Preclinical assessment of a fixed dose combination of novel liposome formulations of idarubicin and gemcitabine showing improved antitumor activity
Bibliographic record
Abstract
1406 Objective: Combination chemotherapy regimens are the mainstay of cancer treatment. In general, established protocols utilizing drug combinations are empirically defined in late phase clinical trials. There is a need to identify effective drug combinations during preclinical studies. The purpose of the studies described herein was to achieve improved therapeutic activity by combining idarubicin (IDA) and gemcitabine (GEM). These drugs were chosen based on their complementary antitumor effects, non-overlapping toxicities and proven efficacy. It is further proposed that the therapeutic properties of the individual drugs will be enhanced when administered in appropriately selected liposomal formulations. The studies established a method to define a fixed dose combination product administered in preclinical animal models at doses selected on the basis of the toxic and therapeutic effects of the individual drugs, whether given alone or in a liposomal formulation. Methods: Combination drug treatments were prepared at drug/drug ratios defined on the basis of maximum tolerable dose (MTD) studies. The efficacy of the combination drug product comprised of free and/or liposomal drugs was then determined at three effective doses in a murine leukemia model. Results: In vitro cytotoxicity data, where combination effects were determined for several different drug/drug ratios, indicated that GEM and IDA exhibited moderate to strong synergism over a broad range of effective doses. A GEM lipid formulation was established in DSPC / Cholesterol / DSPE-PEG2000 (50:45:5 mole ratio). This lipid formulation significantly increased plasma drug circulation lifetimes (T1/2 = 14.3 h) when compared to free GEM (T1/2 = 2.1 h). Similarly, encapsulation of idarubicin in DSPC / DSPE-PEG2000 (98:2 mole ratio) significantly increased plasma drug circulation lifetimes (T1/2 = 6.7) when compared to free IDA (T1/2 = 1.2 h). The combination treatment of liposomal IDA (2 mg/kg) and liposomal GEM (3.4 mg/kg), evaluated in a murine leukemia model, resulted in a 281 % increase in life span (% ILS), yielding a synergistic effect as judged when compared to liposomal IDA (2 mg/kg; 156 % ILS) and liposomal GEM (5 mg/kg; 100 % ILS) administered as single agents. Interestingly, when IDA (2 mg/kg) and GEM (334 mg/kg) were administered as a combination of free drugs, a much lower (125 %) ILS was observed. Conclusions: The combination of IDA and GEM in vitro demonstrated synergistic cytotoxic activity over a broad range of concentrations. In a murine leukemia model, appropriate drug/drug ratios were chosen based on the MTD of a single dose administration for each drug. The combination of the liposomal drugs yielded synergistic % ILS, which was not observed for free/free or free/liposomal drug combinations.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".