Potential therapeutic applications of antisense oligodeoxynucleotides in the treatment of chronic myelogenous leukemia.
Chronic myelogenous leukemia (CML) cell growth may be inhibited by exposure to antisense (AS) oligodeoxynucleotides (ODN). Our initial studies targeted the c-myb protooncogene and were carried out on cells derived from patients in CML blast crisis. Subsequently, we extended these studies to cells isolated from patients in chronic disease phase. We found that c-myb AS ODN inhibited growth of CML CFU-GM in a dose dependent, sequence specific manner in approximately 75% of cases evaluated. Bcr-abl expression was either greatly decreased or nondetectable in the residual colonies and no residual leukemic CFU were demonstrable upon re-plating of treated cells. AS ODN that target the c-kit protooncogene also inhibit CML CFU and lead to downregulation of bcr-abl in responding cells in approximately 50% of cases. Therefore, AS ODN may prove to be useful purging agents. Most recently, we have treated SCID mice engrafted with bcr-abl expressing human K562 cell leukemia with phosphorothioate modified AS ODN. We have found that treated mice survive three to eight times longer than their untreated or sense treated controls. In aggregate, these results suggest that AS ODN may prove useful for both ex vivo and in vivo treatment of patients with CML.
Gewirtz
A M
AM
Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia 19104.
D000818:Animals; D001483:Base Sequence; D001752:Blast Crisis / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology / Q000628:therapy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology / Q000628:therapy*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit; D020598:Proto-Oncogene Proteins c-myb; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016184:Receptors, Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D013873:Thionucleotides / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D016184:Receptors, Colony-Stimulating Factor; D013873:Thionucleotides; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl