Resistance to chemotherapeutic drugs overcome by c-Myc inhibition in a Lewis lung carcinoma murine model
Resistance to chemotherapeutic drugs overcome by c-Myc inhibition in a Lewis lung carcinoma murine model
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DOI：
10.1097/00001813-200301000-00006
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发表时间：
2003-01-01
影响因子：
2.3
通讯作者：
Iversen, PL
中科院分区：
文献类型：
--
作者：
Knapp, DC;Mata, JE;Iversen, PL
化疗耐药是肺癌治疗的一个重要障碍，经常与c-myc癌基因的扩增和过表达相关。早期的研究表明，单独抑制c-Myc在癌症模型中并不总是有效的。本研究的目的是在Lewis肺同源耐药小鼠肿瘤模型中测试不同的给药方案，包括常用化疗药物联合c-Myc抑制。抑制c-myc是通过使用磷酸二酯Morpholino oligomer （PMOs）来实现的，PMOs是一种新的、无毒的反义DNA化学物质，通过不依赖于RNase h的机制抑制基因表达。当顺铂与c-myc PMO （AVI-4126）治疗重叠时，与单用顺铂相比，对肿瘤生长抑制没有额外的影响。相比之下，使用顺铂或紫杉醇治疗AVI-4126之前的给药方案，在研究结束时观察到60%的动物肿瘤面积小于0.5 cm(2)，肿瘤生长速度急剧下降。这种作用是c-Myc抑制所特有的，而其他针对p21或Rad51的反义PMOs在联合化疗时没有这种作用。在研究结束时，免疫印迹和基于高效液相色谱的肿瘤裂解物分析分别证实了c-Myc抑制和完整的AVI-4126检测。总之，AVI-4126以一种时间表依赖的方式增强化疗药物的疗效。抗癌药物14:39-47 (C) 2003 Lippincott Williams Wilkins。
Chemotherapy resistance is a significant obstacle in lung cancer therapy, and has been found to frequently correlate with amplification and overexpression of the c-myc oncogene. Earlier studies have shown that c-Myc inhibition alone is not always effective in cancer models. The purpose of this study was to test different dosing regimen, which included commonly used chemotherapeutic drugs in combination with c-Myc inhibition in a Lewis lung syngeneic drug-resistant murine tumor model. Inhibition of c-myc was specifically achieved by using,phosphorodiamidate Morpholino oligomer (PMOs), a novel, non-toxic antisense DNA chemistry for inhibition of gene expression by an RNase H-independent mechanism. When administration of cisplatin overlapped with c-myc PMO (AVI-4126) treatment there was no additional effect on tumor growth inhibition compared to cisplatin alone. In contrast, using a dosing regimen in which cisplatin or taxol treatment preceded AVI-4126, a dramatic decrease in tumor growth rate was observed with tumor areas less then 0.5 cm(2) in 60% of the animals at the end of the study. This effect was specific to c-Myc inhibition as other antisense PMOs against p21 or Rad51 showed no such effect in combination with chemotherapy. Immunoblot and HPLC-based analysis of tumor lysates at the end of the study confirmed c-Myc inhibition and detection of intact AVI-4126, respectively. In conclusion, AVI-4126 potentiates the efficacy of chemotherapeutic drugs in a manner that is schedule dependent. Anti-Cancer Drugs 14:39-47 (C) 2003 Lippincott Williams Wilkins.