Troxacitabine and imatinib mesylate combination therapy of chronic myeloid leukaemia: preclinical evaluation

• Published in: British journal of haematology 2004-03, Vol.124 (6), p.727-738
• Main Authors: Orsolic, Nada, Giles, Francis J., Gourdeau, Henriette, Golemovic, Mirna, Beran, Miloslav, Cortes, Jorge, Freireich, Emil J, Kantarjian, Hagop, Verstovsek, Srdan
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzamides; Biological and medical sciences; Cell Survival - drug effects; Chemotherapy; Cytosine - administration & dosage; Cytosine - analogs & derivatives; Dioxolanes - administration & dosage; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor - methods; Drug Synergism; Female; Hematologic and hematopoietic diseases; Hematology; Humans; Imatinib Mesylate; in vitro; in vivo; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred ICR; Mice, SCID; Neoplasm Transplantation; Pharmacology. Drug treatments; Piperazines - administration & dosage; Pyrimidines - administration & dosage; Survival Analysis; synergism; Tumor Cells, Cultured; xenograft; Xenograft Model Antitumor Assays - methods
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2004.04831.x

Summary The in vitro and in vivo activity of a deoxycytidine analogue, troxacitabine, alone or in combination with imatinib mesylate (IM), was evaluated against human chronic myeloid leukaemia (CML) cell lines both sensitive (KBM5 and KBM7) and resistant (KBM5‐R and KBM7‐R) to IM. These cell lines differ in their sensitivity to IM but all showed similar sensitivity to treatment with troxacitabine (IC50 = 0·5–1 μmol/l). Combined treatment with troxacitabine and IM revealed additive or synergistic effects. Greater apoptotic response was seen with combined treatment than with either agent alone in KBM7‐R cells. In clonogenic assays, troxacitabine showed activity against mononuclear cells from CML patients (IC50 = 0·01 μmol/l) with either IM‐sensitive or resistant disease. In vivo efficacy studies were carried out in severe combined immunodeficient mice bearing KBM5 or KBM5‐R cells. Troxacitabine was administered i.p. daily for 5 d starting on day 20, at doses of 5, 10, 20, or 25 mg/kg. IM was administered i.p. twice a day for 10 d at a dose of 50 mg/kg starting on day 25. In this setting of late stage disease, troxacitabine led to a significant increase in life span, while IM did not. When IM was combined with troxacitabine at 10 and 25 mg/kg in the KBM5 xenograft model, a further increase in life span was observed and some mice achieved long‐term survival. These data indicate that the combination of troxacitabine and IM has significant preclinical activity in advanced CML and that clinical evaluation of this combination is warranted.