Jagan Sucheta, Paganessi Laura A, Frank Robin R, Venugopal Parameswaran, Larson Melissa, Christopherson Kent W
Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, 1725 West Harrison Street, Chicago, IL 60612, USA ; Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA ; Section of Hematology, Rush University Medical Center, 1725 West Harrison Street, Chicago, IL 60612, USA.
Adv Hematol. 2012;2012:727683. doi: 10.1155/2012/727683. Epub 2012 Sep 23.
Achieving improvements in survival and reducing relapse remains a challenge in acute myelogenous leukemia (AML) patients. This study evaluated the in vitro efficacy of the active form of novel agent sapacitabine, CNDAC, compared to current chemotherapeutic drugs Ara-C and mitoxantrone using two AML cell lines, HL-60 (promyelocytic) and THP-1 (monocytic), as well as bone marrow (BM) and peripheral blood (PB) cells collected from AML patients. Cell lines were exposed to compound for 3-6 days and primary cells for 4 days. The viability of primary cells was additionally evaluated 3, 7, and 31 days after removal of tested compound to determine the durability of the response. Our studies indicate that CNDAC and mitoxantrone have a greater impact on viability than ara-C in primary AML cells and AML cell lines. CNDAC is more effective at reducing viability and inducing apoptosis than ara-C at equivalent concentrations in the THP-1 cell line, which is defined as displaying resistance to ara-C. As sapacitabine has shown in vivo activity at clinically achievable doses, future studies are warranted to assess the potential for combining it with ara-C and/or mitoxantrone, with an emphasis on cells and patients insensitive to ara-C treatment.
在急性髓系白血病（AML）患者中，提高生存率和降低复发率仍然是一项挑战。本研究使用两种AML细胞系HL-60（早幼粒细胞）和THP-1（单核细胞）以及从AML患者收集的骨髓（BM）和外周血（PB）细胞，评估了新型药物沙帕他滨的活性形式CNDAC与当前化疗药物阿糖胞苷和米托蒽醌相比的体外疗效。将细胞系暴露于化合物3 - 6天，原代细胞暴露4天。在去除受试化合物后3天、7天和31天额外评估原代细胞的活力，以确定反应的持久性。我们的研究表明，在原代AML细胞和AML细胞系中，CNDAC和米托蒽醌对活力的影响比阿糖胞苷更大。在等效浓度下，CNDAC在降低THP-1细胞系（被定义为对阿糖胞苷耐药）的活力和诱导凋亡方面比阿糖胞苷更有效。由于沙帕他滨在临床可达到的剂量下已显示出体内活性，未来有必要开展研究以评估将其与阿糖胞苷和/或米托蒽醌联合使用的潜力，重点关注对阿糖胞苷治疗不敏感的细胞和患者。
