Imatinib mesylate (STI571, Glivec, Gleevec) is a powerful inhibitor of the 
tyrosine kinase activity of Bcr-Abl, the oncoprotein responsible for chronic 
myeloid leukemia (CML). The drug shows great efficacy in chronic phase, but is 
less effective in maintaining hematologic remissions in blast crisis patients. 
Our group has previously described several cell lines made resistant to 
imatinib. We now examine the question of cross-resistance to other 
chemotherapeutic drugs used in CML. Four paired imatinib-sensitive/resistant CML 
cell lines were assessed by caspase-3 and MTS assays for their proliferative 
response to cytosine arabinoside (Ara-C), daunorubicin (DNR), homoharringtonine 
(HHT) and hydroxyurea (HU), either alone or in combination with imatinib. 
Primary blasts from advanced-stage CML patients refractory to imatinib therapy 
were studied by semi-solid media clonogenic assays. We found that these drugs 
are generally capable of major inhibition of proliferation of the CML cell 
lines, although differential responses to DNR and HHT were noted between some 
sensitive and resistant cell line pairs, implying that resistance to imatinib 
may confer a growth advantage under such conditions. The four drugs were also 
effective in preventing the formation of progenitor cell colonies from CML 
patients both before treatment with imatinib, and after relapse on the drug. 
Isobolographic analysis implied that these drugs will generally combine well 
with imatinib, and in some cases will be synergistic. We conclude that Ara-C, 
DNR or HHT, either alone or in combination with imatinib, are likely to be the 
best therapeutic alternatives in the management of patients who become resistant 
to imatinib monotherapy.