Modok Szabolcs, Mellor Howard R, Callaghan Richard
Oxford Drug Resistance Group, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
Curr Opin Pharmacol. 2006 Aug;6(4):350-4. doi: 10.1016/j.coph.2006.01.009. Epub 2006 May 11.
Early publications using cultured cancer cells immediately recognized the phenomenon of resistance to anticancer agents. However, it was not until 1973 that it was first demonstrated that a major factor in the resistance of cancer cells was that of reduced drug accumulation. This year marks the 30th anniversary of the discovery by Juliano and Ling that P-glycoprotein mediates this active efflux of chemotherapeutic drugs from cancer cells. Since this seminal finding, the investigation of P-glycoprotein (MDR1, ATP binding cassette [ABC]B1) has proceeded with great vigour. However, it soon became apparent that P-glycoprotein was not expressed in all drug-resistant cells that displayed an accumulation deficiency, which led to the discovery of other ABC transporters involved in drug efflux. In 1992, the multidrug resistance-associated protein (MRP1, ABCC1) was identified in small cell lung cancer followed by breast cancer resistance protein (mitoxantrone resistance protein, ABCG2) in 1999. After three decades of research, can we confidently define the contribution of multidrug resistance transporters to chemoresistance and do we have clinically useful drugs to sensitise cancers?
早期使用培养癌细胞的出版物立即认识到了抗癌药物耐药现象。然而，直到1973年才首次证明癌细胞耐药的一个主要因素是药物积累减少。今年是朱利亚诺和凌发现P-糖蛋白介导癌细胞中化疗药物这种主动外排作用30周年。自从这一开创性发现以来，对P-糖蛋白（多药耐药蛋白1，ATP结合盒转运蛋白[ABC]B1）的研究一直蓬勃开展。然而，很快就发现并非所有表现出积累缺陷的耐药细胞都表达P-糖蛋白，这导致了其他参与药物外排的ABC转运蛋白的发现。1992年，在小细胞肺癌中鉴定出多药耐药相关蛋白（MRP1，ABCC1），随后在1999年发现了乳腺癌耐药蛋白（米托蒽醌耐药蛋白，ABCG2）。经过三十年的研究，我们能否自信地确定多药耐药转运蛋白对化疗耐药的作用，我们是否有临床上有用的药物来使癌症敏感化？
