HIGHLY EFFICIENT ELIMINATION OF PHILADELPHIA LEUKEMIC-CELLS BY EXPOSURE TO BCR ABL ANTISENSE OLIGODEOXYNUCLEOTIDES COMBINED WITH MAFOSFAMIDE/

Synthetic oligodeoxynucleotides complementary to the break-point junct ion of bcr-abl transcripts selectively inhibit the proliferation of Ph iladelphia1-positive leukemic cells, but residual leukemic cells persi st in antisense oligodeoxynucleotides-treated cultures. Cyclophosphami de derivatives such as mafosfamide and 4-hydroperoxycyclophosphamide a re 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 m ight 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 an d assayed for growth ability in clonogenic assays and in immunodeficie nt mice. Bcr-abl transcripts were not detected in residual colonies, a nd cytogenetic analysis of individual colonies revealed a normal karyo type. Normal but not leukemic hematopoietic colonies of human origin w ere also detected in marrows of immunodeficient mice 1 mo after inject ion of the treated cells. Our results indicate that a combination of a conventional chemotherapeutic agent and a tumor-specific antisense ol igodeoxynucleotide is highly effective in killing leukemic cells and i n sparing a much higher number of normal progenitor cells as compared with high-dose mafosfamide treatment. This offers the prospect of a no vel and more selective ex vivo treatment of chronic myelogenous leukem ia.