Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning.
The tyrosine kinase activity of the BCR-ABL oncoprotein results in reduced apoptosis and thus prolongs survival of chronic myelogenous leukaemia cells. The tyrosine kinase inhibitor imatinib (formerly STI571) was reported to selectively suppress the proliferation of BCR-ABL-positive cells. Assuming that imatinib could be included in pretransplantation conditioning therapies, we tested whether combinations of imatinib and gamma-irradiation or alkylating agents such as busulfan or treosulfan would display synergistic activity in BCR-ABL-positive chronic myelogenous leukaemia BV173 and EM-3 cell lines. Further, primary cells of untreated chronic myelogenous leukaemia patients were assayed for colony forming ability under combination therapy with imatinib. Additionally, the cytotoxic effect of these combinations on BCR-ABL-negative cells was investigated. In the cell lines a tetrazolium based MTT assay was used to quantify growth inhibition after exposure to cytotoxic drugs alone or to combinations with imatinib. Irradiation was applied prior to exposure to imatinib. Interaction of drugs was analysed using the median-effect method of Chou and Talalay. The combination index was calculated according to the classic isobologram equation. The combination imatinib + gamma-irradiation proved to be significantly synergistic over a broad range of cell growth inhibition levels in both BCR-ABL-positive cell lines and produced the strongest reduction in primary chronic myelogenous leukaemia colony-forming progenitor cells. Combinations of imatinib + busulfan and imatinib + treosulfan showed merely additive to antagonistic effects. Imatinib did not potentiate the effects of irradiation or cytotoxic agents in BCR-ABL-negative cells. Our data provide the basis to further develop imatinib-containing conditioning therapies for stem cell transplantation in chronic myelogenous leukaemia.
Topaly
J
J
Department of Internal Medicine V, University of Heidelberg, Hospitalstrasse 3, D-69115 Heidelberg, Germany.
Fruehauf
S
S
Ho
A D
AD
Zeller
W J
WJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001549:Benzamides; D002066:Busulfan / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division; D003131:Combined Modality Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology* / Q000628:therapy; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011878:Radiotherapy; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C018404:treosulfan; D002066:Busulfan