588 Topical application of gemcitabine chemotherapy generates microvesicle particles in a platelet-activating factor-receptor- and acid sphingomyelinase-dependent manner

Chemotherapy has remained the mainstay for treatment of multiple types cancers. In particular, topical use chemotherapy been used skin Though effective, limited due to adverse effects such as local and even systemic toxicities. Given our ongoing studies that exposure pro-oxidative stressors, including therapeutic agents induces generation extracellular vesicles known microvesicle particles (MVP) which are dependent on activation Platelet-activating factor-receptor (PAFR), a G-protein coupled receptor present various cell types, acid sphingomyelinase (ASMase), an enzyme required MVP biogenesis. Based upon this premise, we tested hypothesis whether application gemcitabine will induce in human skin. Our ex vivo using explants demonstrate results dose-dependent manner process blocked by PAFR antagonist ASMase inhibitor. To confirm mechanisms, employed PAFR-expressing deficient (Ptafr-/-) mouse models well (Smpd-1-/-). Similar findings explants, gemcitabine-induced release WT mice was blunted Ptafr-/- Smpd-1-/- mice. These possible mechanism can signal systemically, is PAFR-ASMase pathway. Future test abilities blocking effectiveness tolerability chemotherapy.