TZT‐1027, an Antimicrotubule Agent, Attacks Tumor Vasculature and Induces Tumor Cell Death

Abstract

TZT-1027, a dolastatin 10 derivative, is an antimicrotubule agent with potent antitumor activity both in vitro and in vivo. In this study, we performed biochemical and histopathological examinations, and evaluated TZT-1027-induced tumoral vascular collapse and tumor cell death in an advanced tumor model, murine colon 26 adenocarcinoma. In addition, we studied the effects of TZT-1027 on cultured human umbilical vein endothelial cells (HUVEC). Tolerable doses of TZT-1027 induced tumor-selective hemorrhage within 1 h. This hemorrhage occurred mainly in the peripheral area of the tumor mass. Measurements of tumoral hemoglobin content and dye permeation revealed that the hemorrhage occurred firstly and tumor blood flow stopped secondarily. The vascular damage was followed by continuous induction of apoptosis of the tumor cells, tumor tissue necrosis, and tumor regression. In cultured HUVEC, TZT-1027 induced marked cell contraction with membrane blebbing in 30 min. These cell changes were completely inhibited by K252a, a broad-spectrum inhibitor of protein kinases. These effects of TZT-1027 on both tumor vasculature and HUVEC were greater than those of vincristine. In conclusion, TZT-1027 quickly attacked the well-developed vascular system of advanced tumors by a putative protein kinase-dependent mechanism, and then blocked tumor blood flow. Therefore, TZT-1027 has both a conventional antitumor activity and a unique anti-tumoral vascular activity, making it a potentially powerful tool for clinical cancer therapy.

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

“…TZT-1027 is a novel antitumour agent that inhibits microtubule polymerisation and exhibits potent antitumour activity in preclinical models (Miyazaki et al, 1995;Kobayashi et al, 1997;Natsume et al, 2000Natsume et al, , 2003Natsume et al, , 2006Otani et al, 2000;Watanabe et al, 2000Watanabe et al, , 2006a. We investigated the effect of TZT-1027 on cell cycle progression with the use of tsFT210 cells, which can be synchronised in G 2 phase by incubation at 39.41C and consequent inactivation of Cdc2 (Osada et al, 1997;Tamura et al, 1999).…”

“…Several studies have recently shown that treatment with VTAs enhances the therapeutic effect of radiotherapy (Li et al, 1998;Rojiani, 2002, 2005;Horsman and Murata, 2003;Masunaga et al, 2004), consistent with the idea that the components of such combination therapy act in a complementary manner, with VTAs attacking the poorly oxygenated cell population in the central region of tumours and radiation killing the well-oxygenated proliferating cells at the tumour periphery (Li et al, 1998;Siemann and Rojiani, 2002;Wachsberger et al, 2003). TZT-1027 was previously shown to increase vascular permeability and to induce a decrease in tumour blood flow followed by a marked increase in tissue necrosis in the central region of tumour xenografts (Otani et al, 2000;Watanabe et al, 2006b). We have now shown that TZT-1027 treatment resulted in congestion and occlusion of tumour blood vessels followed by extensive necrosis of the tumour core, with only a thin rim of viable tumour cells remaining, in the H460 tumour model, suggesting that TZT-1027 acts as a VTA.…”

“…In vivo, TZT-1027 also manifests a broad spectrum of activity against various murine tumours as well as human tumour xenografts, without inducing a pronounced reduction in body weight (Kobayashi et al, 1997;Watanabe et al, 2000Watanabe et al, , 2006aNatsume et al, 2003Natsume et al, , 2006. Furthermore, the drug exhibited a potent antivascular effect on existing vasculature in an advancedstage tumour model (Otani et al, 2000). TZT-1027 is currently undergoing clinical evaluation, with a reduction in tumour size and disease stabilisation having been observed in a subset of patients (Schoffski et al, 2004;de Jonge et al, 2005;Greystoke et al, 2006;Tamura et al, 2007).…”

Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

“…7 Superior antivascular activity resulting in the collapse of the tumor vasculature was demonstrated, compared with the activities of taxanes and Vinca alkaloids. [8][9][10] The first clinical phase I study of TZT-1027 was initiated in 1994, and another four studies have since been completed; a phase II study is currently ongoing. [11][12][13] The major toxicity was hematological, in the form of neutropenia and leukopenia.…”

Sensitization of Tumor-Associated Endothelial Cell Apoptosis by the Novel Vascular-Targeting Agent ZD6126 in Combination with Cisplatin

“…Vascular-targeting agents exploit the distinctive features of the tumor vasculature to irreversibly arrest blood flow in tumors (12). The resulting ischemia leads to a rapid cascade of secondary tumor cell death and the destruction of central areas of the tumor, which are normally most resistant to conventional therapies (13)(14)(15). ZD6126 is a novel vascular-targeting agent that is rapidly converted by serum phosphatases to ZD6126 phenol (N-acetylcolchinol), which disrupts the tubulin cytoskeleton of endothelial cells, resulting in conformational changes in immature, but not mature, endothe-lial cells (16).…”