McConkey D J, Chandra J, Wright S, Plunkett W, McDonnell T J, Reed J C, Keating M
Department of Cell Biology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
J Immunol. 1996 Apr 1;156(7):2624-30.
Therapeutic agents used in the treatment of chronic lymphocytic leukemia (CLL) are capable of inducing apoptosis in some (but not all) patient isolates. It is not yet clear whether cells that are resistant to one agent will also be resistant to others, and the mechanisms contributing to differential apoptosis sensitivity are not known. Here we report that glucocorticoid hormone and a clinically relevant chemotherapy combination (fludarabine plus mitoxantrone) fail to induce apoptosis in four of 24 CLL patient isolates. Apoptosis resistance was associated with elevated BCL-2 and BAX expression. Interestingly, incubation in vitro led to down-regulation of BCL-2 expression in both apoptosis-sensitive and apoptosis-resistant cells, whereas parallel down-regulation of BAX occurred only in the resistant samples. Evaluation of nuclear endonuclease content indicated that all of the apoptosis-sensitive samples contained appreciable levels of activity, whereas the endonuclease was not detected in the four populations of resistant cells. Our results indicate that nuclear endonuclease activity represents an excellent prognostic indicator of CLL apoptosis sensitivity that may be controlled by differential BCL-2 family polypeptide expression and signals from the in vivo microenvironment.
用于治疗慢性淋巴细胞白血病（CLL）的治疗药物能够在一些（但不是所有）患者分离细胞中诱导凋亡。对一种药物耐药的细胞是否也会对其他药物耐药尚不清楚，导致凋亡敏感性差异的机制也尚不明确。在此我们报告，糖皮质激素和一种临床相关的化疗组合（氟达拉滨加米托蒽醌）在24例CLL患者分离细胞中有4例未能诱导凋亡。凋亡抗性与BCL-2和BAX表达升高有关。有趣的是，体外培养导致凋亡敏感细胞和凋亡抗性细胞中BCL-2表达均下调，而BAX的平行下调仅发生在抗性样本中。对核内核酸酶含量的评估表明，所有凋亡敏感样本均含有相当水平的活性，而在4个抗性细胞群体中未检测到核酸酶。我们的结果表明，核内核酸酶活性是CLL凋亡敏感性的一个优秀预后指标，其可能受BCL-2家族多肽表达差异和体内微环境信号的控制。
