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7-取代喜树碱在激素难治性人前列腺癌模型中抗肿瘤活性的细胞基础

Cellular bases of the antitumor activity of a 7-substituted camptothecin in hormone-refractory human prostate carcinoma models.

作者信息

Zuco Valentina, Supino Rosanna, De Cesare Michelandrea, Carenini Nives, Perego Paola, Gatti Laura, Pratesi Graziella, Pisano Claudio, Martinelli Roberta, Bucci Federica, Zanier Romina, Carminati Paolo, Zunino Franco

机构信息

Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy.

出版信息

Biochem Pharmacol. 2003 Apr 15;65(8):1281-94. doi: 10.1016/s0006-2952(03)00079-0.

Abstract

ST1481, a lead compound of a novel potent 7-substituted lipophilic camptothecin series, is able to overcome several mechanisms of drug resistance and was selected for clinical development. This study was designed to examine the antitumor activity of ST1481 in the treatment of preclinical models of human p53-defective hormone-refractory prostate carcinoma (DU145, PC3, and JCA-1) and to explore the cellular bases of the efficacy of camptothecins. A cellular pharmacology study (cytotoxicity, apoptosis, cellular drug accumulation, DNA damage, and cell cycle perturbation) was performed in DU145 and PC3 cells, characterized by a different cell cycle checkpoint status. The introduction of wild-type p53 in PC3 cells appreciably decreased the drug sensitivity. The 7-substituted camptothecins exhibited a high cytotoxic potency that paralleled their relative ability to induce DNA damage and a substantially increased cellular accumulation as compared to topotecan. The cytotoxic effect of camptothecins in DU145 cells was associated with arrest in S phase and early activation of apoptosis, whereas PC3 cells responded to drugs by a persistent block in G2 phase with a cytostatic effect and a late apoptosis. The efficiency of S phase checkpoint in DU145 cells was supported by a time-dependent decrease of DNA synthesis following treatment. In spite of an apparent cytostatic response and apoptosis resistance, the PC3 tumor was more responsive to in vivo treatment with camptothecins than the DU145 model. Indeed, the therapeutic outcome did not reflect the cell susceptibility to early activation of apoptosis. We suggest that cell death in PC3 cells is a delayed event consequent to persistent arrest in G2 and insufficient repair of DNA damage. ST1481 was appreciably more effective than topotecan in all tested tumors. In conclusion, the results indicated a relevant efficacy of camptothecins against human prostate carcinoma models, in spite of p53 alterations. Although p53 status could influence DNA damage and cell cycle checkpoints, p53 mutation was not a determinant of resistance. The results support that, in addition to the extent and persistence of topoisomerase I-mediated DNA damage, cell cycle checkpoints and DNA damage signaling pathways are critical determinants of tumor responsiveness to camptothecins. A role of cell cycle checkpoints activated by DNA damage in cell response is supported by the modulation of transcriptional profile.

摘要

ST1481是新型强效7-取代亲脂性喜树碱系列的先导化合物,能够克服多种耐药机制,已被选入临床开发阶段。本研究旨在检测ST1481在人p53缺陷型激素难治性前列腺癌(DU145、PC3和JCA-1)临床前模型治疗中的抗肿瘤活性,并探索喜树碱疗效的细胞基础。在DU145和PC3细胞中进行了细胞药理学研究(细胞毒性、凋亡、细胞药物蓄积、DNA损伤和细胞周期扰动),这两种细胞具有不同的细胞周期检查点状态。在PC3细胞中引入野生型p53可显著降低药物敏感性。与拓扑替康相比,7-取代喜树碱表现出高细胞毒性效力,这与其诱导DNA损伤的相对能力以及细胞蓄积的显著增加相关。喜树碱对DU145细胞的细胞毒性作用与S期阻滞和凋亡的早期激活有关,而PC3细胞对药物的反应是在G2期持续阻滞,具有细胞生长抑制作用和晚期凋亡。DU145细胞中S期检查点的效率通过处理后DNA合成的时间依赖性降低得到支持。尽管PC3肿瘤有明显的细胞生长抑制反应和凋亡抗性,但与DU145模型相比,其对喜树碱的体内治疗反应更强。事实上,治疗结果并未反映细胞对凋亡早期激活的易感性。我们认为,PC3细胞中的细胞死亡是G2期持续阻滞和DNA损伤修复不足导致的延迟事件。在所有测试肿瘤中,ST1481比拓扑替康明显更有效。总之,结果表明尽管存在p53改变,喜树碱对人前列腺癌模型仍具有显著疗效。虽然p53状态可能影响DNA损伤和细胞周期检查点,但p53突变并非耐药的决定因素。结果支持,除了拓扑异构酶I介导的DNA损伤的程度和持续性外,细胞周期检查点和DNA损伤信号通路是肿瘤对喜树碱反应性的关键决定因素。DNA损伤激活的细胞周期检查点在细胞反应中的作用得到转录谱调节的支持。

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