Kuffel M J, Reid J M, Ames M M
Department of Oncology, Mayo Clinic, Rochester, MN 55905.
Cancer Chemother Pharmacol. 1992;30(1):51-7. doi: 10.1007/BF00686485.
Anthracyclines are important antitumor agents used in the treatment of solid tumors, lymphomas, and acute lymphoblastic as well as myelocytic leukemias. The clinical utility of agents such as doxorubicin and daunorubicin and their well-characterized cardiotoxicity have prompted many efforts to develop analogs that retain the desired spectrum of activity but are less cardiotoxic. One such analog is idarubicin (4-demethoxydaunorubicin), which is currently under study in the treatment of adult and pediatric leukemias. The major circulating metabolite of idarubicin is the alcohol product of ketoreductase biotransformation, idarubicinol. Following the administration of idarubicin to adult or pediatric patients, systemic exposure to idarubicinol is greater than that to idarubicin. Moreover, we have also documented the presence of idarubicinol in the cerebrospinal fluid of pediatric patients who have received idarubicin. Idarubicinol has been reported to have greater cytotoxic activity than other anthracycline alcohol metabolites, which are regarded as much less active products of metabolism. We therefore evaluated the growth-inhibitory and DNA-damaging activities of idarubicin, daunorubicin, doxorubicin, epirubicin, and their alcohol metabolites against three relevant (CCRF-CEM lymphoblastic leukemia, K562 myelogenous leukemia, and U87-MG glioblastoma) human tumor cell lines. We found that whereas idarubicin was 2-5 times more potent than the other three anthracycline analogs against these tumor cell lines, idarubicinol was 16-122 times more active than the other alcohol metabolites against the same three cell lines. In addition, idarubicinol and the parent drug idarubicin were equipotent, unlike the other anthracycline alcohol metabolites, which were much less cytotoxic than the corresponding parent drugs. We also assessed the ability of the four parent drugs and their alcohol metabolites to induce DNA single-strand breaks. Idarubicin was more potent than the other three anthracycline analogs and idarubicinol was much more effective than the other alcohol metabolites in inducing DNA damage. These studies in human leukemia and human glioblastoma cell lines support the hypothesis that idarubicinol plays an important role in the antitumor activity of idarubicin and that the activities of idarubicin and idarubicinol are related to their ability to damage DNA.
蒽环类药物是用于治疗实体瘤、淋巴瘤、急性淋巴细胞白血病以及髓细胞白血病的重要抗肿瘤药物。阿霉素和柔红霉素等药物的临床应用及其已明确的心脏毒性促使人们努力研发具有所需活性谱但心脏毒性较小的类似物。伊达比星（4-去甲氧基柔红霉素）就是这样一种类似物，目前正在用于治疗成人和儿童白血病的研究中。伊达比星的主要循环代谢产物是酮还原酶生物转化的醇产物伊达比星醇。在给成人或儿童患者使用伊达比星后，全身对伊达比星醇的暴露量大于对伊达比星的暴露量。此外，我们还记录到在接受伊达比星治疗的儿童患者的脑脊液中存在伊达比星醇。据报道，伊达比星醇比其他蒽环类醇代谢产物具有更强的细胞毒性活性，而其他蒽环类醇代谢产物被认为是活性低得多的代谢产物。因此，我们评估了伊达比星、柔红霉素、阿霉素、表柔比星及其醇代谢产物对三种相关的（CCRF-CEM淋巴细胞白血病、K562髓性白血病和U87-MG胶质母细胞瘤）人类肿瘤细胞系的生长抑制和DNA损伤活性。我们发现，虽然伊达比星对这些肿瘤细胞系的效力比其他三种蒽环类类似物高2至5倍，但伊达比星醇对相同的三种细胞系的活性比其他醇代谢产物高16至122倍。此外，与其他蒽环类醇代谢产物不同，伊达比星醇和母体药物伊达比星具有同等效力，其他蒽环类醇代谢产物的细胞毒性比相应的母体药物小得多。我们还评估了四种母体药物及其醇代谢产物诱导DNA单链断裂的能力。在诱导DNA损伤方面，伊达比星比其他三种蒽环类类似物更有效，伊达比星醇比其他醇代谢产物更有效。这些在人类白血病和人类胶质母细胞瘤细胞系中的研究支持了以下假设：伊达比星醇在伊达比星的抗肿瘤活性中起重要作用，并且伊达比星和伊达比星醇的活性与其损伤DNA的能力有关。
