Vascular targeting effect of combretastatin A‐4 phosphate dominates the inherent angiogenesis inhibitory activity

Ahmed, Bisan; Eijk, Loes I. van; Steege, Jessica C.A. Bouma-ter; Schaft, Daisy W. J. van der; Esch, Anita M. van; Joosten-Achjanie, Susan R.; Lambin, Philippe; Landuyt, Willy; Griffioen, Arjan W.

doi:10.1002/ijc.11010

Cited by 45 publications

(36 citation statements)

References 23 publications

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“…These drug exposures are relevant for in vivo studies, where mouse plasma levels of the active CA4P metabolite CA4 were reported in the region of 0.5-2.8 lM, within 90 min of administering 100 mg/kg CA4P. 29,43 Our data confirmed several previous studies [24][25][26][27][28] showing that the mode of direct tumor cell death was anti-proliferative, leading to apoptosis, and that resistance to CA4P was indeed maintained in vivo, since markers of apoptosis, namely DNA fragmentation and cleaved caspase-3 expression were significantly greater in SW1222…”

Section: Discussionsupporting

confidence: 90%

“…It should be noted that endothelial cell death may contribute to the net overall vessel disruption observed in our tumor models 24,36,47 but is not a prerequisite and cannot explain the early collapse in blood flow that manifests within minutes of drug administration. Therefore, we did not explicitly investigate endothelial cell death either by apoptosis or necrosis in these studies but rather the morphological changes in endothelial cells that potentially compromise blood flow.…”

Section: Discussionmentioning

confidence: 86%

“…23 In vitro, CA4P inhibits tumor cell proliferation and causes mitotic arrest by interfering with mitotic spindles and chromosome attachment. [24][25][26][27][28] These effects are dependent on both level and duration of drug exposure. Mitotic-arrested cells subsequently undergo mitotic catastrophe and apoptosis through caspase-dependent and -independent mechanisms.…”

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confidence: 99%

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Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Lunt

Akerman

Hill

et al. 2011

Intl Journal of Cancer

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Vascular‐targeted therapeutics are increasingly used in the clinic. However, less is known about the direct response of tumor cells to these agents. We have developed a combretastatin‐A‐4‐phosphate (CA4P) resistant variant of SW1222 human colorectal carcinoma cells to examine the relative importance of vascular versus tumor cell targeting in the ultimate treatment response. SW1222Res cells were generated through exposure of wild‐type cells (SW1222WT) to increasing CA4P concentrations in vitro. Increased resistance was confirmed through analyses of cell viability, apoptosis and multidrug‐resistance (MDR) protein expression. In vivo, comparative studies examined tumor cell necrosis, apoptosis, vessel morphology and functional vascular end‐points following treatment with CA4P (single 100 mg/kg dose). Tumor response to repeated CA4P dosing (50 mg/kg/day, 5 days/week for 2 weeks) was examined through growth measurement, and ultimate tumor cell survival was studied by ex vivo clonogenic assay. In vitro, SW1222Res cells showed reduced CA4P sensitivity, enhanced MDR protein expression and a reduced apoptotic index. In vivo, CA4P induced significantly lower apoptotic cell death in SW1222Res versus SW1222WT tumors indicating maintenance of resistance characteristics. However, CA4P‐induced tumor necrosis was equivalent in both lines. Similarly, rapid CA4P‐mediated vessel disruption and blood flow shut‐down were observed in both lines. Cell surviving fraction was comparable in the two tumor types following single dose CA4P and SW1222Res tumors were at least as sensitive as SW1222WT tumors to repeated dosing. Despite tumor cell resistance to CA4P, SW1222Res response in vivo was not impaired, strongly supporting the view that vascular damage dominates the therapeutic response to this agent.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

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Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Lunt

Akerman

Hill

et al. 2011

Intl Journal of Cancer

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“…Enhanced efficacy with the AVE8062 and docetaxel combination was observed in each of our models, including the taxane-resistant HeyA8-MDR cell line. The pronounced effect is felt to be primarily due to apoptosis after mitotic arrest (41,42).…”

Section: Discussionmentioning

confidence: 99%

Antitumor and Antivascular Effects of AVE8062 in Ovarian Carcinoma

Kim

Ravoori²,

Landen

et al. 2007

Cancer Research

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The purpose of this study was to examine the therapeutic efficacy and underlying mechanisms of action of a vasculardisrupting agent, AVE8062, and to determine its effects on tumor metabolic activity. The in vitro and in vivo effects of AVE8062 alone and in combination with docetaxel were tested in chemotherapy-sensitive and chemotherapy-resistant ovarian cancer models. Tumors were analyzed for necrosis, microvessel density, endothelial cell apoptosis, and proliferation following treatment. The effect of AVE8062 on tumor regression and metabolic activity was examined by magnetic resonance (MR) or by [18 F]fluorodeoxyglucose ([ 18 F]FDG) uptake by positron emission tomography (PET) with MR imaging, respectively. AVE8062 monotherapy was effective in inhibiting tumor growth in all models (range 43-51% versus control; P < 0.05). Combination therapy was even more effective in inhibiting tumor growth (range 76-90% compared with controls, P < 0.01). AVE8062 in combination with chemotherapy significantly prolonged survival in HeyA8-injected mice (P < 0.001) compared with other groups. AVE8062-based therapy resulted in rapid development of central tumor necrosis, decreased microvessel density, decreased proliferation, and induction of apoptosis of tumor-associated endothelial cells. MR imaging showed regression of established HeyA8 ovarian tumors and [18 F]FDG PET with MR showed rapid decrease in metabolic activity after AVE8062 therapy. Combination of AVE8062 plus docetaxel results in potent inhibition of ovarian cancer growth. These results suggest that AVE8062 may be useful as a clinical therapeutic approach for ovarian cancer patients and that functional [18 F]FDG PET imaging may predict clinical response before an anatomic reduction in tumor size. [Cancer Res 2007;67(19):9337-45]

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“…CA4 is also cytotoxic to a variety of human cancer cell lines. In some studies, activity was observed at concentrations higher than those toxic to endothelial cells (3 orders of magnitude), although in others, significant toxicity was also observed at low concentrations (7,8).…”

Section: Introductionmentioning

confidence: 99%

Phase I Trial of Combretastatin A-4 Phosphate with Carboplatin

Bilenker

Flaherty

Rosen

et al. 2005

Clinical Cancer Research

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Purpose: Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin.Experimental Design: Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion.Results: Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m 2 together with carboplatin at area under the concentrationtime curve (AUC) values of 4 and 5 mg min/mL. The doselimiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m 2 and carboplatin AUC of 4 mg min/mL, although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles.Conclusion: This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia.Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.

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Vascular targeting effect of combretastatin A‐4 phosphate dominates the inherent angiogenesis inhibitory activity

Cited by 45 publications

References 23 publications

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Antitumor and Antivascular Effects of AVE8062 in Ovarian Carcinoma

Phase I Trial of Combretastatin A-4 Phosphate with Carboplatin

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