The novel microtubule-interfering agent TZT-1027 enhances the anticancer effect of radiation in vitro and in vivo
| Autor: | Minoru Suzuki, Kenji Tamura, Tsutomu Iwasa, S Hisada, Kazuhiko Nakagawa, Masahiro Fukuoka, Isamu Okamoto, Yusaku Akashi, Taroh Satoh, Koji Ono |
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| Rok vydání: | 2007 |
| Předmět: |
Radiation-Sensitizing Agents
Cancer Research Programmed cell death Pathology medicine.medical_specialty Lung Neoplasms Mice Nude Antineoplastic Agents Mammary Neoplasms Animal antivascular effect Biology Microtubules Models Biological radiosensitisation Mice In vivo Tumor Cells Cultured medicine Animals Humans Radiosensitivity Clonogenic assay TZT-1027 A549 cell Cyclin-dependent kinase 1 Carcinoma Cell Cycle apoptosis mitotic arrest Cell cycle Combined Modality Therapy Xenograft Model Antitumor Assays Radiation effect Oncology Cancer research Female Translational Therapeutics Oligopeptides microtubule |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | 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 gamma-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. |
| Databáze: | OpenAIRE |
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