In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents

Kano, Yasuhiko; Akutsu, Miyuki; Tsunoda, Saburo; Mano, Hiroyuki; Sato, Yuko; Honma, Yoshio; Furukawa, Yusuke

doi:10.1182/blood.v97.7.1999

Cited by 250 publications

(159 citation statements)

References 28 publications

Supporting

Mentioning

147

Contrasting

Unclassified

Order By: Relevance

“…Overall, our findings are in general agreement with similar reports of drug interactions between STI571 and anti-leukaemic agents that have been published in the last year (Thiesing et al, 2000;Kano et al, 2001;Topaly et al, 2001). While these studies only stopped at highlighting a synergistic reduction in absolute cell number, we went on to specifically identify hyper-additive increases in apoptosis.…”

Section: Molecular and Cellular Pathologysupporting

confidence: 92%

“…Additionally, subsequent flow cytometric analysis showed that cell kill was by apoptosis, occurring from all phases of the cell cycle. These ICvalues were higher than those reported in recent synergy studies (Thiesing et al, 2000;Kano et al, 2001;Topaly et al, 2001). Methodologically, the activity of STI571 in combination in these studies was assessed by the MTT assay, which is strictly a technique for measuring cell number and not cell kill (Carmichael et al, 1987).…”

Section: Molecular and Cellular Pathologymentioning

confidence: 83%

See 1 more Smart Citation

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

2002

View full text Add to dashboard Cite

Chronic myeloid leukaemia is typically characterised by the presence of dysregulated BCR -ABL tyrosine kinase activity, which is central to the oncogenic feature of being resistant to a wide range of cytotoxic agents. We have investigated whether the inhibition of this tyrosine kinase by the novel compound STI571 (formerly CGP57148B) would render K562, KU812 cell lines and chronic myeloid leukaemia-progenitor cells sensitive to induction of cell kill. Proliferation assays showed STI571 to be an effective cytotoxic agent in chronic myeloid leukaemia-derived cell lines (IC 50 on day 5 of 4.6 mg ml 71 and 3.4 mg ml 71 for K562 and KU812 respectively) and in leukaemic blast cells (per cent viability on day 3 at 4 mg ml 71 : 55.5+8.7 vs 96.4+3.7%). STI571 also appeared to specifically target bcr -abl expressing cells, as results from colony forming assays using the surviving cell fraction from STI571-treated peripheral CD34 + chronic myeloid leukaemia blast cells, indicated a reduction in the expansion of colonies of myeloid lineage, but no effect on normal colony formation. Our data also showed synergy between STI571 and other anti-leukaemic agents; as an example, there were significant increases in per cent cell kill in cell lines cultured with both STI571 and etoposide compared to the two alone (per cent cell kill on day 3: 73.7+11.3 vs 44.5+8.7 and 17.8+7.0% in cultures with STI571 and etoposide alone respectively; P50.001). This study confirms the central oncogenic role of BCR -ABL in the pathogenesis of chronic myeloid leukaemia, and highlights the role of targeting this tyrosine kinase as a useful tool in the clinical management of the disease.

show abstract

Section: Molecular and Cellular Pathologysupporting

confidence: 92%

Section: Molecular and Cellular Pathologymentioning

confidence: 83%

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

2002

View full text Add to dashboard Cite

show abstract

“…Whilst similar data have been published for the drug responses of imatinib-sensitive cell lines, [18][19][20][21] to our knowledge this work represents the first investigation of the effect of acquired resistance to imatinib on these drug responses. LAMA84-r showed some cross-resistance to these drugs relative to the sensitive line, but the levels of anti-proliferative effect obtained are still generally substantial.…”

Section: Discussionmentioning

confidence: 63%

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

Tipping

Fx²,

Zafirides

et al. 2002

Leukemia

View full text Add to dashboard Cite

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.

show abstract

“…18 On the basis of dose-response curves of the two drugs, three isoeffect curves were constructed. The area surrounded by the isoeffect curves was referred as the envelope of additivity.…”

Section: Isobolographic Analysis For Determination Of Synergymentioning

confidence: 99%

The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis

Wang

et al. 2009

Leukemia

View full text Add to dashboard Cite

Interactions between inhibitors of the proteasome and histone deacetylases have been examined in human T-leukemia/ lymphoma cells both in vitro and in vivo. Co-exposure of cells to bortezomib and suberoylanilide hydroxamic acid (SAHA) synergistically induces T-leukemia/lymphoma cells to undergo apoptosis, consistent with a significant increase in mitochondrial injury and caspase activation. These events are accompanied by inhibition of cyto-protective signaling pathways, including the nuclear factor (NF)-jB, Raf-1/mitogen-induced extracellular kinase (MEK)/extracellular signal-related kinase (ERK) and AKT pathways, and activation of stress-related cascades, including the stress-activated kinases c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK). Moreover, bortezomib in conjunction with SAHA efficiently induces apoptosis of primary T-leukemia/lymphoma cells and inhibits tumor growth in a murine xenograft model established with subcutaneous injection of Jurkat cells. Taken together, these findings confirm the synergistic anti-tumor effect of the proteasome and histone deacetylase inhibitors, and provide an insight into the future clinical applications of bortezomib-SAHA combining regimen in treating T-cell malignancies.

show abstract

In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents

Cited by 250 publications

References 28 publications

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

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

The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis

Contact Info

Product

Resources

About