Abstract 2526: Detection of Ara-CTP following exposure to CPX-351 and potentiation of action by fludarabine in leukemia cell lines using a bioluminescent bacterial biosensor
Bibliographic record
Abstract
Abstract Background: Cytarabine (ara-C) is a well-established agent widely used for treating AML. At relapse its use clinically has been combined with the purine analogue fludarabine plus idarubicin and G-CSF (FLAG-Ida). Fludarabine is known to potentiate intracellular accumulation of the active cytotoxic metabolite ara-CTP from ara-C via inhibition of ribonucleotide reductase and the normal formation of endogenous dCTP. CPX-351 is a liposomal formulation of a synergistic 5:1 molar ratio of ara-C and DNR, currently in a Phase III trial versus 7+3 ara-C/DNR in newly diagnosed elderly high risk (secondary) AML patients. The aim of the study here was to utilize the well-established Escherichia coli HA1 whole-cell biosensor to measure intracellular ara-C and ara-CTP following in vitro exposure of human immortalised leukemic cell lines to CPX-351, and to assess the ability of fludarabine to potentiate intracellular ara-CTP formation. Methods: Biosensor E. coli HA1 has been engineered to produce a bioluminescent output in response to ara-C. The bacterial biosensor is able to monitor both ara-C and ara-CTP by measuring signals in the absence and presence of alkaline phosphatase, respectively. A range of in vivo-relevant ara-C concentrations (5-50 μM) and incubation times (1-4 hours) were tested. Results: Free ara-C+DNR produced an increase in bioluminescence (and hence ara-CTP) at each time-point tested in line with previous results. Incubation with CPX-351 required a longer time-period to result in similar levels of ara-CTP, but a dose-dependent increase was noted, with the highest increase produced using 4-hour incubation of CPX-351 at a concentration of 25 μM. This delay was consistent with previously observed kinetics of liposomal drug uptake by leukemia cells. Following optimisation of in vitro dosing, potentiation of ara-CTP generation was assessed following 4-hour incubation with fludarabine (5 μM), a dose previously shown to increase ara-CTP accumulation in susceptible cell lines. Potentiation of ara-CTP generation from CPX-351 was observed in three of the four cell lines tested, with the largest increase observed in THP-1 cells. No potentiation was observed in CCRF-CEM cells, in line with previous findings with ara-C. Conclusions: This study demonstrates the ability of fludarabine to potentiate formation of ara-CTP upon exposure of leukemia cells to CPX-351, suggesting a favourable impact on efficacy for this combination. Additional testing in ex vivo blasts from AML patients may be warranted to support the further investigation of this combination. Citation Format: Lawrence D. Mayer, Elizabeth Anderson, Heather Bone, Gareth Robinson, Garreth Reynolds, Vyvyan Salisbury. Detection of Ara-CTP following exposure to CPX-351 and potentiation of action by fludarabine in leukemia cell lines using a bioluminescent bacterial biosensor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2526. doi:10.1158/1538-7445.AM2015-2526
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".