Enhancement of radiation therapy by the novel vascular targeting agent ZD6126

Siemann, Dietmar W.; Rojiani, Amyn M.

doi:10.1016/s0360-3016(02)02742-6

Cited by 130 publications

(92 citation statements)

References 20 publications

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“…A recent study (Wachsberger et al, 2005), however, drew more contrasting conclusions with data suggesting that the optimal therapeutic benefit of ZD6126 plus RT (U87 glioblastoma xenograft) is schedule-dependent with combinations of ZD6126 before each dose of RT being less effective than RT alone. The importance of the scheduling involving ZD6126 and RT was also reported by a previous study (Siemann and Rojiani, 2002) that showed that this association increased tumour cell killing of KHT mouse sarcoma when given 24 h before RT or 1 h or more following RT, but was not found to be as effective if given 1 h before RT. In the present study, the sequence of association between RT and ZD6126 was taken into consideration as the drug was given 2 h after RT.…”

Section: Discussionsupporting

confidence: 59%

“…Previous experimental studies showed potential beneficial antitumour effects when combining ZD6126 with RT (Siemann and Rojiani, 2002;Raben et al, 2004). A recent study (Wachsberger et al, 2005), however, drew more contrasting conclusions with data suggesting that the optimal therapeutic benefit of ZD6126 plus RT (U87 glioblastoma xenograft) is schedule-dependent with combinations of ZD6126 before each dose of RT being less effective than RT alone.…”

Section: Discussionmentioning

confidence: 99%

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Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126

et al. 2006

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Current experimental and clinical knowledge supports the optimisation of endothelial cell targeting using a strategy combining anti-EGFR drugs with antivascular agents. The purpose of the present study was to examine the effects of the association of ZD6126, an antivascular microtubule-destabilising agent, with gefitinib and irradiation on the growth of six head and neck human cancer cell lines xenografted in nude mice and to study predictive and molecular factors responsible for antitumour effects. CAL33-and Hep-2-grafted cell lines were the most sensitive to ZD6126 treatment, with VEGF levels significantly higher (P ¼ 0.0336) in these tumour xenografts compared to Detroit 562-and CAL27-grafted cell lines with relatively low VEGF levels that were not sensitive to ZD6126. In contrast, neither IL8 levels nor EGFR expression was linked to the antitumour effects of ZD6126. ZD6126 in combination with gefitinib resulted in a synergistic cytotoxic interaction with greater antitumour effects than gefitinib alone. The synergistic interaction between ZD6126 and gefitinib was corroborated by a significant decrease in CD31 labelling. The present study may serve for future innovative clinical applications, as it suggests that VEGF tumour levels are possible predictors for ZD6126 antitumour efficacy. It also supports the notion of antitumour supra-additivity when combining gefitinib and ZD6126, and identifies neoangiogenesis as the main determinant of this synergistic combination.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126

et al. 2006

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“…Given that these residual tumour cells are likely well oxygenated (Wachsberger et al, 2003), they are an ideal target for radiation therapy. 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).…”

Section: Discussionmentioning

confidence: 73%

“…Treatment with VTAs such as ZD6126 and combretastatin A-4-P typically results in the destruction of large areas of a tumour, with surviving cells remaining only at the tumour periphery (Dark et al, 1997;Blakey et al, 2002). These peripheral viable tumour cells presumably derive their nutritional support from nearby normal blood vessels that are not responsive to VTA treatment (Li et al, 1998;Siemann and Rojiani, 2002). Such support together with a rapid upregulation of angiogenic factors such as vascular endothelial growth factor may directly facilitate the growth and expansion of the remaining tumour cells (Wachsberger et al, 2003;Thorpe, 2004).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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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.

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“…Combined treatment of ZD6126 with the cytotoxic agents paclitaxel or cisplatin or irradiation has demonstrated additional growth delay in tumor xenografts. However, the mechanism of action by which these combined therapies cause an enhanced antitumor effect has yet to be established (16,18,19).…”

Section: Introductionmentioning

confidence: 99%

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

Goto

Yano²,

Matsumori³

et al. 2004

Clinical Cancer Research

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Purpose: ZD6126 is a novel vascular-targeting agent that selectively disrupts the tubulin cytoskeleton of endothelial cells. In the immature vessels characteristic of tumor vasculature, this leads to endothelial cell contraction, blood vessel congestion, and, consequently, tumor cell death. ZD6126 has been shown to delay tumor growth in a range of xenograft models. The antitumor effect of ZD6126 can be increased in combination with cisplatin or radiation therapy, although the precise mechanism of this enhancement has not been demonstrated. ZD6126 treatment has also been shown to inhibit lung metastasis, and the present study has explored the potential to increase the antimetastatic effect of ZD6126 by combining with cisplatin, and the underlining mechanism has been investigated.Experimental Design: Human lung adenocarcinoma PC14PE6 cells were injected into the tail vein of nude mice. Five weeks after injection animals were treated with ZD6126 (200 mg/kg i.p.), cisplatin (6 mg/kg i.v.), or a combination of the two agents. The animals were sacrificed 24 hours later, and the extent of lung metastases and the presence of apoptotic cells were assessed.Results: Histologic analysis revealed that the ZD6126/ cisplatin combination resulted in a 2 to 4-fold increase in the total number of tumor-associated apoptotic cells compared with either treatment alone. ZD6126 alone induced apoptosis of tumor-associated endothelial cells in tumors, and the extent of apoptosis was increased 2-fold in combination with cisplatin. The lung weight was significantly reduced, and the number of metastatic nodules significantly was lower in the combined treatment group than in the control group.Conclusions: These data suggest that the antimetastatic effect of the vascular-targeting agent ZD6126 can be increased by use in combination with cisplatin, which increases the incidence of endothelial cell apoptosis.

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Enhancement of radiation therapy by the novel vascular targeting agent ZD6126

Cited by 130 publications

References 20 publications

Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126

Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126

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

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

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