Ripamonti M, Capolongo L, Melegaro G, Gornati C, Bargiotti A, Caruso M, Grandi M, Suarato A
Pharmacia Research Center, Oncology Department, Milano, Merviano, Italy.
Invest New Drugs. 1996;14(2):139-46. doi: 10.1007/BF00210784.
The relationship between different chemical modifications on morpholinylanthracyclines and their ability to overcome multidrug resistance (MDR) has been evaluated testing all compounds in vitro on LoVo and LoVo/DX human colon adenocarcinoma cells and in vivo disseminated P388 and P388/DX murine leukemias. Results obtained led us to the following conclusions: 1) the insertion of the morpholinyl or the methoxymorpholinyl group on position 3' of the sugar moiety confers the ability to overcome MDR in vitro and in vivo; conversely, 4' morpholinyl compounds are effective on MDR cells only in vitro and result inactive in vivo on DX-resistant leukemia; 2) all chemical modifications performed on 3' morpholinyl or methoxymorpholinyl derivatives, that is substitutions on the aglycone or on position 2 of the morpholino ring, do not interfere with the activity of the compounds: all derivatives present in fact the same efficacy on sensitive and resistant models. It is concluded that position 3' in the sugar moiety plays a crucial role in the ability of morpholinyl-anthracyclines to overcome MDR.
通过在体外对LoVo和LoVo/DX人结肠腺癌细胞以及在体内对播散性P388和P388/DX小鼠白血病进行测试，评估了吗啉代蒽环类药物上不同化学修饰与其克服多药耐药性（MDR）能力之间的关系。所得结果使我们得出以下结论：1）在糖部分的3'位插入吗啉基或甲氧基吗啉基赋予了在体外和体内克服MDR的能力；相反，4'吗啉基化合物仅在体外对MDR细胞有效，而在体内对DX耐药白血病无活性；2）对3'吗啉基或甲氧基吗啉基衍生物进行的所有化学修饰，即在糖苷配基或吗啉环的2位上的取代，均不干扰化合物的活性：事实上，所有衍生物在敏感和耐药模型上具有相同的疗效。得出的结论是，糖部分的3'位在吗啉代蒽环类药物克服MDR的能力中起关键作用。
