Vinflunine, the latest Vinca alkaloid in clinical development

Kruczynski, Anna; Hill, Bridget T.

doi:10.1016/s1040-8428(01)00183-4

Cited by 141 publications

(77 citation statements)

References 45 publications

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“…For example, vinflunine is significantly less potent in vitro and in vivo than either vinblastine or vincristine, with IC 50 values in cells in the range we obtained for CB694. Nevertheless, vinflunine is more effective in numerous in vivo tumor models than the standard vinca alkaloids, 32,33 and consequently, it is currently undergoing clinical evaluation. CB694 is a poor substrate for transport by Pgp, in contrast to a number of natural products such as Taxol and the vinca alkaloids.…”

Section: Discussionmentioning

confidence: 99%

CB694, a novel antimitotic with antitumor activities

Weiderhold

Randall-Hlubek

Polin

et al. 2005

Intl Journal of Cancer

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During the course of a mechanism-based screening program aimed at identifying new antimitotic agents, a novel microtubule depolymerizing piperazine derivative, 1-(5-chloro-2-methoxybenzoyl)-4-(3-chlorophenyl) piperazine, was identified. The compound, designated CB694, caused inhibition of proliferation of a wide range of cancer cell lines, with an average IC 50 of 85 nM. A multidrug-resistant cell line was sensitive to inhibition by CB694, suggesting that this compound is a poor substrate for transport by P-glycoprotein. CB694 caused formation of abnormal mitotic structures in HeLa cells. Specifically, CB694 caused a concentration-dependent increase in bipolar spindles with lagging chromosomes and, with slightly higher concentrations, formation of multipolar mitotic spindles. These mitotic abnormalities occurred at concentrations that did not cause significant changes in the appearance or quantity of interphase microtubules. Coincident with the formation of abnormal mitotic spindles, CB694 caused G 2 /M arrest. CB694 inhibited the assembly of purified tubulin with an IC 50 of 2.3 lM. Colchicine binding was strongly inhibited by CB694, suggesting that it binds to tubulin at the colchicine site. Bcl-2 phosphorylation and activation of ERK and JNK and caspase 3-dependent cleavage of PARP were observed in MDA-MB-435 cells treated with CB694. CB694 caused phosphorylation of Aurora A within 8 hr of treatment, and increases in Aurora A protein levels were coincident with mitotic accumulation. The efficacy of CB694 against a syngeneic murine transplantable solid tumor, Mammary 16/C, was also evaluated. CB694 was well tolerated and showed antitumor activity. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

CB694, a novel antimitotic with antitumor activities

Weiderhold

Randall-Hlubek

Polin

et al. 2005

Intl Journal of Cancer

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“…Vinflunine presents a differential affinity for tubulin with a higher reversibility of interaction with its target (58,59). This unique mechanism of action may underlie the superior in vivo activity observed with vinflunine compared with other vinca alkaloids (66,67). In phase 1 pharmacokinetic studies, the active metabolite of vinflunine 4-O-deacetylvinflunine was found to have a half-life of ∼5 days (68).…”

Section: Vinca Alkaloids Vinfluninementioning

confidence: 99%

“…In phase 1 pharmacokinetic studies, the active metabolite of vinflunine 4-O-deacetylvinflunine was found to have a half-life of ∼5 days (68). Furthermore, as a weak substrate for P-gp, in vitro and in vivo resistance to vinflunine develops at a slow rate (66,67).…”

Section: Vinca Alkaloids Vinfluninementioning

confidence: 99%

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

Perez

2009

Molecular Cancer Therapeutics

432

339

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Microtubules are important cellular targets for anticancer therapy because of their key role in mitosis. Microtubule inhibitors (MTI) such as taxanes, vinca alkaloids, and epothilones stabilize or destabilize microtubules, thereby suppressing microtubule dynamics required for proper mitotic function, effectively blocking cell cycle progression and resulting in apoptosis. In spite of their antitumor activity, innate or acquired drug resistance to MTIs such as the taxanes is common, limiting their overall clinical efficacy. Further insight into the mechanisms of action of microtubule-targeting drugs has lead to the discovery of novel agents that may provide higher efficacy with limited toxicity and help overcome resistance to conventional MTIs. This review will focus on the different mechanisms of action of MTIs, potential factors related to resistance and tolerability, and will discuss the recent approval as well as the development of new antineoplastic agents.

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“…1; ref. 1) that led to a different and broader spectrum of activity relative to other Vinca alkaloids (2). Interestingly, its nonfluorinated counterpart was deprived of activity against experimental models highlighting the essential contribution of the fluorine atoms to this identified antitumor activity (1).…”

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confidence: 99%

Vinflunine: A New Microtubule Inhibitor Agent

Bennouna

Delord

Campone

et al. 2008

Clinical Cancer Research

102

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Vinflunine (Javlor) is the first fluorinated microtubule inhibitor belonging to the Vinca alkaloids family.Vinflunine is obtained by semisynthesis using superacidic chemistry to selectively introduce two fluorine atoms at the 20 ¶ position of the catharanthine moiety. This compound has been selected for clinical development on the basis of encouraging preclinical activity that warrants study in patients with a wide spectrum of solid tumors. Clinically significant activity has been seen in phase II studies, mainly in the treatment of transitional cell carcinoma of the urothelial tract, non^small cell lung cancer, and carcinoma of the breast. Vinflunine is currently in phase III trial assessment in patients with (second line) transitional cell carcinoma of the urothelium and firstline advanced breast cancer. The efficacy of vinflunine in patients with advanced non^small cell lung cancer previously treated with a platinum-containing regimen was confirmed by a large phase III trial.

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Vinflunine, the latest Vinca alkaloid in clinical development

Cited by 141 publications

References 45 publications

CB694, a novel antimitotic with antitumor activities

CB694, a novel antimitotic with antitumor activities

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

Vinflunine: A New Microtubule Inhibitor Agent

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