title: Oligodeoxynucleotide-mediated inhibition of c-myb gene expression in autografted bone marrow: a pilot study.
abstract: Antisense oligodeoxynucleotide (ODN) drugs might be more effective if their delivery was optimized and they were targeted to short-lived proteins encoded by messenger RNA (mRNA) species with equally short half-lives. To test this hypothesis, an ODN targeted to the c-myb proto-oncogene was developed and used to purge marrow autografts administered to allograft-ineligible chronic myelogenous leukemia patients. CD34(+) marrow cells were purged with ODN for either 24 (n = 19) or 72 (n = 5) hours. After purging, Myb mRNA levels declined substantially in approximately 50% of patients. Analysis of bcr/abl expression in long-term culture-initiating cells suggested that purging had been accomplished at a primitive cell level in more than 50% of patients and was ODN dependent. Day-100 cytogenetics were evaluated in surviving patients who engrafted without infusion of unmanipulated "backup" marrow (n = 14). Whereas all patients were approximately 100% Philadelphia chromosome-positive (Ph(+)) before transplantation, 2 patients had complete cytogenetic remissions; 3 patients had fewer than 33% Ph(+) metaphases; and 8 remained 100% Ph(+). One patient's marrow yielded no metaphases, but fluorescent in situ hybridization evaluation approximately 18 months after transplantation revealed approximately 45% bcr/abl(+) cells, suggesting that 6 of 14 patients had originally obtained a major cytogenetic response. Conclusions regarding clinical efficacy of ODN marrow purging cannot be drawn from this small pilot study. Nevertheless, these results lead to the speculation that enhanced delivery of ODN, targeted to critical proteins of short half-life, might lead to the development of more effective nucleic acid drugs and the enhanced clinical utility of these compounds in the future.
authors.affiliation: Division of Hematology/Oncology and the Stem Cell Biology/Therapeutics Program, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
authors.forename: Stephen G
authors.initials: SG
authors.lastname: O'Brien
authors.forename: Janina
authors.initials: J
authors.lastname: Ratajczak
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.forename: Peter C
authors.initials: PC
authors.lastname: Nowell
authors.forename: John M
authors.initials: JM
authors.lastname: Goldman
authors.forename: Alan M
authors.initials: AM
authors.lastname: Gewirtz
mesh_terms: D000328:Adult; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation / Q000379:methods; D020732:Cytogenetic Analysis; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000032:analysis; D015870:Gene Expression / Q000187:drug effects; D020570:Genes, myb / Q000187:drug effects* / Q000235:genetics; D006085:Graft Survival; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000628:therapy; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D010865:Pilot Projects; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D014182:Transplantation, Autologous / Q000379:methods; D016896:Treatment Outcome
chemical_list: C000715470:MAS1 protein, human; D020319:Oligodeoxyribonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016044:Fusion Proteins, bcr-abl