TY - JOUR
T1 - Troxacitabine and imatinib mesylate combination therapy of chronic myeloid leukaemia
T2 - Preclinical evaluation
AU - Orsolic, Nada
AU - Giles, Francis J.
AU - Gourdeau, Henriette
AU - Golemovic, Mirna
AU - Beran, Miloslav
AU - Cortes, Jorge
AU - Freireich, Emu J.
AU - Kantarjian, Hagop
AU - Verstovsek, Srdan
PY - 2004/3
Y1 - 2004/3
N2 - 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.
AB - 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.
KW - In vitro
KW - In vivo
KW - Synergism
KW - Xenograft
UR - http://www.scopus.com/inward/record.url?scp=1642280989&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1642280989&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2141.2004.04831.x
DO - 10.1111/j.1365-2141.2004.04831.x
M3 - Article
C2 - 15009060
AN - SCOPUS:1642280989
SN - 0007-1048
VL - 124
SP - 727
EP - 738
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 6
ER -