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

Anticancer Drugs. 2003 Jan;14(1):39-47. doi: 10.1097/00001813-200301000-00006.

Abstract

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 cm2 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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / metabolism*
  • DNA, Antisense / pharmacology
  • Drug Resistance, Neoplasm / physiology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / physiology
  • Genes, myc / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Morpholinos
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / genetics*
  • Rats

Substances

  • Antineoplastic Agents
  • DNA, Antisense
  • Morpholines
  • Morpholinos
  • Proto-Oncogene Proteins c-myc