title: The antiproliferative cytostatic effects of a self-activating viridin prodrug.
abstract: Although 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 micromol/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 micromol/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 micromol/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.
authors.affiliation: Massachusetts General Hospital, Center for Molecular Imaging Research, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Smith
authors.forename: Joseph
authors.initials: J
authors.lastname: Blois
authors.forename: Hushan
authors.initials: H
authors.lastname: Yuan
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
authors.forename: Christian
authors.initials: C
authors.lastname: Ellson
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Rainer
authors.initials: R
authors.lastname: Kohler
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Lee
authors.initials: L
authors.lastname: Josephson
mesh_terms: D000736:Androstenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001430:Bacteriocins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001808:Blood Vessels / Q000378:metabolism; D002232:Carbocyanines / Q000737:chemistry; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D054697:Cytostatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004423:Ear / Q000098:blood supply; D005434:Flow Cytometry; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D010537:Peritoneum / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000736:Androstenes; D001430:Bacteriocins; D002232:Carbocyanines; D054697:Cytostatic Agents; D011355:Prodrugs; C085321:cyanine dye 5; C012097:viridin