Vinflunine, a second generation novel Vinca alkaloid with a distinctive pharmacological profile, now in clinical development and prospects for futuremitotic blockers

The pharmacological profile of vinflunine, a novel bi-fluorinated derivativ e of vinorelbine is summarised. Detailed comparisons, based on in vitro and in vivo experimental preclinical data, of vinflunine with its parent molec ule and the classic Vinca alkaloids, exemplified by vincristine or vinblast ine, have revealed certain qualitative and quantitative differences between these first and second generation Vincas. Evidence is gradually accruing i ndicating that certain more subtle mechanistic differences exist in relatio n to the precise interactions of these individual molecules with cellular m icrotubules involving, for example, their suppression of microtubule dynami cs. It is tempting, but premature, to suggest that these may be associated with the markedly superior in vivo antitumour activity of vinflunine docume nted in a series of murine and human xenografted tumour models. The in vivo antivascular effects of vinflunine, identified at doses below those requir ed for optimal antitumour activity, coupled with the demonstrated potential value of vinflunine as a component of combination regimens, together with the finding that resistance to vinflunine was generated far less readily th an to vinorelbine, augur well for the ongoing clinical development of this new agent, Finally, it is proposed that as our knowledge of the basic event s involved in initiation and completion of mitosis and in defining the prec ise, yet multifacted, functions of microtubules increases, alternative intr acellular targets will be identified. Such targets may prove suitable for p harmacological exploitation and more effective antimitotic antitumour agent s will undoubtedly emerge. However, whether these will be third generation Vincas or molecules with quite different structures remains an open questio n.