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Preclinical Analysis of Tasidotin HCl in Ewing's Sarcoma, Rhabdomyosarcoma, Synovial Sarcoma, and Osteosarcoma

Authors' Affiliations: ¹ Tufts University School of Medicine, Boston, Massachusetts and ² Department of Pediatric Hematology/Oncology, Albert Einstein College of Medicine, Bronx, New York

Requests for reprints: E. Anders Kolb, Department of Pediatric Hematology/Oncology, Albert Einstein College of Medicine, The Children's Hospital at Montefiore, 3415 Bainbridge Avenue, Bronx, NY 10467. Phone: 718-741-2342; Fax: 302-651-4918; E-mail: eakolb{at}montefiore.org.

Purpose: 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.

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

Results: The IC₅₀ in Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, and synovial sarcoma lines ranged from 0.002 µ to 0.32 µmol/L. In the SK-ES1 and RH30 cell lines, tasidotin induced a G₂-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 G₂-M block in treated cells ultimately resulting in apoptosis. Antitumor activity is confirmed in vivo in preclinical xenograft models of pediatric sarcomas.