MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors

Jerry Jaboin, Jason Wild, Habib Hamidi, Chand Khanna, Chong Jai Kim, Robert Robey, Susan E. Bates, Carol J. Thiele

Research output: Contribution to journalArticlepeer-review

191 Scopus citations

Abstract

The antitumor efficacy of the synthetic benzamide derivative MS-27-275 (MS-275), an inhibitor of histone deacetylation [T. Suzuki et al., J. Med. Chem., 42: 3001-3003, 1999], was evaluated in a series of pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma (EWS), retinoblastoma, medulloblastoma, undifferentiated sarcoma (US), osteosarcoma, and malignant rhabdoid tumors. Treatment with MS-275 results in an increase in acetylation of histones within 4 h of drug exposure. The cell lines were treated with various concentrations of MS-275 for 3 days and incubated with [3H]thymidine for 20 h before cell harvest. MS-275 inhibited [3H]thymidine uptake in a dose-dependent manner in all tumor cell lines examined. The IC50 ranged from 50 nm in the D283 medulloblastoma cell line to 1.3 μM in the US. A common feature of MS-275 treatment of pediatric tumor cell lines was induction of p21mRNA. However, the effects on cell cycle were diverse because in some cases MS-275 induced an increase in G1 or G2, whereas in others, there was an induction of apoptosis. In EWS, the EWS/fli chimeric transcription factor created by the t(11;22) suppresses transforming growth factor (TGF) βRII transcription, however, MS-275 was able to induce an increase in TGF-βRII mRNA and restore TGF-β signaling. Using xenograft orthotopic models of US, EWS, and neuroblastoma, we find that the growth of established tumors is inhibited in mice treated with MS-275.

Original languageEnglish (US)
Pages (from-to)6108-6115
Number of pages8
JournalCancer Research
Volume62
Issue number21
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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