Comparison of Dasatinib, Nilotinib, and Imatinib in the Treatment of Chronic Myeloid Leukemia

Ciarcia, Roberto; Damiano, Sara; Puzio, Maria Valeria; Montagnaro, Serena; Pagnini, Francesco; Pacilio, Carmen; Caparrotti, Giuseppe; Bellan, Cristiana; Garofano, Tiziana; Polito, Maria Sole; Giordano, Antonio; Florio, Salvatore

doi:10.1002/jcp.25118

Cited by 20 publications

(10 citation statements)

References 43 publications

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“…Nilotinib is a selective BCR‐ABL tyrosine kinase inhibitor, while dasatinib is a multi‐targeted inhibitor of BCR‐ABL tyrosine kinase and SRC family kinases (Ciarcia et al , ; Marfe et al , ). There is also some evidence that dasatinib may inhibit the circadian clock kinase CK1 (Karaman et al , ), which may explain its period‐lengthening effects (Fig A).…”

Section: Resultsmentioning

confidence: 99%

Identification of circadian clock modulators from existing drugs

et al. 2018

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Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet‐lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time‐consuming. We therefore performed a high‐throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period‐shortening compound dehydroepiandrosterone (DHEA; also known as prasterone). DHEA is one of the most abundant circulating steroid hormones in humans and is available as a dietary supplement in the USA. Dietary administration of DHEA to mice shortened free‐running circadian period and accelerated re‐entrainment to advanced light–dark (LD) cycles, thereby reducing jet‐lag. Our drug screen also revealed the involvement of tyrosine kinases, ABL1 and ABL2, and the BCR serine/threonine kinase in regulating circadian period. Thus, drug repurposing is a useful approach to identify new circadian clock modulators and potential therapies for circadian disorders.

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Section: Resultsmentioning

confidence: 99%

Identification of circadian clock modulators from existing drugs

et al. 2018

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“…24,25) Dasatinib has a remarkably short half-life compared with those of other TKIs and the plasma concentration of dasatinib cannot be maintained for a long time. However, the therapeutic effect of dasatinib has been reported to be superior to those of other TKIs 20,26,27) Previous studies showed that dasatinib not only inhibited its therapeutic target BCR-ABL but also strongly inhibited other tyrosine kinases involved in cell proliferation such as SRC, whereas imatinib inhibited only BCR-ABL. 28,29) Thus, the mechanisms underlying the thera-peutic effects of imatinib and dasatinib are different.…”

Section: Discussionmentioning

confidence: 99%

Continuous Cytostatic Effects of BCR-ABL Tyrosine Kinase Inhibitors (TKIs) after Washout in Human Leukemic K562 Cells

Aoyama

Shibayama

Furukawa

et al. 2019

Biological & Pharmaceutical Bulletin

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Tyrosine kinase inhibitors (TKIs) are used as the first choice for chronic myeloid leukemia (CML) pharmacotherapeutics. Some patients taking these drugs showed good therapeutic reactivity despite the disappearance of drugs from blood. We investigated whether these drugs have sustained effects even after their disappearance and whether their effects depend on their amounts of intracellular accumulation. Cell proliferation after exposure of K562 cells or Multidrug resistance-1 (MDR-1)-transfected K562 cells was determined by a cell counting kit-8 assay. The intracellular accumulation amount of the drug showing a sustained cytostatic effect was measured by ultra high performance liquid chromatography mass spectrometry. Cell viability decreased in a culture time-dependent manner after washing out nilotinib and dasatinib. The sustained cytostatic effect of dasatinib, but not that of nilotinib, correlated with the intracellular accumulation level. In contrast, imatinib showed continuous a cytostatic effect after drug washout for long-term exposure but not after drug washout for short-term exposure. These results suggest that a good response in patients with a low serum concentration of imatinib, nilotinib or dasatinib may be due to the cytostatic effect of that drug continues even after its disappearance in plasma.

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“…The use of tyrosine-kinase inhibitors (TKIs) has been well studied in the context of CML, with imatinib and dasatnib being examples. 37,38 On the other hand, data on the use of TKIs for treating CLL/ SLL is limited. 39,40 Veldurthy et al 41 demonstrated that CLL/SLL with parameters associated with unfavorable outcomes (IGVH unmutated, ZAP70, and CD38 expression) showed some response with dasatinib therapy.…”

Section: Discussionmentioning

confidence: 99%

Chronic Myelogenous Leukemia Diagnosed in the Setting of Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

et al. 2019

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Chronic myeloid leukemia (CML) is rarely reported to occur in treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this article, we report a woman in her 70s, diagnosed with CLL/SLL in 2000, untreated, who subsequently presented 12 years later with de novo CML, BCR-ABL1+. Her IGHV mutated CLL/SLL based on the initial sample in our laboratory showed homozygous and heterozygous 13q14.3 deletions, whereas her CML, at presentation, showed a 46,XX,t(9;22)(q34;q11.2)[7]/46,XX[18] karyotype with a p190 BCR-ABL1 transcript. The tumor burden of each clone varied with treatment, including when treated with dasatinib, used to target both clones. In addition, the cytogenetic abnormalities evolved over time and treatments and included acquisition of an extra chromosome 8 in the CML clone and a novel K1992T ATM missense mutation (47% allele frequency) in the CLL/SLL clone. The patient’s last bone marrow biopsy, 5 years after her CML diagnosis and 17 years after the CLL/SLL diagnosis, showed residual CML with extensive involvement by CLL/SLL (80%). Cytogenetic studies showed a 46,XX karyotype, while FISH identified 13q14.3 deletion and the BCR-ABL1 translocation in the CLL/SLL and CML clones, respectively. To date, this is the fourth case of concurrent CML, BCR-ABL1+ arising in untreated CLL/SLL. Here we show dynamic variation in the size of the 2 clonal processes reflecting the variable responsiveness to specific therapies. In addition to the unusual BCR-ABL1+ p190 transcript in the patient’s CML, a novel ATM K1992T mutation was identified in the CLL/SLL population.

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Comparison of Dasatinib, Nilotinib, and Imatinib in the Treatment of Chronic Myeloid Leukemia

Cited by 20 publications

References 43 publications

Identification of circadian clock modulators from existing drugs

Identification of circadian clock modulators from existing drugs

Continuous Cytostatic Effects of BCR-ABL Tyrosine Kinase Inhibitors (TKIs) after Washout in Human Leukemic K562 Cells

Chronic Myelogenous Leukemia Diagnosed in the Setting of Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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