Nucleic Acid Therapeutics for Human Leukemia: Development and Early Clinical Experience with Oligodeoxynucleotides Directed at c-myb
For the past several years, we have been engaged in trying to develop an effective strategy of disrupting specific gene function with antisense oligodeoxynucleotides (ODN). We have also been actively engaged in attempting to utilize this strategy in the clinic. This latter pursuit has focused on finding appropriate gene targets that can be successfully targeted using an antisense approach and then developing “scale-up” methods so that techniques developed in the laboratory can be applied in the clinic. It was our opinion that human leukemias would be particularly amenable to this therapeutic strategy. They can be successfully manipulated ex vivo, the tumor is “liquid” in vivo and therefore more likely to successfully take up ODN, and a great deal is known about their cell and molecular biology. The latter in particular facilitates the choice of a gene target. Accordingly, if ODN were going to be developed as therapeutics, the hematopoietic system seemed an ideal model system.
KeywordsK562 Cell Chronic Myelogenous Leukemia Acute Myelogenous Leukemia Human Leukemia Chronic Myeloid Leukemia Cell
Unable to display preview. Download preview PDF.
- Calabretta B, Sims RB, Valtieri M, Caracciolo D, Szczylik C, Venturelli D, Ratajczak M, Beran M, Gewirtz AM (1991) Normal and leukemic hematopoietic cells manifest differential sensitivity to inhibitory effects of c-myb antisense oligodeoxynucleotides: an in vitro study relevant to bone marrow purging. Proc Natl Acad Sci USA 88:2351–2355PubMedCrossRefGoogle Scholar
- Gewirtz AM, Luger S, Sokol D, Gowdin B, Stadtmauer E, Reccio A, Ratajczak MZ (1996a) Oligodeoxynucleotide therapeutics for human myelogenous leukemia: interim results. Blood 88 [Suppl 1]:270aGoogle Scholar
- Ku DH, Wen SC, Engelhard A, Nicolaides NC, Lipson KE, Marino TA, Calabretta B (1993) c-myb transactivates cdc2 expression via Myb binding sites in the 5’-flanking region of the human cdc2 gene [published erratum appears in J Biol Chem 1993 Jun 15; 268(17):13010]. J Biol Chem 268:2255–2259Google Scholar
- Ratajczak MZ, Hijiya N, Catani L, DeRiel K, Luger SM, McGlave P, Gewirtz AM (1992a) Acute-and chronic-phase chronic myelogenous leukemia colony-forming units are highly sensitive to the growth inhibitory effects of c-myb antisense oligodeoxynucleotides. Blood 79:1956–1961Google Scholar
- Small D, Levenstein M, Kim, E, Carow C, Amin S, Rockwell P, Witte L, Burrow C, Ratajczak MZ, Gewirtz AM et al (1994) STK-1, the human homolog of Flk-2/Flt3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci USA 91:459–463PubMedCrossRefGoogle Scholar
- Spitler DG, Tidd DM (1995) Nuclear delivery of antisense oligodeoxynucleotides through reversible permeabilization of human leukemia cells with streptolysin O. Antisense Res Dev 5:13–21Google Scholar