The novel microtubule-interfering agent TZT-1027 enhances the anticancer effect of radiation in vitro and in vivo

Y. Akashi, I. Okamoto, M. Suzuki, K. Tamura, T. Iwasa, S. Hisada, T. Satoh, K. Nakagawa, K. Ono, M. Fukuoka

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

TZT-1027 is a novel anticancer agent that inhibits microtubule polymerisation and manifests potent antitumour activity in preclinical models. We have examined the effect of TZT-1027 on cell cycle progression as well as the anticancer activity of this drug both in vitro and in vivo. With the use of tsFT210 cells, which express a temperature-sensitive mutant of Cdc2, we found that TZT-1027 arrests cell cycle progression in mitosis, the phase of the cell cycle most sensitive to radiation. A clonogenic assay indeed revealed that TZT-1027 increased the sensitivity of H460 cells to γ-radiation, with a dose enhancement factor of 1.2. Furthermore, TZT-1027 increased the radiosensitivity of H460 and A549 cells in nude mice, as revealed by a marked delay in tumour growth and an enhancement factor of 3.0 and 2.2, respectively. TZT-1027 also potentiated the induction of apoptosis in H460 cells by radiation both in vitro and in vivo. Histological evaluation of H460 tumours revealed that TZT-1027 induced morphological damage to the vascular endothelium followed by extensive central tumour necrosis. Our results thus suggest that TZT-1027 enhances the antitumour effect of ionising radiation, and that this action is attributable in part to potentiation of apoptosis induction and to an antivascular effect. Combined treatment with TZT-1027 and radiation therefore warrants investigation in clinical trials as a potential anticancer strategy.

Original languageEnglish
Pages (from-to)1532-1539
Number of pages8
JournalBritish journal of cancer
Volume96
Issue number10
DOIs
Publication statusPublished - May 21 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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