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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1150-1158
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Oligodeoxynucleotide-mediated inhibition of c-myb gene
expression in autografted bone marrow: a pilot study
Selina M. Luger,
Stephen G. O'Brien,
Janina Ratajczak,
Mariusz Z. Ratajczak,
Rosemarie Mick,
Edward A. Stadtmauer,
Peter C. Nowell,
John M. Goldman, and
Alan M. Gewirtz
From the Division of Hematology/Oncology and the Stem
Cell Biology/Therapeutics Program, Departments of Medicine, Pathology,
and Biostatistics and Epidemiology, and the Cancer Center, University
of Pennsylvania School of Medicine, Philadelphia; the Department of
Haematology, University of Newcastle, United Kingdom; and the
Department of Haematology, Imperial College School of Science,
Technology and Medicine, London, United Kingdom.
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.
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