Chemical and immunological properties of carcinogen-protein conjugates. (1952)

It is obvious from the remarks of the preceding speakers that steady progress toward a more com plete understanding of the many complex chemi cal and biological factors involved in tumor trans plantation and in carcinogenesis is being made by the application of a variety of experimental pro cedures. Also, it seems likely that the interesting observations on the in vivocombination of carcino gens with proteins just presented by Dr. E. Miller eventually will be found to be clearly related to those on the synthetic carcinogen-protein conju gates which I am privileged to review today. This work requires the knowledge and technics of sev eral scientific disciplines, and I have been fortu nate in having many capable collaborators since this research was started in 1935. Without their enthusiasm and co-operation, the problem prob ably would have been abandoned long ago. In addition to the financial and scientific support re ceived at the University of Toronto, Harvard Uni versity, the University of Maryland, and the In stitute for Cancer Research in Philadelphia, I also wish to acknowledge with appreciation grants-inaid given by the International Cancer Research Foundation and the American Cancer Society acting through the Committee on Growth of the National Research Council. The goal of the research is to inhibit carcino genesis by immunological methods. There seems to be no theoretical reason why this cannot be done. From the practical standpoint, however, it was evident from the beginning that even partial attainment of the final aims would require patience and continuous over-all optimism. It has been a source of satisfaction to us that developments of practical importance to other problems and to other workers have emerged from time to time during the course of the experimentation. The attack on the problem was based upon two separate observations. The first of these was the brilliant work of Landsteiner and his group (30), who discovered that the chemical attachment of a relatively complex, foreign, organic compound to a protein produced a conjugate which showed a new type of antigenic activity called prosthetic group, determinant group, or haptenic group ac tivity. These workers demonstrated that antisera, elicited by the injection of such conjugates in to animals, reacted serologically both with the protein component and with the foreign pros thetic group of the test antigens. Moreover, the reactivity of such antisera was not confined solely to protein conjugates. It was shown that these antisera would react in vitro and in vivowith the for eign compound alone or with a soluble, nonantigenic conjugate made by attaching the prosthetic group to an amino acid or peptide. The second set of ob servations consisted of the demonstration by Kennaway, Cook, Hieger, et al. (3) in England and Fieser, Shear, and others (19, 21) in this coun try of the carcinogenicity of a variety of carefully characterized chemicals of the polynuclear aro matic hydrocarbon type. Concurrently, there emerged the possibility that structurally related compounds, elaborated in animals as a result of abnormal metabolism, might be responsible for the production of certain spontaneous tumors. It seemed of interest, therefore, to determine whether the combination of various chemical car cinogens with proteins would produce antigens which, upon injection into animals, would elicit antisera capable of preventing carcinogenesis. From the practical point of view, the obvious pro cedure was to combine several polynuclear aromatic hydrocarbons with proteins, study their antigenic properties, and determine their potentialities in pro tecting animals against the carcinogenic activity of known chemicals. Preliminary investigations (9,10, 22) conducted with Drs. W. R. Franks and F. G. Banting at the University of Toronto in the pe-