A pharmaceutical approach to achieve synergy in vivo: A fixed ratio formulation of Irinotecan and Floxuridine for treatment of colorectal cancer
Bibliographic record
Abstract
550 Purpose: To define a fixed ratio formulation of irinotecan and floxuridine (CPX-1) for use in the treatment of colorectal cancer. Methods: The cytotoxic effects of irinotecan and floxuridine were examined alone and combined at various fixed ratios in a number of tumor cell lines. These in vitro data were analyzed utilizing the median effect principle (Chou and Talalay, Adv Enzyme Regul, 22: 27-55, 1984). Liposomal formulations were developed for the drug combination with the goal of identifying a single lipid composition capable of encapsulating both drugs in a manner where the rate of drug release from the liposomes following intravenous administration was matched for both agents. The resulting co-encapsulated fixed ratio CPX-1 formulation was then assessed in a number of in vivo tumor models. Results: In vitro results demonstrate that synergistic interactions for irinotecan and floxuridine combinations were dependent on drug-to-drug ratio. In the human colorectal cell lines HCT-116 and HT-29, mole ratios of irinotecan and floxuridine of 1:1, 1:5 and 1:10 produced the largest synergistic effects over the broadest range of effective doses. Exposure of cancer cells to a mole ratio of 10:1 typically resulted in additive or antagonistic interactions. A mole ratio of 1:1 was defined as optimal for a range of tumor cell lines and a liposomal formulation was developed with co-encapsulated irinotecan and floxuridine at this ratio. Evaluations of the co-encapsulated drugs indicated that following i.v. administration the concentrations of each drug in the plasma were comparable over time, thus the drug-to-drug ratio in the plasma was maintained at the optimal 1:1 mole ratio. For HT-29 efficacy studies, delays in tumor growth achieved following treatment with the maximum tolerated dose of the free drug cocktail were significantly less than those achieved with the fixed ratio formulation administered at an 8-fold lower dose. Control tumors grew to 500 mg 28 days after cell inoculation. Using identical drug doses (25 mg/kg of irinotecan and 9.25 mg/kg floxuridine) and treatment schedule (Q7D x 3), HT29 tumors grew to 500 mg by day 30 and 60 following treatment with free irinotecan:floxuridine and CPX-1, respectively. Similar results were seen when evaluating therapy in the HCT-116 xenograft tumor model. Conclusion: Irinotecan and floxuridine acted synergistically in vitro when combined at a molar ratio of 1:1. When evaluated in preclinical models of human solid tumors, a fixed ratio formulation exhibited dramatic improvements in antitumor activity.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".