Ribozyme-mediated reversal of the multidrug-resistant phenotype

Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11123-7. doi: 10.1073/pnas.91.23.11123.


This study examined the effects of suppressing c-fos oncogene expression on multidrug resistance (MDR). A2780S human ovarian carcinoma cells with resistance to actinomycin D were isolated and the resultant A2780AD cells exhibited the MDR phenotype. A hammerhead ribozyme designed to cleave fos RNA cloned into the pMAMneo plasmid was transfected into A2780AD cells. Induction of the ribozyme resulted in decreased expression of c-fos, as well as that of the MDR gene (mdr-1), c-jun, and mutant p53. The transformants displayed altered morphology and restored sensitivity to chemotherapeutic agents comprising the MDR phenotype. An anti-mdr ribozyme separately expressed in A2780AD cells efficiently degraded mdr-1 mRNA. However, reversal of the MDR phenotype by the anti-mdr ribozyme occurred one-fourth as rapidly as that induced by the anti-fos ribozyme. These results reinforce the central role played by c-fos in drug resistance through its participation in signal transduction pathways.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • Base Sequence
  • Drug Resistance, Multiple*
  • Gene Expression Regulation
  • Genes, fos*
  • Genes, jun
  • Humans
  • In Vitro Techniques
  • Molecular Sequence Data
  • RNA, Catalytic / chemistry
  • RNA, Catalytic / pharmacology*
  • RNA, Messenger / genetics
  • Transcription Factor AP-1 / physiology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • RNA, Catalytic
  • RNA, Messenger
  • Transcription Factor AP-1