Anti-N-myc ribozymes (RBZ) as biotherapeutic agents (Meeting abstract). NLM AIDSLINE Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

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Anti-N-myc ribozymes (RBZ) as biotherapeutic agents (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A2502 1994. Unique Identifier : AIDSLINE ICDB/95604187
Avramis VI; Larson GP; Kwock R; Rossi JJ; Beckman Res. Inst., City of Hope, Duarte, CA

Abstract: Hammerhead ribozymes (RBZ) consist of two base-paired stems surrounding a central catalytic domain. We designed hammerhead RBZ and utilized a chemically synthesized modified RBZ (MRBZ) bearing a truncation in the stem of the catalytic domain to cleave N-myc RNA at a specific site within the second exon. These ribozymes recognize a sequence of 6 nucleotides (nt) 3' and 5' end of the GUC cleavage site. N-myc mRNA overexpression is a determinant of poor prognosis in neuroblastoma. The selected GUC site is 7 nt upstream of the translational start site of the second exon, within a region highly conserved in various tumors. Anti-N-myc ribozymes cleaved up to 65% of a N-myc target RNA of 212 nt in an in vitro assay to the predicted 64 and 148 nt products of RBZ or MRBZ catalysis. Liposome-encapsulated MRBZ was transferred into a human neuroblastoma cell line KCNR, which overexpresses N-myc. The tumor regression was shown to be MRBZ exposure dependent. KCNR treated cells with 30 and 100 pmol MRBZ were inhibited 50% to 90% of control. In addition, 32P and fluorescein-labeled MRBZ demonstrated that the ribozyme localizes to both the cytoplasm and nucleus of KCNR cells, suggesting that MRBZ can be delivered intact at the site of mRNA production for catalysis. Since ribozymes have been used as anti-HIV, anti-ras and anti-MDR1 agents, the availability of a ribozyme against N-myc mRNA offers the possibility that tumors dependent on the overexpression of this phenotype may be ablated by anti-N-myc biotherapeutic ribozymes.
Keywords: Cell Nucleus/ENZYMOLOGY Cytoplasm/ENZYMOLOGY Exons Human Liposomes Proto-Oncogene Proteins c-myc/*METABOLISM RNA, Catalytic/*METABOLISM Translation, Genetic Tumor Cells, Cultured ABSTRACTKWDcellnucleus/enzymologycytoplasm/enzymologyexonshumanliposomesproto-oncogeneproteinsc-myc/KWDmetabolismrna,catalytic/KWDmetabolismtranslation,genetictumorcells,culturedabstract
950330
M9530846

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