Vinflunine, the latest Vinca alkaloid in clinical development -: A review of its preclinical anticancer properties

被引:127
作者
Kruczynski, A [1 ]
Hill, BT [1 ]
机构
[1] Ctr Rech Pierre Fabre, Div Cancerol Expt, F-81106 Castres 06, France
关键词
Vinca alkaloid; tubulin binding; microtubule dynamics; combination chemotherapy; in vivo anticancer activity;
D O I
10.1016/S1040-8428(01)00183-4
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Vinflunine is a new Vinca alkaloid uniquely fluorinated, by the use of superacid chemistry, in a little exploited region of the catharanthine moiety. In vitro investigations have confirmed the mitotic-arresting and tubulin-interacting properties of vinflunine shared by other Vinca alkaloids. However, differences in terms of the inhibitory effects of vinflunine on microtubules dynamics and its tubulin binding affinities have been identified which appear to distinguish it from the other Vinca alkaloids. Vinflunine induced smaller spirals with a shorter relaxation time, effects, which might be associated with reduced neurotoxicity. Studies investigating the in vitro cytotoxicity of vinflunine in combination therapy have revealed a high level of synergy when vinflunine was combined with either cisplatin, mitomycin C, doxorubicin or 5-fluorouracil. Furthermore, although vinflunine appears to participate in P-glycoprotein-mediated drug resistance mechanisms, it has proved only a weak substrate for this protein and a far less potent inducer of resistance than vinorelbine. Vinflunine was identified in preclinical studies as having marked antitumour activity in vivo against a large panel of experimental tumour models, with tumour regressions being recorded in human renal and small cell lung cancer tumour xenografts. Overall its level of activity was superior to that of vinorelbine in many of the experimental models used. Interestingly, an in vivo study using a well vascularised adenocarcinoma of the colon has suggested that vinflunine mediates its antitumour activity at least in part via an antivascular mechanism, even at sub-cytotoxic doses. Therefore, these data provide a favourable preclinical profile for vinflunine, supporting its promising candidacy for clinical development. Phase I evaluations of vinflunine have been completed in Europe and phase II clinical trials are now ongoing. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:159 / 173
页数:15
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