Annals of the New York Academy of Sciences 1958/3. [antikvár]

INTROD UCTORY REMARKS By L. H. Schmidt The Chrisl Hospitál Institute of Medical Research, Cincinnati, Ohio In opening this monograph it seems appropriate to cite a series of observations made by Paul Ehrlich in 18981 in a manuscript dealing with the relationships between chemical constitution, distribution, and pharmacological action. In this report Ehrlich said: "I have made extensive experiments with many hundreds of different compounds and in all of these I have discovered only one substance to which I am inclined to ascribe a substituting action on protoplasm. This substance, vinylamine, discovered by Gábriel, is förmed by extracting bromine from bromoethylamine. . . . Marckwald has shown that this substance cannot, as was first supposed, contain a double bond. It can therefore only possess a constitution of dimethylenimine. In view of this a complete analogy exists between ethylenimine and ethylene oxidé. . . . These two substances, ethylenimine and ethylene oxidé, are highly toxic compounds, as has been shown by the research of Levaditi and myself. . . . The pathological changes excited by dimethylenimine are especially interesting. Administered to a great variety of animals in doses which caused death after one and a half or two days or more, this substance causes totál necrosis of the renal papillae. In the rabbit Levaditi found besides this marked changes extending from the pelvis of the ureter to the urethra and consisting of necrosis of the lining epithelium, hemorrhages, and edema. Everyone who has learned to recognize these changes, absolutely unique in pathology, would be forced to the assumption that this localization is dependent on a direct attack of the vinylamine on the affected epithelium, the ethylenimine group entering the protoplasmic molecule." These references to ethylenimine and ethylene oxidé seem to represent the first recognition of the unique biological features of alkylating agents. It was to be more than forty-five years, however, before these observations were applied to the treatment of neoplastic diseases, and another three years before there was generál knowledge of this application. It was not until 1942 that Goodman and Gilman, while working on the pharmacology of certain nitrogén mustard derivatives, noted the effects of these compounds on lymphoid tissue and rapidly dividing cells and suggested the possibility of their use in certain neoplasms of lymphoid character. This led to studies on experimentál neoplasms and, subsequently, to clinical investigations at Yale University, New Haven, Conn., which showed that methyl-bis-(/3- chloroethyl)-amine had significant activity against Hodgkin's disease and evoked limited regressive changes in certain cases of lymphosarcoma. Within a brief period these observations were confirmed and extended by investigators in Boston, Chicago, and Salt Laké City. Because of wartime secrecy these observations were not published immediately. They did not become generally known until 1946, when Gilman and Philips2 presented km