Bielack S S, Kallenbach K, Looft G, Erttmann R, Winkler K
Department of Pediatric Hematology and Oncology, Pediatric University Hospital Hamburg-Eppendorf, Germany.
Anticancer Res. 1995 Jul-Aug;15(4):1279-84.
Resistance to the classical anthracyclines may be due to one or several mechanisms, most notably p-glycoprotein (pGP) associated multidrug resistance (mdr1, "typical mdr") and altered activity of topoisomerase II (topo II) ("atypical mdr"). Modulators of mdr1 will be of limited value in case of combined forms of resistance. A Friend murine erythroleukemia cell line (F4-6R) carrying both mdrl and topo II mediated anthracycline resistance was used to determine the efficacy of structurally altered anthracyclines against such extended multidrug resistance. Proliferation assays showed that 3'N-morpholinyl substituted anthracyclines were able to retain much of their activity even in this setting. MX2 (KRN8602; 3'-deamino-3'-[4-morpholinyl]-13-deoxo-10-hydroxycarminomycin+ ++), which is 9-alkylated in addition to carrying a 3'N-morpholinyl group, was the most promising agent tested.
对传统蒽环类药物的耐药性可能归因于一种或多种机制，最显著的是与P-糖蛋白（pGP）相关的多药耐药性（mdr1，“典型的mdr”）和拓扑异构酶II（topo II）活性改变（“非典型mdr”）。在联合耐药形式的情况下，mdr1调节剂的价值有限。使用携带mdr1和topo II介导的蒽环类药物耐药性的Friend小鼠红白血病细胞系（F4-6R）来确定结构改变的蒽环类药物对这种扩展的多药耐药性的疗效。增殖试验表明，即使在这种情况下，3'-N-吗啉基取代的蒽环类药物仍能保留其大部分活性。MX2（KRN8602；3'-脱氨基-3'-[4-吗啉基]-13-脱氧-10-羟基柔红霉素+++）除了带有3'-N-吗啉基外还进行了9-烷基化，是测试的最有前景的药物。
