Karp J E, Donehower R C, Burke P J
Semin Oncol. 1987 Jun;14(2 Suppl 1):172-81.
The relationship between in vitro leukemic cell growth kinetics, intracellular biochemical pharmacology of 1-beta-D-arabinofuranosylcytosine (ara-C), and clinical response to ara-C-containing timed sequential therapy was examined in leukemic marrow populations from 62 adults with acute myelogenous leukemia (AML). Leukemic blasts from 45 previously untreated and 17 relapse patients were obtained before therapy, and cultured in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). While all cell populations cultured in HSA demonstrated increased proliferation, only growth-stimulated cohorts from those patients achieving complete remission with ara-C-based therapy demonstrated enhanced intracellular drug activation and active drug retention relative to cells maintained in APS, whereas cells from nonresponsive patients demonstrated no such HSA-induced increases in intracellular ara-C metabolism. In this in vitro model system, sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA-perturbed growth and net pharmacologic parameters, while refractory cohorts evince uncoupling of these determinants in the growth-stimulated state. This model identifies behavior patterns that may discriminate clinical sensitivity from clinical resistance and may serve to predict clinical outcome to timed sequential therapy with ara-C.
在62例成人急性髓性白血病（AML）患者的白血病骨髓样本中，研究了体外白血病细胞生长动力学、1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷，ara-C）的细胞内生化药理学以及含阿糖胞苷的定时序贯疗法的临床反应之间的关系。在治疗前获取了45例初治患者和17例复发患者的白血病原始细胞，并在自体预处理血清（APS）以及含有药物诱导的体液刺激活性（HSA）的血清中进行培养。虽然所有在HSA中培养的细胞群体均表现出增殖增加，但相对于维持在APS中的细胞，只有那些接受基于阿糖胞苷治疗而达到完全缓解的患者的生长刺激组显示出细胞内药物激活增强和活性药物滞留，而无反应患者的细胞则未表现出这种HSA诱导的细胞内阿糖胞苷代谢增加。在这个体外模型系统中，敏感的AML群体表现与正常造血群体相似，HSA干扰的生长与净药理学参数直接相关，而难治性群体在生长刺激状态下则表现出这些决定因素的解偶联。该模型确定了可能区分临床敏感性和临床耐药性的行为模式，并可能用于预测阿糖胞苷定时序贯疗法的临床结果。
