Vinflunine, a second generation novel Vinca Alkaloid with a distinctive pharmacological profile, now in clinical development and prospects for future mitotic blockers.
The pharmacological profile of vinflunine, a novel bi-fluorinated derivative of vinorelbine is summarised. Detailed comparisons, based on in vitro and in vivo experimental preclinical data, of vinflunine with its parent molecule and the classic Vinca alkaloids, exemplified by vincristine or vinblastine, have revealed certain qualitative and quantitative differences between these first and second generation Vincas. Evidence is gradually accruing indicating that certain more subtle mechanistic differences exist in relation to the precise interactions of these individual molecules with cellular microtubules involving, for example, their suppression of microtubule dynamics. It is tempting, but premature, to suggest that these may be associated with the markedly superior in vivo antitumour activity of vinflunine documented in a series of murine and human xenografted tumour models. The in vivo antivascular effects of vinflunine, identified at doses below those required 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 than to vinorelbine, augur well for the ongoing clinical development of this new agent. Finally, it is proposed that as our knowledge of the basic events involved in initiation and completion of mitosis and in defining the precise, yet multifaceted, functions of microtubules increases, alternative intracellular targets will be identified. Such targets may prove suitable for pharmacological exploitation and more effective antimitotic antitumour agents will undoubtedly emerge. However, whether these will be third generation Vincas or molecules with quite different structures remains an open question.
Hill
B T
BT
Division de Cancerologie Experimentale, Centre de Recherche Pierre Fabre, Castres, 81106, France. bridget.hill@pierre-fabre.com
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; C111217:vinflunine; D014747:Vinblastine