Chang B D, Broude E V, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel E S, Lausch E, Christov K, Roninson I B
Department of Molecular Genetics, University of Illinois at Chicago, 60607-7170, USA.
Cancer Res. 1999 Aug 1;59(15):3761-7.
Exposure of human tumor cell lines to different chemotherapeutic drugs, ionizing radiation, and differentiating agents induced morphological, enzymatic, and ploidy changes resembling replicative senescence of normal cells. Moderate doses of doxorubicin induced this senescence-like phenotype (SLP) in 11 of 14 tested cell lines derived from different types of human solid tumors, including all of the lines with wild-type p53 and half of p53-mutated cell lines. SLP induction seemed to be independent from mitotic cell death, the other major effect of drug treatment. Among cells that survived drug exposure, SLP markers distinguished those cells that became terminally growth-arrested within a small number of cell divisions from the cells that recovered and resumed proliferation. SLP induction in breast carcinoma cells treated with retinoids in vitro or in vivo was found to correlate with permanent growth inhibition under the conditions of minimal cytotoxicity, suggesting that this response may be particularly important for the antiproliferative effect of differentiating agents. The senescence-like program of terminal proliferation arrest may provide an important determinant of treatment outcome and a target for augmentation in cancer therapy.
将人类肿瘤细胞系暴露于不同的化疗药物、电离辐射和分化剂中，会诱导出形态、酶活性和倍性变化，这些变化类似于正常细胞的复制性衰老。中等剂量的阿霉素在14种源自不同类型人类实体瘤的受试细胞系中的11种中诱导出这种衰老样表型（SLP），其中包括所有具有野生型p53的细胞系以及一半p53突变的细胞系。SLP的诱导似乎独立于有丝分裂细胞死亡，而有丝分裂细胞死亡是药物治疗的另一个主要效应。在药物暴露后存活的细胞中，SLP标志物区分出那些在少数细胞分裂内进入终末生长停滞的细胞和那些恢复并重新增殖的细胞。发现在体外或体内用类视黄醇处理的乳腺癌细胞中SLP的诱导与在最小细胞毒性条件下的永久生长抑制相关，这表明这种反应可能对分化剂的抗增殖作用特别重要。终末增殖停滞的衰老样程序可能是治疗结果的重要决定因素，也是癌症治疗中增强疗效的靶点。
