Stability of extemporaneously prepared cytarabine, methotrexate sodium, and methylprednisolone sodium succinate

Cancer cell line panels are important tools to characterize the in vitro activity of new investigational drugs. Here, we present the inhibition profiles of 122 anticancer agents in proliferation assays with 44 or 66 genetically characterized cancer cell lines from diverse tumor tissues (Oncolines). The library includes 29 cytotoxics, 68 kinase inhibitors, and 11 epigenetic modulators. For 38 compounds this is the first comparative profiling in a cell line panel. By strictly maintaining optimized assay protocols, biological variation was kept to a minimum. Replicate profiles of 16 agents over three years show a high average Pearson correlation of 0.8 using IC values and 0.9 using GI values. Good correlations were observed with other panels. Curve fitting appears a large source of variation. Hierarchical clustering revealed 44 basic clusters, of which 26 contain compounds with common mechanisms of action, of which 9 were not reported before, including TTK, BET and two clusters of EZH2 inhibitors. To investigate unexpected clusterings, sets of BTK, Aurora and PI3K inhibitors were profiled in biochemical enzyme activity assays and surface plasmon resonance binding assays. The BTK inhibitor ibrutinib clusters with EGFR inhibitors, because it cross-reacts with EGFR. Aurora kinase inhibitors separate into two clusters, related to Aurora A or pan-Aurora selectivity. Similarly, 12 inhibitors in the PI3K/AKT/mTOR pathway separated into different clusters, reflecting biochemical selectivity (pan-PI3K, PI3Kβγδ-isoform selective or mTOR-selective). Of these, only allosteric mTOR inhibitors preferentially targeted PTEN-mutated cell lines. This shows that cell line profiling is an excellent tool for the unbiased classification of antiproliferative compounds. Mol Cancer Ther; 15(12); 3097-109. ©2016 AACR.

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“…2C). One reason might be that our solutions were always freshly made and that methotrexate can easily degrade when lightexposed (33,34).…”

Section: Accuracy Of Cell Line Profilingmentioning

confidence: 99%

Cell Panel Profiling Reveals Conserved Therapeutic Clusters and Differentiates the Mechanism of Action of Different PI3K/mTOR, Aurora Kinase and EZH2 Inhibitors

Uitdehaag¹,

Roos²,

Prinsen³

et al. 2016

Molecular Cancer Therapeutics

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“…Besides the commonly used C18 fused-core columns, where separation efficiency under different conditions was investigated for a wide variety of chemical components [11] , [15] , [16] , [17] , [18] , [19] , [20] , other fused-core columns such as C8, HILIC, RP-amide, peptide, phenyl-hexyl are becoming available. In contrast to C18 fused-core columns, little investigation has been carried out on the column performance of these other stationary phases [21] , [22] , [23] .…”

Section: Resultsmentioning

confidence: 99%

A critical quality parameter in quantitative fused-core chromatography: The injection volume

Boonen

D׳Hondt

Veryser

et al. 2013

Journal of Pharmaceutical Analysis

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As part of the method development, the injection volume as a critical quality attribute in fast fused-core chromatography was evaluated. Spilanthol, a pharmaceutically interesting N-alkylamide currently under investigation in our laboratory, was chosen as the model compound. Spilanthol was dissolved in both PBS and MeOH/H2O (70/30, v/v) and subsequently analyzed using a fused-core system hereby selecting five chromatographic characteristics (retention time, area, height, theoretical plates and symmetry factor) as responses. We demonstrated that the injection volume significantly influenced both the qualitative and quantitative performance of fused-core chromatography, a phenomenon which is confounded with the nature of the used sample solvent. From 2 μL up to 100 μL injection volume with PBS as solvent, the symmetry factor decreased favorably by 20%. Moreover, the theoretical plates and the quantitative parameters (area and height) increased up to 30%. On the contrary, in this injection volume range, the theoretical plates for the methanol-based samples decreased by more than 60%, while the symmetry factor increased and the height decreased, both by 30%. The injection volume is thus a critical and often overlooked parameter in fused-core method description and validation.

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“…D’Hondt et al. 16 assessed the stability of a triple intrathecal therapy containing cytarabine, metothexate sodium, and methylprednisolone sodium succinate in 0.9% sodium chloride injection added to different packaging materials and stored at 5℃, 25℃, and 40℃; cytarabine and methotrexate were found to be stable for 48 h at the different storage conditions and light protected, but significant methylprednisolone degradation was seen throughout all storage conditions. The results from our study are consistent with the above-mentioned, with the exception of the chemical stability of hydrocortisone.…”

Section: Discussionmentioning

confidence: 99%

Stability of four standardized preparations of methotrexate, cytarabine, and hydrocortisone for intrathecal use

Olmos-Jiménez

Espuny-Miró

Díaz-Carrasco

et al. 2016

J Oncol Pharm Pract

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Stability of extemporaneously prepared cytarabine, methotrexate sodium, and methylprednisolone sodium succinate

Abstract: Triple intrathecal solution of cytarabine, methotrexate sodium, and methylprednisolone sodium succinate was stable for up to 12 hours when stored at 5 °C and protected from light.

Cited by 13 publications

References 19 publications

Cell Panel Profiling Reveals Conserved Therapeutic Clusters and Differentiates the Mechanism of Action of Different PI3K/mTOR, Aurora Kinase and EZH2 Inhibitors

Cell Panel Profiling Reveals Conserved Therapeutic Clusters and Differentiates the Mechanism of Action of Different PI3K/mTOR, Aurora Kinase and EZH2 Inhibitors

A critical quality parameter in quantitative fused-core chromatography: The injection volume

Stability of four standardized preparations of methotrexate, cytarabine, and hydrocortisone for intrathecal use

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