Introduction: Pancreatic adenocarcinoma a highly lethal malignancy (5 yr survival ∼ 5%) is poorly responsive to all chemotherapy, in part related to presence of chemo resistant pathways: prosurvival (AKT/PI3K/mTOR and mutant KRAS. We have previously demonstrated reversal of these resistant pathways by C6 Ceramide and now are pursuing optimum intracellular delivery using selected liposomal preparations ofC6Ceramide.
Methods: C6 Ceramide housed in 4 different liposomal vesicle formulations were tested against pancreatic cell lines L3.6, PANC1 and MIA, using combination therapy with chemotherapy agents Gemcitabine, Paclitaxel and Cetuximab with determination of the MTT anti tumor response. Liposomal preparations included : (#1)18:1 PC(1,2-dioleoyl-sn-glycero-3-phosphocholine; (#3),18:0 PC (1,2-distearoyl-sn-glycero-3-phosphocholine;(#5) DPGG (1,2-dipalmitoyl-sn-glycero-3-galloyl); and (#7) 18:0 PEG2 PE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethylene glycol)-2000. (#1)18:1 PC- has low transition temp and is fluid at bodyT*(# 3). 18:0 PC- has high transition Temperature(T*) is rigid at body T*;#5 DPGG- avoids RE System (is fluid at bodyT*, induces long circulations)#7. 18:0 PEG 2 PE - industry standard (also avoids RE system) Biologic effects of the 4 lipid formulations with/without C6 Ceramide were initially assessed invitro.
Results: Dose response MTT assay demonstrated no distinctive response of C6 combined liposomes vesicles # 1 & 3, but confirmed high activity in preparations #5 & 7.
Conclusion: Liposomal C6 preparations show high activity in potentiating chemo toxicity by Gemcitabine, Paclitaxel and Cetuximab against Pancreatic Cancer. Confirmatory in vivo studies are in process.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B104.
Citation Format: Harold J. Wanebo, Cong Cao, Shaun Lu, David Shrayer, Yinsheng Wan, Wayne Bowen, Wayne Bowen. Liposomal C6 Ceramide appears to potentiate chemotoxicity of paclitaxel, gemcitabine and cetuximab against aggressive pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B104.