Resistance to chemotherapeutic drugs overcome by c-Myc inhibition in a Lewis lung carcinoma murine model

被引:56
作者
Knapp, DC [1 ]
Mata, JE [1 ]
Reddy, MT [1 ]
Devi, GR [1 ]
Iversen, PL [1 ]
机构
[1] AVI Biopharma Inc, Canc & Endocrine Div, Corvallis, OR 97333 USA
关键词
antisense; c-myc; lung cancer; phosphorodiamidate Morpholino oligomer;
D O I
10.1097/00001813-200301000-00006
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:39 / 47
页数:9
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