Ribozyme-mediated reversal of the multidrug-resistant phenotype.
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.
Department of Medical Oncology, City of Hope Medical Center, Duarte, CA 91010.
K J
KJ
Scanlon
H
H
Ishida
M
M
Kashani-Sabet
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D001483:Base Sequence; D018432:Drug Resistance, Multiple; D005786:Gene Expression Regulation; D016762:Genes, fos; D016758:Genes, jun; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D016337:RNA, Catalytic / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016337:RNA, Catalytic; D012333:RNA, Messenger; D018808:Transcription Factor AP-1