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  • Title: Highly efficient elimination of Philadelphia leukemic cells by exposure to bcr/abl antisense oligodeoxynucleotides combined with mafosfamide.
    Author: Skorski T, Nieborowska-Skorska M, Barletta C, Malaguarnera L, Szcyzlik C, Chen ST, Lange B, Calabretta B.
    Journal: J Clin Invest; 1993 Jul; 92(1):194-202. PubMed ID: 8325984.
    Abstract:
    Synthetic oligodeoxynucleotides complementary to the break-point junction of bcr-abl transcripts selectively inhibit the proliferation of Philadelphia-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 Philadelphia 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 Philadelphia 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.
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