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Preclinical analysis of tasidotin HCl in Ewing's sarcoma, rhabdomyosarcoma, synovial sarcoma, and osteosarcoma

Preclinical analysis of tasidotin HCl in Ewing's sarcoma, rhabdomyosarcoma, synovial sarcoma, and osteosarcoma

Clinical Cancer Research 13(18 Pt 1): 5446-5454

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

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Accession: 055095139

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PMID: 17875774

DOI: 10.1158/1078-0432.ccr-06-2661

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