The inhibitory effect of docetaxel and p38 MAPK inhibitor on TZT-1027 (Soblidotin)-induced antivascular activity.

Background: TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim was to elucidate the mechanism of TZT-1027-induced antivascular activity by investigating the impact of various inhibitors.

Materials And Methods: The inhibitory effects on TZT-1027-induced antivascular activity were evaluated by a tumor perfusion study in mice bearing Colon26 tumors and a vascular permeability study on human umbilical vein endothelial cells monolayer.

Comparison of the antivascular and cytotoxic activities of TZT-1027 (Soblidotin) with those of other anticancer agents.

TZT-1027 (Soblidotin), a microtubule-depolymerizing agent exerts both a direct cytotoxic activity against cancer cells and an indirect antivascular activity against tumor vascular endothelial cells. We compared both activities of TZT-1027 with those of various anticancer agents having different mechanisms of action, including vinca alkaloids, a vascular targeting agent, a taxane and nonmicrotubule-binding agents. In the MTT assay, TZT-1027 most potently inhibited the growth of both murine colon C26 cancer cells and human umbilical vein endothelial cells, implying its potent antivascular activity against tumor vasculature in addition to its cytotoxic activity against cancer cells.

Antiangiogenic activity of TZT-1027 (soblidotin) on chick chorioallantoic membrane and human umbilical vein endothelial cells.

Background: TZT-1027 (Soblidotin), a microtubule-depolymerizing agent, has antivascular activity which disrupts newly formed tumor vasculature. In this study, it was investigated whether TZT-1027 has also antiangiogenic activity preventing neovascularization.

Materials And Methods: Antiangiogenic activities were evaluated in vivo in a chick embryo chorioallantoic membrane (CAM) assay and in vitro in a tube formation assay on human umbilical vein endothelial cells (HUVEC).

Tumor-specific antivascular effect of TZT-1027 (Soblidotin) elucidated by magnetic resonance imaging and confocal laser scanning microscopy.

TZT-1027 (soblidotin), an antimicrotubule agent, has previously been evaluated in terms of its antivascular effects. In this study, Evans blue perfusion, magnetic resonance imaging (MRI), and confocal laser scanning microscopy (CLSM) were utilized to further elucidate the antivascular effect of TZT-1027 in female nude mice and rats bearing human breast tumor MX-1, as well as in female Sprague-Dawley rats that developed breast tumors induced by dimethylbenz(a)anthracene (DMBA). Therapeutic doses of TZT-1027 caused nearly complete regression of implanted MX-1 tumors in nude mice and rats as well as DMBA-induced tumors in rats.

Antivascular effects of TZT-1027 (Soblidotin) on murine Colon26 adenocarcinoma.

We investigated the ability of TZT-1027 (Soblidotin), a novel antimicrotubule agent, to induce antivascular effects, because most vascular targeting agents that selectively disrupt tumor vasculature also inhibit tubulin polymerization. Treatment with 10(-7) g/mL TZT-1027 rapidly disrupted the microtubule cytoskeleton in human umbilical vascular endothelial cells (HUVEC), and significantly enhanced vascular permeability in HUVEC monolayers. In addition, single intravenous administration of 2 mg/kg TZT-1027 to mice bearing Colon26 tumors significantly reduced tumor perfusion and caused extravascular leakage of erythrocytes 1 h after administration.

Combination effect of TZT-1027 (Soblidotin) with other anticancer drugs.

Background: TZT-1027 (Soblidotin), an antimicrotubule drug, has shown potent antitumor efficacy in various antitumor models, and has entered into phase I clinical trials. To determine those anticancer drugs to be combined with TZT-1027 in clinical trials, the combination effects of TZT-1027 with other anticancer drugs were examined.

Materials And Methods: Two in vivo antitumor models, the murine P388 leukemia ascites tumor model and the human non-small cell lung cancer A549 solid tumor model, were used and cisplatin (CDDP), gemcitabine (GEM), irinotecan hydrochloride (CPT-11), fluorouracil (5-FU), paclitaxel (PTX) and docetaxel (DTX) were selected to be combined with TZT-1027.

Antitumor activity of TZT-1027 (Soblidotin) against vascular endothelial growth factor-secreting human lung cancer in vivo.

TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study.

Enhanced antitumor activities of TZT-1027 against TNF-alpha or IL-6 secreting Lewis lung carcinoma in vivo.

Purpose: TZT-1027, an antimicrotubule agent that inhibits the polymerization of tubulin, shows potent antitumor activity in various transplantable tumor models in vivo. The high antitumor activity of TZT-1027 prompted us to speculate that this compound may have a mode of action other than its antimicrotubule and antimitotic activities. To elucidate the interaction of antitumor cytokines with TZT-1027 in tumors in vivo, we examined the antitumor activity of this agent against various cytokine gene-transfected Lewis lung carcinoma (LLC) cells inoculated into C57BL/6 mice.