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

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 g-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.

PTEN/pAkt/p53 signaling pathway correlates with the radioresponse of non-small cell lung cancer

“…The combination of modalities for cancer treatment offers improvements in the survival of patients compared with individual therapeutic approaches (32). These therapeutic benefits have been achieved with combinations of chemotherapy and radiotherapy in a variety of cancers (32).…”

“…These therapeutic benefits have been achieved with combinations of chemotherapy and radiotherapy in a variety of cancers (32). The cytotoxicity of most chemotherapeutic agents as well as that of radiation is highly dependent on the phase of the cell cycle; for example, the ability of anti-microtubule agents to block cell cycle progression in the G 2 /M phase is the biologic basis for combination of these agents with radiation (32,33).…”

“…These therapeutic benefits have been achieved with combinations of chemotherapy and radiotherapy in a variety of cancers (32). The cytotoxicity of most chemotherapeutic agents as well as that of radiation is highly dependent on the phase of the cell cycle; for example, the ability of anti-microtubule agents to block cell cycle progression in the G 2 /M phase is the biologic basis for combination of these agents with radiation (32,33). The G 2 /M phase is the one most sensitive to ionizing radiation; thus, many research efforts have focused on the combination of radiotherapy methods that arrest cells in the G 2 /M phase by using specific chemicals and then irradiating the cells to increase the radiosensitivity potential (11)(12)(13)34,35).…”

Filamentous tropical marine cyanobacteria: a rich source of natural products for anticancer drug discovery

“…Such dual activities make TZT-1027 a useful agent for the treatment of solid tumors (Watanabe et al 2007a). Furthermore, this synthetic analogue was found to enhance the antitumor effect of radiation in H460 cells in in vitro studies as well as in in vivo system using nude mice (Akashi et al 2007).…”

In Vivo Antitumor Activity of Meretrix meretrix Glycopeptide

“…Significant tumor inhibitation effects of the glycoproteins extracted from Aplysia, Patinopecten yessoensis and Meretrix meretrix had been reported previously [3][4][5] , And the mechanism of action is complex and diverse, and the immune mechanism is particularly prominent in [6][7][8][9][10][11][12], so it is important to strengthen the anti tumor immunity in tumor prevention and treatment. In this study, we we explored the in vivo antitumor activity and stability of MGP 0501 , one kind of glycopeptides which we firstly extracted from Meretrix meretrix in our laboratory.…”