氟尿嘧啶、依托泊苷和一种喜树碱衍生物，MRP2的mRNA表达与对顺铂的耐药性显著相关。MRP2可能对结直肠癌顺铂治疗的耐药性很重要。
