Synergistic Cytarabine:Daunorubicin Ratios Delivered by CPX-351 to Human Leukemia Xenografts Is Associated with Liposome-Mediated Bone Marrow Drug Accumulation, Intracellular Delivery of Encapsulated Agents to Leukemia Cells, and Increased Efficacy.
Bibliographic record
Abstract
Abstract CPX-351, a liposomal formulation of cytarabine:daunorubicin co-encapsulated at a synergistic 5:1 molar drug ratio, has been previously shown to be highly active in various preclinical leukemia models. In the present investigations, we utilized a bone marrow engrafted human lymphocytic leukemia xenograft model in order to elucidate the pharmacodynamic basis for its superior efficacy compared to un-encapsulated cytarabine:daunorubicin combinations. In normal bone marrow, the un-encapsulated cytarabine:daunorubicin saline-based cocktail and CPX-351 provided comparable cell suppression after intravenous treatment at maximum tolerated dose. In contrast, when these formulations were administered to tumor bearing mice, CPX-351 completely ablated leukemia cells from the bone marrow for multiple weeks whereas the saline-based drug cocktail induced only transient leukemia suppression. Examination of drug levels in the bone marrow compartment revealed that cytarabine:daunorubicin concentrations were significantly elevated for CPX-351. More striking was the observation that whereas bone marrow drug concentrations over time appeared comparable after each dose of the saline-based drug cocktail, the first dose of CPX-351 promoted elevated bone marrow drug accumulation for subsequent doses. Under these conditions, the cytarabine:daunorubicin ratio in bone marrow was maintained near the administered 5:1 molar ratio for CPX- 351 while the drug ratio changed more than 100-fold within 4 hours after administration of the saline-based drug cocktail. Confocal fluorescence microscopy of leukemia cells exposed to CPX-351 in vitro revealed that CPX-351 liposomes were taken up into cytoplasmic vacuoles and subsequently released their drug contents intracellularly. Taken together, these results indicate that the improved efficacy observed following CPX-351 administration in vivo is related to liposome-mediated prolonged and direct exposure of leukemia cells to synergistic drug ratios.
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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) | 0.000 | 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".