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

Abstract：

: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 micromol/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 micromol/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.

journal_name

Br J Haematol

journal_title

British journal of haematology

authors

Orsolic N,Giles FJ,Gourdeau H,Golemovic M,Beran M,Cortes J,Freireich EJ,Kantarjian H,Verstovsek S

doi

10.1111/j.1365-2141.2004.04831.x

subject

Has Abstract

pub_date

2004-03-01 00:00:00

pages

727-38

issue

6

eissn

0007-1048

issn

1365-2141

pii

4831

journal_volume

124

pub_type

杂志文章

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