Evaluation of toxicity and antitumor activity of cycloviolacin O2 in mice.
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.
Burman
Robert
R
Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Svedlund
Erika
E
Felth
Jenny
J
Hassan
Saadia
S
Herrmann
Anders
A
Clark
Richard J
RJ
Craik
David J
DJ
Bohlin
Lars
L
Claeson
Per
P
Göransson
Ulf
U
Gullbo
Joachim
J
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
D000970:Antineoplastic Agents; D047169:Cyclotides; D010940:Plant Proteins; C473355:cycloviolacin O2