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07V THE BIOLOGICAL ALKYLATING AGENTS ALEXANDER HADDOW* Les poisons peuvent être employés comme agents de destruction de la vie ou comme moyens de guérison des maladies; mais, outre ces deux usages bien connus de tout le monde, il en est un troisième qui intéresse particulièrement le physiologiste. Pour lui, le poison devient un instrument qui dissocie et analyse les phénomènes les plus délicats de la machine vivante, et, en étudiant attentivement le mécanisme de la mort . . . il s'instruit par voie indirecte sur le mécanisme physiologique de la vie.—Claude Bernard, La Science expérimentale, 1878. Introduction Of necessity, this review, on the one hand, considers only a minute fraction of the vast literature on the alkylating agents, and, on the other, pays perhaps disproportionate attention to the work of the Chester Beatty Research Institute on these compounds [I]. The great Paul Ehrlich is very properly considered the father of the alkylating agents, and, toward the end of the nineteenth century he gave as his opinion that, of all the many hundreds of types he had considered, he regarded vinylamine—later recognised as dimethyleneimine—as being unique in altering the hereditary properties of the cell through a process of chemical combination with what he then called protoplasm (see [2]). At the same time, it was thought appropriate to pause at what is a veritable milestone and to estimate the path and direction of future progress. Mustard gas was first synthesised by Guthrie [3] and Niemann [4] in 1860 and was found to be a powerful vesicant. Meyer [5] prepared a pure gas which was liquid at ordinary temperatures. In 1919, Krumbhaar [6] related the leucopenia to marrow injury, a fact which was also observed during the classic and later researches of * Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital , London SW3 6JB. The author wishes to acknowledge the inestimable help of his literary assistant, Miss A. M. Whitecross, of Mrs. Audrey Stewart of the Chester Beatty Research Institute Library, and of Professor W. C. J. Ross. Perspectives in Biology and Medicine · Summer 1973 \ 503 Winternitz and his school, bearing upon the nitrogen mustards of the Second World War and upon various accidental circumstances, of which that occurring at Bari was a famous example. Herrman [7] and Warthin and Weiler [8, 9] had noted erosions and ulcers in the stomach and intestines of patients who had been severely gassed in the First World War. Other workers, including Heitzman [10] and von den Velden [11], described the occurrence of headache, nausea, and progressive cachexia, which implicated the nervous system. In 1935, Ward [12] prepared tris(beta-chloroethyl)amine HCl as an alternative to S-mustard for war purposes. Regression of superficial mouse tumours following local application of mustard was noticed by Adair and Bagg ([13], see also [14]), and Visser and Vos [15] produced tumour regression in mice and rats with S-mustard, early preludes to the chemotherapeutic application of the alkylating agents. Swords may be beaten into ploughshares, and surely there could have been no more striking example. Soddy, while professor at Aberdeen, separated ethylene from coal gas and used it to make mustard gas (ca. 1914-1918). A special feature has also been the implication of the alkylating agents in a wide range of biological phenomena including mutation [16], the induction of changes in genes and chromosomes [17, 18], reduced titer of antibody in mice treated with cancer chemotherapeutic agents ([19], see also [20, 21]), the effects of different halogenated alkyl amines on the division of sea-urchin eggs [22], genetical effects of nitrogen mustard in the house mouse [23], inhibition of mitosis in the roots of the broad bean (Vicia faba) by nitrogen mustard [24], testis atrophy [25, 26], sensitivity of Drosophila germ cells to mutagens [27], alkylating treatment of frog sperm [28], depigmentation of hair as a biological radiation dosimeter [29], effects upon cell division in Chilomonas Paramecium and Saccharomyces cerevisiae [30], and effects upon Paramecium aurelia [31]. Very comprehensive reviews have been given through the specialised symposia held under the auspices of the American Academy of Sciences and published in 1958 and 1969. Aromatic...


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