Abstract
Synthetic oligodeoxynucleotides complementary to the breakpoint junction of bcr-abl transcripts selectively inhibit the proliferation of Philadelphia1-positive leukemic cells, but residual leukemic cells persist in antisense oligodeoxynucleotides-treated cultures. Cyclophosphamide derivatives such as mafosfamide and 4-hydroperoxycyclophosphamide are used at high doses for purging of Philadelphia1 leukemic cells from marrows but such treatment can be associated with delayed engraftment and prolonged cytopenias. To develop a more effective procedure that might optimize the killing of leukemia cells and the sparing of normal hematopoietic progenitor cells, a 1:1 mixture of Philadelphia1 leukemic cells and normal bone marrow cells was exposed to a combination of a low dose of mafosfamide and bcr-abl antisense oligodeoxynucleotides and assayed for growth ability in clonogenic assays and in immunodeficient mice. Bcr-abl transcripts were not detected in residual colonies, and cytogenetic analysis of individual colonies revealed a normal karyotype. Normal but not leukemic hematopoietic colonies of human origin were also detected in marrows of immunodeficient mice 1 mo after injection of the treated cells. Our results indicate that a combination of a conventional chemotherapeutic agent and a tumor-specific antisense oligodeoxynucleotide is highly effective in killing leukemic cells and in sparing a much higher number of normal progenitor cells as compared with high-dose mafosfamide treatment. This offers the prospect of a novel and more selective ex vivo treatment of chronic myelogenous leukemia.
Original language | English |
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Pages (from-to) | 194-202 |
Number of pages | 9 |
Journal | Journal of Clinical Investigation |
Volume | 92 |
Issue number | 1 |
DOIs | |
State | Published - Jul 1993 |
Keywords
- Animals
- Antineoplastic Agents/administration & dosage
- Bone Marrow Transplantation
- Bone Marrow/drug effects
- Cyclophosphamide/administration & dosage
- Dose-Response Relationship, Drug
- Drug Synergism
- Fusion Proteins, bcr-abl/genetics
- Gene Expression/drug effects
- Hematopoiesis/drug effects
- Hematopoietic Stem Cells/drug effects
- Humans
- In Vitro Techniques
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy
- Mice
- Oligonucleotides, Antisense/administration & dosage
- RNA, Messenger/genetics
- Transplantation, Heterologous