Anti-vascular effects of vinflunine in the MAC 15A transplantable adenocarcinoma model

Holwell, Sarah; Hill, Bridget T.; Bibby, Michael C.

doi:10.1054/bjoc.2000.1587

Cited by 54 publications

(24 citation statements)

References 20 publications

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“…On the other hand, vinflunine did not significantly affect transition frequencies as opposed to paclitaxel. We also showed that, in addition to its antivascular effect at cytotoxic concentrations (22), vinflunine, at low concentrations, exhibits an antiangiogenic effect through the inhibition of both migration and morphogenesis of HMEC-1. Altogether, our results confirm that the increase in microtubule dynamics is involved in the antiangiogenic activity of MTDs and highlight the crucial role of interphase microtubule functions in angiogenesis.…”

Section: Introductionmentioning

confidence: 62%

Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells

et al. 2006

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Angiogenesis is a key event in tumor progression and metastasis. This complex process, which constitutes a potent target for cancer therapy, is inhibited by very low concentrations of microtubule-targeting drugs (MTD). However, the intimate mechanisms of the antiangiogenic activity of MTDs remain unclear. Recently, we have shown that low antiangiogenic and noncytotoxic concentrations of paclitaxel induced an unexpected increase in microtubule dynamics in endothelial cells. In this study, we showed that vinflunine, the newest Vinca alkaloid, increased microtubule dynamic instability in human endothelial cells after 4-hour incubation at low concentrations (29% and 54% at 0.1 and 2 nmol/L). The growth and shortening rates were increased, and the percentage of time spent in pause and the mean duration of pauses were decreased, as previously observed with paclitaxel. As opposed to paclitaxel, the transition frequencies were not significantly disturbed by vinflunine. Moreover, low concentrations of vinflunine did not affect mitotic index and anaphase/metaphase ratio. Interestingly, these low vinflunine concentrations that increased microtubule dynamics exhibited an antiangiogenic effect through the inhibition of both morphogenesis and random motility. Capillary tube formation on Matrigel was decreased up to 44%. The cell speed and the random motility coefficient were decreased (13% and 19% and 13% and 33% at 0.1 and 2 nmol/L, respectively) and the persistent time was statistically increased. Altogether, our results confirm that the increase in microtubule dynamics is involved in MTD antiangiogenic activity and highlight the crucial role of interphase microtubule dynamics in angiogenesis. (Cancer Res 2006; 66(6): 3256-63)

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Section: Introductionmentioning

confidence: 62%

Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells

et al. 2006

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“…Little is known about the potency of the different family members of the Vinca alkaloids in inhibiting angiogenesis. It has been reported that vincristine, vinorelbine, and vinflunine are all able to shut down tumor vasculature in in vivo models (28). The antiangiogenic effects of low vinblastine concentrations are well established in a variety of in vitro and in vivo experiments (10,11).…”

Section: Discussionmentioning

confidence: 99%

Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton

Bijman¹,

Amerongen

Laurens

et al. 2006

Molecular Cancer Therapeutics

105

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Conventional anticancer agents may display antiangiogenic effects, but the underlying mechanism is poorly understood. We determined the antiangiogenic properties of cisplatin, doxorubicin, and the microtubule-targeting agents docetaxel, epothilone B, and vinblastine at concentrations not affecting cell proliferation. We also assessed tubulin and actin morphology and the activity of two key molecules in cell motility, the small Rho GTPases Cdc42 and Rac1. The highest non-toxic concentration (HNTC) of each drug was defined as the concentration inhibiting a maximum of 10% human umbilical vein endothelial cell growth on a 1-hour drug exposure, being for cisplatin 10 Mmol/L, doxorubicin 100 nmol/L, docetaxel 10 nmol/L, epothilone B 1 nmol/L, and vinblastine 10 nmol/L. Comparative endothelial cell functional assays using HNTCs for an exposure time of 1 hour indicated that endothelial cell migration in the wound assay, endothelial cell invasion in a transwell invasion system, and endothelial cell formation into tubelike structures on a layer of Matrigel were significantly inhibited by docetaxel, epothilone B, and vinblastine (P < 0.05), but not by cisplatin and doxorubicin. Docetaxel was slightly more efficient in the inhibition of endothelial cell motility than epothilone B and vinblastine. Fluorescence microscopy revealed that only the microtubule-targeting agents affected the integrity of the tubulin and F-actin cytoskeleton, which showed disturbed microtubule structures, less F-actin stress fiber formation, and appearance of nuclear F-actin rings. These observations were associated with early inhibition of Rac1 and Cdc42 activity. In conclusion, HNTCs of microtubuletargeting agents efficiently reduce endothelial cell motility by interference with microtubule dynamics preventing the activation of Rac1/Cdc42 and disorganizing the actin cytoskeleton. [Mol Cancer Ther 2006;5(9):2348 -57]

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“…Podophyllotoxin was not applied clinically, however, because of its strong toxicity. A research group in the United Kingdom and New Zealand continued to develop this approach and found that drugs related to flavone acetic acid and tubulin-binding agents such as vinca alkaloids markedly decreased TBF (Bibby et al, 1989;Hill et al, 1989Hill et al, , 1993Zwi et al, 1989;Baguley et al, 1991;Ching et al, 1994;Chaplin et al, 1996;Holwell et al, 2001). However, the decrease in TBF by flavone acetic acid was accompanied by a marked reduction in systemic blood pressure, and an effective decrease in TBF by vinca alkaloids was achieved only at doses approaching the maximum tolerated dose.…”

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confidence: 99%

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs

2002

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In a previous study, we used subcutaneous LY80 tumours (a subline of Yoshida sarcoma), Sato lung carcinoma, and methylcholanthrene-induced primary tumours, to demonstrate that a novel water-soluble combretastatin A-4 derivative, AC7700, abruptly and irreversibly stopped tumour blood flow. As a result of this interrupted supply of nutrients, extensive necrosis was induced within the tumour. In the present study, we investigated whether AC7700 acts in the same way against solid tumours growing in the liver, stomach, kidney, muscle, and lymph nodes. Tumour blood flow and the change in tumour blood flow induced by AC7700 were measured by the hydrogen clearance method. In a model of cancer chemotherapy against metastases, LY80 cells (2610 6 ) were injected into the lateral tail vein, and AC7700 at 10 mg kg 71 was injected i.v. five times at intervals of 2 days, starting on day 7 after tumour cell injection. The number and size of tumours were compared with those in the control group. The change in tumour blood flow and the therapeutic effect of AC7700 on microtumours were observed directly by using Sato lung carcinoma implanted in a rat transparent chamber. AC7700 caused a marked decrease in the tumour blood flow of all LY80 tumours developing in various tissues and organs and growth of all tumours including lymph node metastases and microtumours was inhibited. In every tumour, tumour blood flow began to decrease immediately after AC7700 administration and reached a minimum at approximately 30 min after injection. In many tumour capillaries, blood flow completely stopped within 3 min after AC7700 administration. These results demonstrate that AC7700 is effective for tumours growing in various tissues and organs and for metastases. We conclude that tumour blood flow stanching induced by AC7700 may become an effective therapeutic strategy for all cancers, including refractory cancers because the therapeutic effect is independent of tumour site and specific type of cancer.

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Anti-vascular effects of vinflunine in the MAC 15A transplantable adenocarcinoma model

Cited by 54 publications

References 20 publications

Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells

Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells

Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs

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