Highly efficient elimination of Philadelphia1 leukemic cells by exposure to bcr/abl antisense oligodeoxynucleotides combined with mafosfamide

Tomasz Skorski, Margaret Nieborowska-Skorska, Cosimo Barletta, Lucia Malaguarnera, Cezary Szczylik, Sing Tsung Chen, Beverly Lange, Bruno Calabretta

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

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 languageEnglish
Pages (from-to)194-202
Number of pages9
JournalJournal of Clinical Investigation
Volume92
Issue number1
DOIs
StatePublished - 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

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