Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells

Löfgren, Christina; Hjortsberg, Linn; Blennow, Malin; Lotfi, Kourosh; Paul, Christer; Eriksson, Staffan; Albertioni, Freidoun

doi:10.1016/j.bbrc.2004.06.016

Cited by 11 publications

(6 citation statements)

References 23 publications

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“…In T-ALL cell lines, there was significant IC 50 correlation between DNR, DOX, VCR and ARA-C, consistent with previous studies indicating mechanisms of cross-resistance for these drugs Martin-Aragon et al, 2000;Lofgren et al, 2004). We found a positive correlation between glucocorticoid and ASP resistance, indicating that sensitivity to these unrelated compounds may also be influenced by common biological factors, possibly through alterations in apoptosis (Holleman et al, 2003).…”

Section: Discussionsupporting

confidence: 91%

Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

et al. 2006

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Cell lines are important models for drug resistance in acute lymphoblastic leukaemia (ALL), but are often criticised as being unrepresentative of primary disease. There are also doubts regarding the authenticity of many lines. We have characterised a panel of ALL cell lines for growth and drug resistance and compared data with that published for primary patient specimens. In contrast to the convention that cell lines are highly proliferative, those established in our laboratory grow at rates similar to estimates of leukaemic cells in vivo (doubling time 53 -442 h). Authenticity was confirmed by genetic fingerprinting, which also demonstrated the potential stability of long-term cultures. In vitro glucocorticoid resistance correlated well with that measured ex vivo, but all lines were significantly more sensitive to vincristine than primary specimens. Sensitivity to methotrexate was inversely correlated to that of glucocorticoids and L-asparaginase, indicating possible reciprocity in resistance mechanisms. A cell line identified as highly methotrexate resistant (IC 50 48000-fold higher than other lines) was derived from a patient receiving escalating doses of the drug, indicating in vivo selection of resistance as a cause of relapse. Many of these lines are suitable as models to study naturally occurring resistance phenotypes in paediatric ALL.

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Section: Discussionsupporting

confidence: 91%

Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

et al. 2006

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“…To investigate the feasibility of using CETSA for assessing acquired drug resistance, multidrug-resistant K562-R cells were studied. The K562-R cells are previously described as vincristine-resistant due to overexpression of P-gp 28 . We used AlphaLISA as readout method for ITDR-CETSA in order to compare the dose dependence of different taxanes in K562-R and the parental counterpart K562-P after a 1 h 45 min exposure to drugs.…”

Section: Resultsmentioning

confidence: 99%

CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance

Langebäck

Bacanu

Laursen

et al. 2019

Sci Rep

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The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical setting allowing for treatment and dose stratification for individual patients. To assess treatment efficacy up to the level of drug target engagement, we have established several formats of tubulin-specific Cellular Thermal Shift Assays (CETSAs). This technique was evaluated in breast and prostate cancer models and in a cohort of breast cancer patients. Here we show that taxanes induce significant CETSA shifts in cell lines as well as in animal models including patient-derived xenograft (PDX) models. Furthermore, isothermal dose response CETSA measurements allowed for drugs to be rapidly ranked according to their reported potency. Using multidrug resistant cancer cell lines and taxane-resistant PDX models we demonstrate that CETSA can identify taxane resistance up to the level of target engagement. An imaging-based CETSA format was also established, which in principle allows for taxane target engagement to be accessed in specific cell types in complex cell mixtures. Using a highly sensitive implementation of CETSA, we measured target engagement in fine needle aspirates from breast cancer patients, revealing a range of different sensitivities. Together, our data support that CETSA is a robust tool for assessing taxane target engagement in preclinical models and clinical material and therefore should be evaluated as a prognostic tool during taxane-based therapies.

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“…The data analysis revealed 1223 genes with an at least two-fold differential expression between the MOLT-4 and MOLT-4/AraG900 cells. On considering the most up-regulated genes, several fetal hemoglobin genes were represented, as well as the ABCB1 gene (Table 1) encoding for the membrane transporter P-gp involved in multidrug resistance [10]. Upregulated genes also included KLF1, involved in hemoglobin gamma expression [11], and BLVRB, encoding biliverdin reductase B, which is involved in hemoglobin degradation.…”

Section: Microarray Expression Data Analysismentioning

confidence: 99%

Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells

Fyrberg

Peterson

Kågedal

et al. 2010

Cancer Chemother Pharmacol

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Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells

Cited by 11 publications

References 23 publications

Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance

Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells

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