Mechanism of Colchicine-Mitosis 413 



i-i-^: Complex organic inolccitlrs. The mechanism ot action of 

 most of the substances mentioned in this subsection is unknown; 

 molecular structures are widely different. However, these drug;s are 

 all very active, and it is felt that they modify the spindle more by a 

 chemical than by a physical change. The resin of Podophyllum sp. 

 (mandrake) contains several toxic substances, the principal ones being 

 podophyllotoxin, a- and {^-peltatius, and quercetin. The crude resin 

 was a popular remedy against warts in the United States, and this 

 observation led to a scientific study of the active substances-^^- -' (XV) . 

 These jjroved to be efficient spindle poisons, and to act most similarly 

 to cokhicine, both in skin tumors of man, and in various animal 

 materials."'^ From a chemical point of vie^v, they are complex lac- 

 tones. '•'• Another instance of a lactone acting as a mitotic poison is 

 the antibiotic patuUu (Bacitracin, clavacin) (XVI) . 1 his inhibits 

 remarkably the spindles of erythroblasts in the chick and in many 

 tissues of mice.^ 



It is interesting to compare the formula of patulin with that of 

 roumarin (XVII) , which has been described as a weak metaphase poi- 

 son in Allium and Lilium. Its action may be of the "physical" type, 

 though combination with -SH groups is also possible. ^-^ 



Other substances of plant origin have been foimd to inhibit mitosis, 

 mainly in tissue cultures of fibroblasts. Chelidonine^^ is of interest 

 because of its use in cancer chemotherapy (Chapter 10) . In an ex- 

 tensive study of alkaloids, it has been shown that the only active ones 

 were found in the group which is chemically related to stilbylamine, 

 and thus to a-phenyl-i^ {p-metho\yphenyl) -ethylamine (cf. 17.4-1). 

 These are narcotin, gnoscopin, chelidonine, liomocJielidonnie, meth- 

 oxychelidonine, and protopin."'^ Many other substances may yet be 

 discovered ^vhcn further systematic studies are conduced. This is al- 

 ready underway, and has demonstrated c-mitotic activity in extracts 

 of Clumapliila maculata and Sassafras albidum.' 



Other complex substances extracted from plants are anctliol*''- and 

 apiol,^^ which may induce polyploidy. This has also been observed 

 in Allium root tips treated -with veratrine.^-^ Sanguinarine and cryp- 

 topleuriue are also spindle poisons, and the second, extracted from 

 Crypt oca ria pleurospora, has been considered as effective as colchi- 

 cine.'' Positive effects on mitosis have also been found with extracts 

 of the following plants: Ervatamia augustifolia, Aristolocliia clegans, 

 Euphorbia peplus, Bulbina bulbosa, and Strychnos arborea. Proto- 

 a)icmonii)i is an interesting poison,-^^' ^-^ for its action on the spindle 

 may be prevented by dimercaptopropanol (BAL) ; this is evidence of 

 a chemical reaction. 



The list of c-mitotic active substances is much longer, and among 

 chemicals of animal origin or related to the growth of animal cells, 

 adrenalin^''''- "^ has been found to arrest metaphases in fibroblast ( ul 



