Some Observations on the Cytological Effects of Antimitotic Poisons

Extract

Recently discovered substances with antimitotic action fall in the two categories which have been defined since many years, i. e. spindle poisons and chromatin (or “radiomimetic”) poisons. The most recently studied are hydroxyurea — a powerful inhibitor of DNA synthesis — and the Vinca alcaloids — which destroy the tubular components of the spindle, bringing a prolonged arrest in metaphase.

The mechanisms of action of many of these drugs remain most obscure. In the field of spindle-poisons, there has been no explanation sofar of the relationship between their chemical structure and cytological action. While it is known that minor changes in the chemical structure of colchicine can prevent its specific action on the spindle, the precise relation which appears to exist between this complex molecule and the spindle structures remains obscure. The same remark applies to the Vinca alcaloids. Progress is being made however in this field. The ultrastructural aspects of the spindle have been analysed by electron microscopy, and a precise definition in chemical terms of the spindle may be close. These observations have shown the similarity between the tubules of the spindle and other tubular structures of identifical size: the neurotubules. Some recent observations indicate that these may also be destroyed by colchicine, a fact which may be related to the well-known and severe neurotoxicity of this alcaloid. What remains to be explained is the fact that the most effective spindle poisons are molecules of the size and complexity of those of vinblastine, while simple inorganic substances (arsenicals, heavy metals) may exert identical if not so powerful effects on the spindle structures. Another point which needs further research is the cause of the extensive cellular destruction which follows, in animal cells, any prolonged inhibition of the spindle function. The chemotherapic actions of spindle poisons are most probably related, not only to the growth inhibiting effects of these drugs, but most of all to the cellular breakdown which is observed in cells when they have been kept for several hours in metaphase.