Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs

Abstract

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 crossresistance 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 advancedstage 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.

Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells

“…This is not an unusual occurrence, as it has also been observed for other drugs in IM-resistant cells. 34,44,45 A possible reason for this phenomenon is that at low doses that do not induce apoptosis but are suffcient to reduce Bcr-Abl kinase activation, IM is able to sensitize the resistant cells to the antiproliferative or cytotoxic effect of the second drug. An alternative explanation is that these resistant cells still retain some quantitative sensitivity to IM, 46 and synergism with a second drug can only be achieved when combined with a dose of IM high enough to overcome resistance.…”

“…34 Cells were plated in quadruplicate and exposed to escalating doses of each drug independently. Three independent experiments were performed.…”

Vaccination of chronic myeloid leukemia patients with autologous in vitro cultured leukemic dendritic cells

“…Also, the emergence of resistance mechanisms against STI571 has been reported. 12 Therefore, adjuvant immunotherapy is still a viable option in the management of CML, particularly in patients with MRD after STI571 treatment. Our study indicates that autologous CML/DCbased vaccination may be a valid approach in this regard.…”

Imatinib sensitizes CLL lymphocytes to chlorambucil

“…While the mechanism involved has not been addressed yet, imatinib used in combination with drugs that interfere with DNA metabolism have a synergistic cytotoxic effect in primary CML cells. 15,16 Virtually all CML cases express a constitutively active c-abl kinase as a consequence of the t(9, 22) (q34, 11) translocation. In contrast in CLL patients, BCR/ABL translocations have not been reported.…”