A pharmaceutical approach to achieve synergy in vivo: A fixed ratio formulation of Irinotecan and Floxuridine for treatment of colorectal cancer
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».