NEW ASPECTS OF THE PHARMACOLOGY OF ANTIMITOTIC AGENTS
Authors: PIERRE DUSTIN
Journal: Pharmacological Reviews (1963)

At this point, it may appear that, although only a small number of the mitotic inhibitors has been considered, the problem of antimitotic action remains rather confused. Clear-cut classifications are no longer possible; in the same group of substances ( e.g. , the steroid hormones) actions are to be found varying between mitotic stimulation and selective inhibition of one of the steps of mitosis. Moreover, several substances may affect either spindle or chromosomes, depending on the experimental conditions. The biochemical basis of most antimitotic action is shrouded in obscurity, even though some discoveries about the chemistry of the mitotic apparatus, the role of folic coenzymes in nucleic acid metabolism, the structure of the spindle fibers, and the antagonists of mitotic poisons, open the path for further clarifications of the subject.

It was pointed out several years ago (64) that mitotic poisons appeared far more promising in the biochemical analysis of cellular division than in cancer chemotherapy. Since then, thousands of drugs have been tested, and so far, the only ones which have found some use in medicine remain dangerous, for the fundamental reason that they are mitotic poisons, and that some normal tissues grow faster than many neoplastic ones. If an antimitotic substance acting selectively on neoplastic growth is to be discovered, it should have no action on normal cells. That such a possibility may exist is indicated by the rare examples of mitotic antagonists with a specific action on some tissues: for instance, cortisone vs. lymphoid tissue, and griseofulvin vs. skin.

On the positive side, it must be emphasized that knowledge not only of cell division, but also of many fundamental biochemical changes related to cellular growth, has benefited from work with mitotic inhibitors. The study of DNA synthesis, the isolation of the mitotic apparatus, morphological studies of chromosomes, have considerably progressed because some of the mitotic poisons have proven to be useful tools.

Mitotic inhibitors are more than possible drugs for cancer chemotherapy; they are tools which enable the cytologist to dissect the interrelated phases of the mitotic cycle. This type of approach would certainly be facilitated if more nearly uniform methods were used. On the other hand, chance observations, like those which led to the discovery of griseofulvin and vinblastine (155), will always play a fundamental part in the development of science.

It should be evident from this review that many important aspects of mitosis have not been touched by the use of mitotic inhibitors. The reduplication of the centrioles (a remarkably complex phenomenon), the disappearance and synthesis of the nucleolus, the mechanisms of cleavage, the modifications of cell surface, the multiplication of mitochondria and other cell organelles, the control of mitosis itself in the pluricellular animal, remain poorly understood. Mitosis in plants and animals appears to be quite similar, and many mitotic poisons, among them the most active, act similarly on both. Cortisone, however, would never had been found to have an antimitotic action if only plant cells had been used. In pluricellular organisms, growth may be controlled by organ-specific substances that inhibit mitosis, but these remain to be isolated.

Apart from the pharmacological and toxicological aspects of these problems, it should be pointed out in fine that the antimitotic properties of so many natural substances-hormones, plant extracts, antibiotics-indicate that the various types of mitotic inhibition belong to general biology, and that their study helps to understand better the normal control of mitotic activity.