extremely grateful to the Burroughs Wellcome Co. and to Hoffmann-La Roche Inc. for their support of my research in Tuckahoe from 1960 to 1970 and in Nutley from 1970 to the present. Looking back at the names of earlier recipients of the Clowes Award, I realize that I am the 6th Clowes Lecturer who, at one time or another in his career, has been associated with the McArdle Laboratory for Cancer Research at the University of Wisconsin. I believe that the large number of awardees associated with McArdle is telling us something about the genius of Dr. Harold Rusch who established McArdle with a handful of outstanding young investigators. Dr. Rusch helped to develop in his associates an intense devotion to fundamental cancer research, and he provided his colleagues with an at mosphere that encouraged them to have critical but construc tive interactions with each other in ways that stimulated excel lence in research by all of the members of the group. In 1952, I had the good fortune of coming to McArdle as a graduate student of Drs. James and Elizabeth Miller. Although I failed in my first research assignment, which was to synthesize pure 2amino-1-naphthol, the Millers had great patience with me, and they tried very hard to instill their high standards into my research. Whatever small accomplishments I may have made to biomÃ©dical research were in large part the result of the excellent training and encouragement that I received from Jim and Betty Miller. An important problem that has been of great interest to me for many years is individuality in the response of human beings and other living organisms to foreign chemicals. Why does a drug or an environmental pollutant cause toxicity in one person and not in another person? Why do some cigarette smokers develop lung cancer whereas other cigarette smokers do not? One of the causes of variability in the response of human beings to a foreign chemical is individuality in the rate of metabolism of the chemical. By the mid-1960s, it was recog nized by clinical pharmacologists that the plasma half-lives and steady state plasma concentrations of drugs varied by as much as 10to 20-fold among different individuals (42, 115, 204, 318). Because it seemed likely that there were also large differences in the metabolism of chemical carcinogens in dif ferent individuals, we investigated the metabolism of BP2 by

https://cancerres.aacrjournals.org/content/canres/42/12/4875.full.pdf

Induction of Microsomal Enzymes by Foreign Chemicals and Carcinogenesis by Polycyclic Aromatic Hydrocarbons: G. H. A. Clowes Memorial Lecture

CARCINOGENIC polycyclic hydrocarbons such as the widespread environmental contaminant, benzo(a)pyrene (Fig. 1a), undoubtedly require metabolic activitation. Boyland1 proposed that epoxides, whose formation is catalysed by the NADPH-dependent microsomal mono-oxygenases2,3, are the initial products of double-bond oxidation and we have suggested that epoxides are the important reactive metabolites responsible for the biological effects of these carcinogens4.

Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide

https://science.sciencemag.org/content/sci/185/4151/573.full.pdf

Arene oxides: a new aspect of drug metabolism.

https://cancerres.aacrjournals.org/content/canres/38/6/1479.full.pdf

Some Current Perspectives on Chemical Carcinogenesis in Humans and Experimental Animals: Presidential Address

Studies on a variety of chemical carcinogens have demonstrated that their ultimate reactive and carcinogenic forms are strong electrophiles. Some carcinogens, such as alkylating agents, are in their ultimate forms as administered, but most require metabolism to these active derivatives. The ultimate carcinogens react, usually non-enzymatically, with nucleophilic constituents in vivo. Of particular interest in regard to their possible importance in carcinogenesis have been the covalent interactions of these electrophilic reactants with cellular informational macromolecules, the DNAs, RNAs, and proteins. Current data are consistent with the idea that the initiation step of chemical carcinogenesis is a mutagenic event and is caused by alteration of DNA by the ultimate carcinogens. The nature of the carcinogen metabolite(s) involved in the promotion phase has not been determined, but there appears to be no requirement that they be electrophilic. The development of the concept of ultimate chemical carcinogens as strong electrophilic reactants is reviewed, especially with respect to the studies carried in the authors' laboratory.

Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules

Metabolic conversion of benzo(a)pyrene by Syrian hamster liver microsomes and binding of metabolites to deoxyribonucleic acid.

Aus Benzo(a)pyren (Ia) werden die Metaboliten (Ib), (Ic), (II), (III) sowie (IVa) und (IVb) erhalten und in ihrer Struktur bestatigt.

N. Castagnoli

Papers

Metabolic conversion of benzo(a)pyrene by Syrian hamster liver microsomes and binding of metabolites to deoxyribonucleic acid.

Metabolic conversion of benzo(a)pyrene by syrian hamster liver microsomes and binding of metabolites of deoxyribonucleic acid