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

Vaani Garg, Wendong Zhang, Pooja Gidwani, Mimi Kim, E. Anders Kolb

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)5446-5454
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2007

Fingerprint

Synovial Sarcoma
Ewing's Sarcoma
Rhabdomyosarcoma
Osteosarcoma
Heterografts
Sarcoma
Pediatrics
Apoptosis
Hares
Cell Line
Neoplasms
Tubulin
tasidotin
Mitosis
Oceans and Seas
Polymerization
Inhibitory Concentration 50
Research Design
Peptides
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Preclinical analysis of tasidotin HCl in Ewing's sarcoma, rhabdomyosarcoma, synovial sarcoma, and osteosarcoma. / Garg, Vaani; Zhang, Wendong; Gidwani, Pooja; Kim, Mimi; Kolb, E. Anders.

In: Clinical Cancer Research, Vol. 13, No. 18, 15.09.2007, p. 5446-5454.

Research output: Contribution to journalArticle

Garg, Vaani ; Zhang, Wendong ; Gidwani, Pooja ; Kim, Mimi ; Kolb, E. Anders. / Preclinical analysis of tasidotin HCl in Ewing's sarcoma, rhabdomyosarcoma, synovial sarcoma, and osteosarcoma. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 18. pp. 5446-5454.
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AU - Kolb, E. Anders

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