title: 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.affiliation: AVI BioPharma Inc, Corvallis, OR 97333, USA. grdevi@avibio.com
authors.forename: Derek C
authors.initials: DC
authors.lastname: Knapp
authors.forename: John E
authors.initials: JE
authors.lastname: Mata
authors.forename: Muralimohan T
authors.initials: MT
authors.lastname: Reddy
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Iversen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016373:DNA, Antisense / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D016259:Genes, myc / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D060172:Morpholinos; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D016373:DNA, Antisense; D009025:Morpholines; D060172:Morpholinos; D016271:Proto-Oncogene Proteins c-myc