Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib

Deininger, Michael W.; Druker, Brian J.

doi:10.1124/pr.55.3.4

Cited by 311 publications

(202 citation statements)

References 160 publications

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“…Kinases are currently one of the most promising and most intensively pursued drug targets (Arkin and Wells 2004), because of their high efficiency and low toxicity. One example is Imatinib (O'Dwyer et al 2002;Deininger and Druker 2003), the first selective tyrosine kinase inhibitor targeting Bcr-Abl protein, which has shown clinical efficacy in the treatment of Chronic Myeloid Leukemia (CML). Small molecule inhibitors such as Imatinib, have the ability to bind specifically to cancer cells, and spare healthy, non-cancerous cells.…”

Section: Discussionmentioning

confidence: 99%

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The Worst Drug Rule Revisited: Mathematical Modeling of Cyclic Cancer Treatments

Katouli

Komarova

2010

Bull Math Biol

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In drug treatments of cancer, cyclic treatment strategies are characterized by alternating applications of two (or more) different drugs, given one at a time. One of the main problems of drug treatment in cancer is associated with the generation of drug resistance by mutations of cancerous cells. We use mathematical methods to develop general guidelines on optimal cyclic treatment scheduling, with the aim of minimizing the resistance generation. We define a condition on the drugs' potencies which allows for a relatively successful application of cyclic therapies. We find that the best strategy is to start with the stronger drug, but use longer cycle durations for the weaker drug. We further investigate the situation where a degree of crossresistance is present, such that certain mutations cause cells to become resistant to both drugs simultaneously. We show that the general rule (best-drug-first, worst-druglonger) is unchanged by the presence of cross-resistance. We design a systematic method to test all strategies and come up with the optimal timing and drug order. The role of various constraints in the optimal therapy design, and in particular, suboptimal treatment durations and drug toxicity, is considered. The connection with the "worst drug rule" of Day (Cancer Res. 46:3876, 1986b) is discussed.

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Section: Discussionmentioning

confidence: 99%

“…Currently there are three small molecule inhibitors approved for treatment of CML: Imatinib (O'Dwyer et al 2002;Deininger and Druker 2003), Dasatinib, and Nilotinib (Bradeen et al 2006;Weisberg et al 2007). These drugs are all inhibitors of the BCR-ABL gene product.…”

Section: The Role Of Cross-resistancementioning

confidence: 99%

The Worst Drug Rule Revisited: Mathematical Modeling of Cyclic Cancer Treatments

Katouli

Komarova

2010

Bull Math Biol

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“…We also show that the combination of imatinib and rapamycin is able to inhibit translation to a greater extent than either agent alone, and that this is associated with a more profound effect on protein expression. Finally, we demonstrate that the combination acts synergistically against committed CML progenitor cells at concentrations that are achievable in patients for both drugs (Meier-Kriesche and Kaplan, 2000;Deininger and Druker, 2003).…”

mentioning

confidence: 99%

A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation

et al. 2006

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“…The other added value of our high-content assay strategy allows for quantification of remaining nuclei per well postfixation as a measure of cytotoxicity; in the case of imatinib-treated KP cells, an average of 1,957 -29 nuclei was counted versus an average of 1,766 -26 in the DMSO control wells, suggesting that imatinib is not cytotoxic to the KP cells since our threshold for cytotoxic compounds is the standard 80% loss of nuclei count. 20 We next investigated the ability of our assay to identify reversers of the KP-transformed phenotype by performing dose-response studies against a panel of seven compounds: imatinib (a known PDGFRa inhibitor), 14 16 and, finally, gefitinib and erlotinib (both phenylquinazolin-4-amine-based compounds and well-characterized inhibitors of EGFR). 21 The chemical structures of each compound are summarized in Figure 5A.…”

Section: Analyzing Images Of Cellular Clusters and Quantifying Reversmentioning

confidence: 99%

“…After the establishment of assay conditions, a sensitivity assessment was performed as a dose-response run against the following five known PDGFRa inhibitors and two epidermal growth factor receptor (EGFR) inhibitors: imatinib, 14 16 gefitinib, and erlotinib. The dose-response was assessed using 12-point doubling dilutions with 10 mM compound concentration as the upper limit.…”

Section: Cell-based Assay Development and Validationmentioning

confidence: 99%

Validation of a High-Content Screening Assay Using Whole-Well Imaging of Transformed Phenotypes

Ramirez

Ozawa

Takagi

et al. 2011

ASSAY and Drug Development Technologies

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Automated microscopy was introduced two decades ago and has become an integral part of the discovery process as a high-content screening platform with noticeable challenges in executing cell-based assays. It would be of interest to use it to screen for reversers of a transformed cell phenotype. In this report, we present data obtained from an optimized assay that identifies compounds that reverse a transformed phenotype induced in NIH-3T3 cells by expressing a novel oncogene, KP, resulting from fusion between platelet derived growth factor receptor alpha (PDGFRa) and kinase insert domain receptor (KDR), that was identified in human glioblastoma. Initial image acquisitions using multiple tiles per well were found to be insufficient as to accurately image and quantify the clusters; whole-well imaging, performed on the IN Cell Analyzer 2000, while still two-dimensional imaging, was found to accurately image and quantify clusters, due largely to the inherent variability of their size and well location. The resulting assay exhibited a Z ' value of 0.79 and a signal-to-noise ratio of 15, and it was validated against known effectors and shown to identify only PDGFRa inhibitors, and then tested in a pilot screen against a library of 58 known inhibitors identifying mostly PDGFRa inhibitors as reversers of the KP induced transformed phenotype. In conclusion, our optimized and validated assay using whole-well imaging is robust and sensitive in identifying compounds that reverse the transformed phenotype induced by KP with a broader applicability to other cell-based assays that are challenging in HTS against chemical and RNAi libraries.

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Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib

Cited by 311 publications

References 160 publications

The Worst Drug Rule Revisited: Mathematical Modeling of Cyclic Cancer Treatments

The Worst Drug Rule Revisited: Mathematical Modeling of Cyclic Cancer Treatments

A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation

Validation of a High-Content Screening Assay Using Whole-Well Imaging of Transformed Phenotypes

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