Snail neurons as a possible model for testing neurotoxic side effects of antitumor agents: paracrystal formation by Vinca alkaloids.

The suitability of neurons of the freshwater snail Lymnaea stagnalis as a test system for the neurotoxic side effects of antitumour Vinca alkaloids has been investigated, by studying the process of paracrystal induction by Vinca antitumour agents. Three Vinca alkaloids have been compared: the natural vinblastine and vincristine and the semisynthetic vindesine. They appear to induce two types of inclusion. The first type is paracrystalline and has a rod-like shape with a width of 0.3-2.5 micron and a length of 1-10 micron. It consists of hexagonally arranged tubules with a lattice constant of approximately 28 nm. The second type appears as ladder-like profiles with a periodicity of approximately 30 nm. It is proposed that the ladder-like profiles are in fact helical structures and are precursors of the paracrystals. Both types of inclusion may fill up large parts of the axons; they are rare in axon terminals and almost absent from the neuronal somata. It has been concluded that the process of paracrystal induction by Vinca alkaloids in Lymnaea neurons is very much the same as in mammalian neurons and may be largely responsible for the neurotoxic effects of the Vinca drugs, because it impairs axonal transport of neuronal secretory granules. Apparently, in this respect vindesine behaves in a similar way as the conventional vincristine and vinblastine drugs. Vincristine induces clearly more paracrystals than vindesine, whereas the least paracrystals occur in vinblastine-treated material. These differences correlate with the different clinical neurotoxicities of these drugs. Therefore, because Lymnaea neurons can be considered as excellent model systems for studies of the functioning of neurons in general, it is expected that counting the number of paracrystals in Lymnaea nervous tissue will prove to be a good method to predict the degree of clinical neurotoxicity of newly developed antitumor Vinca alkaloids.