Landowski T H, Gleason-Guzman M C, Dalton W S
Department of Medicine, University of Arizona, Tucson, USA.
Blood. 1997 Mar 15;89(6):1854-61.
Recent evidence has supported the hypothesis that chemotherapeutic drugs and radiation induce an apoptotic pathway that requires the active participation of the cell. One pathway of apoptosis in malignant lymphoid cells is mediated by the Fas antigen. We studied the human myeloma (8226) and T-cell leukemia (CEM) cell lines selected for resistance to the anthracenes, doxorubicin or mitoxantrone, by continuous culture in the presence of either agent. We found that these drug-resistant cell lines were also resistant to Fas-mediated apoptosis in a dose-dependent manner. The degree of resistance to Fas-mediated apoptosis correlated directly with the level of resistance to chemotherapeutic drugs. These observations indicate that, as cancer cell lines develop mechanisms of drug resistance, they may also develop mechanisms of resistance to physiologic signals of apoptosis. Two mechanisms of resistance to Fas-mediated apoptosis were observed in these cell lines. One mechanism was associated with a dose-dependent reduction in the surface expression of Fas antigen. Analysis of RNA by reverse transcriptase-polymerase chain reaction assays showed that the reduction of Fas antigen expression occurred at the level of transcription. A second mechanism of drug resistance showed no decrease of Fas antigen expression; however, the apoptotic response was diminished. In this situation, removal of the chemotherapeutic agent resulted in a partial reversion to chemosensitivity and re-expression of the Fas antigen, but these cell lines did not regain the ability to undergo apoptosis in response to cross-linking by anti-Fas antibody. These findings support the hypothesis that apoptosis mediated by both chemotherapeutic agents and physiologic stimuli may share a common downstream effector. The demonstration that selection for drug resistance in hematopoietic cell lines results in a simultaneous resistance to Fas-mediated apoptosis may have clinical implications in the development of strategies for the treatment of resistant disease. Further analysis of the molecular mechanisms of Fas expression and function will facilitate the design of biological response modifying agents for the treatment of malignancy.
近期证据支持了这样一种假说，即化疗药物和辐射会诱导一种需要细胞积极参与的凋亡途径。恶性淋巴细胞凋亡的一条途径由Fas抗原介导。我们研究了通过在阿霉素或米托蒽醌存在下连续培养而对蒽环类药物产生抗性的人骨髓瘤（8226）和T细胞白血病（CEM）细胞系。我们发现这些耐药细胞系对Fas介导的凋亡也呈剂量依赖性抗性。对Fas介导凋亡的抗性程度与对化疗药物的抗性水平直接相关。这些观察结果表明，随着癌细胞系产生耐药机制，它们可能也会产生对凋亡生理信号的抗性机制。在这些细胞系中观察到了两种对Fas介导凋亡的抗性机制。一种机制与Fas抗原表面表达的剂量依赖性降低有关。通过逆转录酶 - 聚合酶链反应分析RNA表明，Fas抗原表达的降低发生在转录水平。第二种耐药机制表现为Fas抗原表达未降低；然而，凋亡反应减弱。在这种情况下，去除化疗药物会导致对化疗敏感性部分恢复以及Fas抗原重新表达，但这些细胞系并未恢复对抗Fas抗体交联产生凋亡反应的能力。这些发现支持了这样的假说，即化疗药物和生理刺激介导的凋亡可能共享一个共同的下游效应器。造血细胞系中对耐药性的选择导致同时对Fas介导凋亡产生抗性这一证明，可能对耐药疾病治疗策略的制定具有临床意义。对Fas表达和功能分子机制的进一步分析将有助于设计用于治疗恶性肿瘤的生物反应调节剂。
