Abstract 4506: Computational-driven metronomics: application to gemcitabine in neuroblastoma-bearing mice
Authors: Ciccolini Joseph , Pasquier Eddy , Lombard Aurelie , Giacometti Sarah , Faivre Christian , Fanciullino Raphaelle , Serdjebi Cindy , Barbolosi Dominique , Andre Nicolas 
Published: August 2015

Metronomics (i.e., repeated administration of small doses of drugs over a long period of time) is an attractive strategy to reduce treatment-related toxicities while possibly offering unexpected novel mechanisms of action such as anti-angiogenesis or immuno-stimulatory properties. Defining an optimal metronomic schedule remains uneasy because of the variety of possible combinations between dosing, frequency and duration. Our group has developed innovative modeling tools to optimize metronomic schedules. Here, we have used this computational approach to test whether metronomics gemcitabine would make better than standard gemcitabine in mice bearing human neuroblastoma. In silico simulation suggested that shifting from standard 100 mg/kg/w over 4 consecutive weeks to the metronomic 1 mg/kg/d schedule for 28 consecutive days would achieve higher antitumoral efficacy while being well tolerated. To test this hypothesis, 100 000 human GI-ME-N neuroblastoma cells stably transfected with luciferase were subcutaneously grafted in 40 nude mice. Mice were next split in 3 groups: control, 100 mg/kg/w gemcitabine (STD-GEM) and 1 mg/kg/d gemcitabine (MetroGem-1). An additional satellite group was treated with 0.5 mg/kg/d (MetroGem-0.5). Metro-Gem was administrated using an osmotic pump implanted subcutaneously. Efficacy (i.e., comparison in tumor growth) was the main endpoint. Pharmacokinetics, tumor inflammation, and vascular density were the secondary endpoints. Gemcitabine assay showed that whereas Cmax up to 80 μg/ml were reached in mice treated with STD-GEM, steady-state concentrations of 0.1 μg/ml only were observed in animals undergoing MetroGem-1. Measuring cathepsin expression by fluorescence imaging suggested reduced inflammation in mice treated with the metronomic schedule. Similarly, fluorescence imaging showed smaller vascular density in mice treated with MetroGem-1 or -0.5 as compared with control or STD-GEM animals. To further check a possible anti-angiogenic effect, tumor perfusion rate was measuring next using luciferine, and fully confirmed that mice treated with Metro-Gem exhibited reduced blood flow as compared with other groups. Finally, bioluminescence monitoring of tumor growth showed that whereas STD-GEM was totally ineffective, both MetroGem-1 and MetroGem-0.5 achieved 60% reduction in tumor mass at the end of the treatment (p&lt;0.05, Anova). Much interestingly, tumor growth with metronomics was kept under control for up to 40 days after stopping treatment. Overall, this study shows how computational approaches can help to refine and to rationalize metronomic dosing. Here, higher efficacy and long-lasting stabilization was achieved with metronomics. Impact on tumor angiogenesis could explain, at least partly, this increase in efficacy in a chemo-resistant model.

Citation Format: Joseph Ciccolini, Eddy Pasquier, Aurelie Lombard, Sarah Giacometti, Christian Faivre, Raphaelle Fanciullino, Cindy Serdjebi, Dominique Barbolosi, Nicolas Andre. Computational-driven metronomics: application to gemcitabine in neuroblastoma-bearing mice. [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 4506. doi:10.1158/1538-7445.AM2015-4506