title: Evaluation of toxicity and antitumor activity of cycloviolacin O2 in mice.
abstract: Cycloviolacin O2 is a small cyclic cysteine-rich protein belonging to the group of plant proteins called cyclotides. This cyclotide has been previously shown to exert cytotoxic activity against a variety of human tumor cell lines as well as primary cultures of human tumor cells in vitro. This study is the first evaluation of its tolerability and antitumor activity in vivo. Maximal-tolerated doses were estimated to 1.5 mg/kg for single intravenous (i.v.) dosing and 0.5 mg/kg for daily repeated dosing, respectively. Two different in vivo methods were used: the hollow fiber method with single dosing (i.v., 1.0 mg/kg) and traditional xenografts with repeated dosing over 2 weeks (i.v., 0.5 mg/kg daily, 5 days a week). The human tumor cell lines used displayed dose-dependent in vitro sensitivity (including growth in hollow fibers to confirm passage of cycloviolacin O2 through the polyvinylidene fluoride fibers), with IC5o values in the micromolar range. Despite this sensitivity in vitro, no significant antitumor effects were detected in vivo, neither with single dosing in the hollow fiber method nor with repeated dosing in xenografts. In summary, the results indicate that antitumor effects are minor or absent at tolerable (sublethal) doses, and cycloviolacin O2 has a very abrupt in vivo toxicity profile, with lethality after single injection at 2 mg/kg, but no signs of discomfort to the animals at 1.5 mg/kg. Repeated dosing of 1 mg/kg gave a local-inflammatory reaction at the site of injection after 2-3 days; lower doses were without complications.
authors.affiliation: Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Burman
authors.forename: Erika
authors.initials: E
authors.lastname: Svedlund
authors.forename: Jenny
authors.initials: J
authors.lastname: Felth
authors.forename: Saadia
authors.initials: S
authors.lastname: Hassan
authors.forename: Anders
authors.initials: A
authors.lastname: Herrmann
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Clark
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.forename: Lars
authors.initials: L
authors.lastname: Bohlin
authors.forename: Per
authors.initials: P
authors.lastname: Claeson
authors.forename: Ulf
authors.initials: U
authors.lastname: Göransson
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects*; D047169:Cyclotides / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010940:Plant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D047169:Cyclotides; D010940:Plant Proteins; C473355:cycloviolacin O2