Abstract 2616: Comparison of the cytotoxicity and increase of reactive oxygen species and dihydroceramides of fenretinide to its major metabolites (4-oxo- and 4-methoxyphenyl fenretinide) in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines

Introduction: Early-phase clinical trials of fenretinide (4-HPR, a synthetic retinoid) have demonstrated durable complete responses in T-cell lymphoma (TCL), neuroblastoma (NB), and signals of activity in ovarian cancer (OV). Cytotoxic mechanisms of 4-HPR include increase of reactive oxygen species (ROS) and dihydroceramides (DHCs). Major 4-HPR metabolites are N-(4-methoxyphenyl)retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (oxo-HPR). MPR is more abundant in human plasma; oxo-HPR is present in lower concentrations. We assessed the relative cytotoxicity and increase of ROS and DHCs at equimolar concentrations of 4-HPR, MPR, and oxo-HPR in TCL, NB, and OV cell lines.Methods: A panel of twelve TCL, NB, and OV cell lines was studied in room air (20% O2) and physiologic (5% O2) cultured conditions. Cytotoxicity (0-10 μM) was assessed by DIMSCAN fluorescence cytotoxicity assay. ROS was measured via DCFDA with flow cytometry and sphingolipids (including DHCs, ceramides, sphingoid bases, sphingomyelins, and glycosylated ceramides) by quantitative tandem mass spectrometry.Results: 4-HPR (10 μM) demonstrated >3 logs of cell kill in 6 of 12 cell lines. Oxo-HPR demonstrated comparable cytotoxicity to that of 4-HPR in all cell lines. MPR lacked cytotoxicity and when combined with 4-HPR, did not increase cytotoxicity or induce antagonism. There was no observed difference in cytotoxicity between 4-HPR and oxo-HPR in either oxygen condition. Both 4-HPR and oxo-HPR significantly ...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Experimental and Molecular Therapeutics Source Type: research