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

Vinflunine is a new Vinca alkaloid uniquely fluorinated, by the use of supe racid chemistry, in a little exploited region of tile catharanthine moiety. In vitro investigations have confirmed the mitotic-arresting and tubulin-i nteracting properties of vinflunine shared by other Vinca alkaloids. Howeve r, differences in terms of the inhibitory effects of vinflunine on microtub ules dynamics and its tubulin binding affinities have been identified which appear to distinguish it from the other Vinca alkaloids. Vinflunine induce d smaller spirals with a shorter relaxation time, effects, which might be a ssociated with reduced neurotoxicity. Studies investigating the in vitro cy totoxicity 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 s tudies as having marked antitumour activity in vivo against a large panel o f experimental tumour models, with tumour regressions being recorded in hum an renal and small cell lung cancer tumour xenografts. Overall its level of activity was superior to that of vinorelbine in many of the experimental m odels used. Interestingly, an in vivo study using a well vascularised adeno carcinoma of the colon has suggested that vinflunine mediates its antitumou r activity at least in part via an antivascular mechanism, even at sub-cyto toxic doses. Therefore, these data provide a favourable preclinical profile for vinflunine, supporting its promising candidacy for clinical developmen t. Phase I evaluations of vinflunine have been completed in Europe and phas e II clinical trials are now ongoing. (C) 2001 Elsevier Science Ireland Ltd . All rights reserved.