Preclinical analysis of tasidotin HCl in Ewing's sarcoma, rhabdomyosarcoma, synovial sarcoma, and osteosarcoma.
OBJECTIVE
Dolastatins are a group of structurally unique peptides originally isolated from a sea hare, Dolabella auricularia, which seem to inhibit tubulin polymerization and mitosis. Tasidotin hydrochloride (tasidotin), a novel synthetic analogue of dolastatin 15, is evaluated in preclinical models of pediatric tumors.


METHODS
The cytotoxicity of tasidotin was evaluated in a panel of pediatric sarcoma cell lines in vitro and in vivo.


RESULTS
The IC(50) in Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, and synovial sarcoma lines ranged from 0.002 micro to 0.32 micromol/L. In the SK-ES1 and RH30 cell lines, tasidotin induced a G(2)-M arrest that persisted for 48 h after the drug was washed from the cells. In vitro, more than half the cells were in the early or late phase of apoptosis 48 h after treatment with tasidotin. In vivo, a significant increase in apoptotic nuclei was apparent in xenograft tumors harvested within 24 h after a 5-day course of tasidotin. In vivo response was determined in severe combined immunodeficient xenograft models of pediatric sarcomas implanted heterotopically. Significant antitumor activity was observed in all tumor lines tested. A complete response was observed in 2 synovial sarcoma lines, 1 osteosarcoma line, 1 rhabdomyosarcoma line, and 1 Ewing's sarcoma line. A partial response was observed in 1 rhabdomyosarcoma and 1 Ewing's sarcoma.


CONCLUSIONS
Tasidotin induces a G(2)-M block in treated cells ultimately resulting in apoptosis. Antitumor activity is confirmed in vivo in preclinical xenograft models of pediatric sarcomas.
Garg
Vaani
V
Tufts University School of Medicine, Boston, Massachusetts, USA.
Zhang
Wendong
W
Gidwani
Pooja
P
Kim
Mimi
M
Kolb
E Anders
EA
D000818:Animals; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000473:pathology; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000473:pathology; D013584:Sarcoma, Synovial / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D009842:Oligopeptides; C504233:tasidotin