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

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.

• Authors: Derek C Knapp, John E Mata, Muralimohan T Reddy, Gayathri R Devi, Patrick L Iversen
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 14 Issue 1 Pg. 39-47 (Jan 2003) ISSN: 0959-4973 [Print] England
• PMID: 12544257 (Publication Type: Journal Article)
• Copyright: Copyright 2003 Lippincott Williams & Wilkins

Chemical References

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

Topics

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