Smith, AdamBlois, JosephYuan, HushanAikawa, ElenaEllson, ChristianFigueiredo, Jose-LuizWeissleder, RalphKohler, RainerYaffe, Michael B.Cantley, Lewis C.Josephson, Lee2019-09-212009Smith, A., J. Blois, H. Yuan, E. Aikawa, C. Ellson, J.-L. Figueiredo, R. Weissleder, et al. 2009. “The Antiproliferative Cytostatic Effects of a Self-Activating Viridin Prodrug.” Molecular Cancer Therapeutics 8 (6): 1666–75. https://doi.org/10.1158/1535-7163.mct-08-1012.1535-71631538-8514http://nrs.harvard.edu/urn-3:HUL.InstRepos:41384271Although viridins like wortmannin (Wm) have long been examined as anticancer agents, their ability to self-activate has only recently been recognized. Here, we describe the cytostatic effects of a self-activating viridin (SAV), which is an inactive, polymeric prodrug. SAV self-activates to generate a bioactive, fluorescent viridin NBD-Wm with a half-time of 9.2 hours. With cultured A549 cells, 10 mu mol/L SAV caused growth arrest without inducing apoptosis or cell death, a cytostatic action markedly different from other chemotherapeutic agents (vinblastine, camptothecin, and paclitaxel). In vivo, a SAV dosing of 1 mg/kg once in 48 hours (i.p.) resulted in growth arrest of an A549 tumor xenograft, with growth resuming when dosing ceased. With a peak serum concentration of SAV of 2.36 mu mol/L (at 2 hours post i.p. injection), the concentration of bioactive NBD-Wm was 41 nmol/L based on the partial inhibition of neutrophil respiratory burst. Therefore, SAV was present as an inactive prodrug in serum (peak = 2.36 mu mol/L), which generated low concentrations of active viridin (41 nmol/L). SAV is a prodrug, the slow release and cytostatic activities of which suggest that it might be useful as a component of metronomic-based chemotherapeutic strategies. [Mol Cancer Ther 2009;8(6):1666-75]en-USJournal Article2019-09-2110.1158/1535-7163.MCT-08-1012