Mutagenesis, Vol. 17, No. 4, 281-287,
July 2002
© 2002 UK Environmental Mutagen Society/Oxford University Press
AWARD LECTURE |
Hunting for electrophiles that harm human DNA: Frits Sobels Award Lecture
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Abstract
This lecture is dedicated to Frits Sobels and his farsighted vision on research directions in genetic toxicology. Some accomplishments by the author's research group in the area of cancer etiology research and pre-clinical drug safety evaluation are presented. Praziquantel, an antischistosomal drug, was found to be devoid of any genetic effects which determined the drug companies to proceed with further safety evaluation and marketing. This highly efficient life-saving drug is now in use world wide. Biomonitoring methods have been developed to quantitate carcinogens, their metabolites or DNA adducts in humans exposed environmentally and endogenously to genotoxic agents. The methods were applied in ecological and case–control studies aimed at establishing causal relationships between exposure and disease. Results from both field studies in Iran and laboratory investigations supported the hypothesis that opium use, in particular ingestion of its pyrolysates, may be a risk factor for esophageal cancer in this region, probably acting together with nutritional deficiencies and thermal injury. By applying the nitrosoproline (NPRO) test in ecological studies on esophageal cancer causation in China some support was obtained for the involvement of N-nitroso compounds. In inhabitants of high risk areas endogenous nitrosamine synthesis could be markedly reduced by ingestion of vitamin C. Ultrasensitive detection methods for etheno-DNA adducts, which are formed by lipid peroxidation products resulting from increased oxidative stress, have been developed. Known cancer risk factors such as metal storage, chronic inflammatory processes and a high 
-6 PUFA fat diet increased the background level of these miscoding DNA adducts many times. They were found to increase progressively in premalignant lesions of cancer-prone tissues of humans and rodents, probably contributing to the genetic instability that drives cells to malignancy. Etheno-DNA adducts are thus promising markers to verify the efficiency of chemopreventive measures in humans.
Acceptance remarks
Mr Chairman and distinguished Members of the Award Committee, I am very honored that you have selected me for the EEMS Frits Sobels Award 2001. I accept this recognition on behalf of my co-workers, all of whom benefited from the farsighted vision of Frits Sobels in the 1960s with regard to research directions in genetic toxicology. Many therefore refer to Frederik Hendrik Sobels (1922–1993) as the `European father of mutation research'. He is shown in Figure 1
with the `mother of chemical mutagenesis', Charlotte Auerbach (see Kilbey, 1995), when they both attended a meeting at IARC in Lyon, France, which I had organized in the 1980s.
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Frits had a talent for attracting people who were top researchers at that time and for gently forcing them to solve problems together in meetings in the fields of genetic toxicology, environmental mutagenesis and carcinogenesis. I was always impressed by Frits' persistence in keeping in contact with scientists in countries behind the Iron Curtain. For decades, he helped many of them to survive under difficult circumstances.
Turning now to my own scientific work, I would like to state again that most of what I may have achieved depended heavily on the skills of my co-workers, of whom it has been my good fortune to have had so many over the past 30 years (see Acknowledgments). I tried to highlight their contributions in a recent review article, entitled `Studies on biomarkers in cancer etiology and prevention: a summary and challenge of 20 years of interdisciplinary research', which appeared in a special issue of Mutation Research (Bartsch, 2000) dedicated to R. Montesano, a distinguished colleague at IARC, who, together with Lorenzo Tomatis (see Figure 1
), was instrumental in building up research activities in experimental carcinogenesis in the newly inaugurated center. So, if you are interested in what I did (or did not do) during 20 years at IARC, Lyon, this is the reference.
Biochemical and molecular epidemiology: difficult birth of a new discipline
In 1973, after returning from the USA, where I had spent a few years as a post-doctoral fellow (at the McArdle Laboratory for Cancer Research, Madison, WI) under the unforgettable guidance of the late Elisabeth C. and James A. Miller, I began research in the `Ivory Tower', as IARC was sometimes called, with a spirit of enquiry and the hope that my efforts would contribute to the prevention and/or cure of human diseases. I soon realized the enormous gap between laboratory bench work and studies in humans themselves. In order to bridge the gap between two groups with distinct characteristics—`the medically qualified, sound in biology and poor in statistics and statistically qualified, weak in biology'—I organized a series of multidisciplinary meetings. One of the first ones was a `think tank' in Cape Sunion, Greece, called Host Factors in Human Carcinogenesis (Bartsch and Armstrong, 1982). Participants at that meeting, held in 1981 and bringing together epidemiologists, biostatisticians and experimentalists, were clearly stimulated, and they outlined directions for future research involving integrated laboratory and field programs. The rapporteurs' reports emphasized that host factors, including genetically acquired make-up, determine why human beings are so different from one another in terms of disease susceptibility. On the cover page of the proceedings, beneath a watercolor of the Poseidon temple at Cape Sunion painted by a reputed Japanese participant, the late T. Hirayama, we cited a passage from Hypocrates' Air, Waters, Places: `Some men have constitutions that are like wooded mountains running with springs, others like those with poor soil and little water, still others like land such as in pastures and marshes, and yet others like the bare, dry earth of the plain'. For the book cover we chose a detail from the painting `Le jardin des delices' by Hieronymus Bosch (Figure 2), in which a man looks at a rat and the rat stares back through a glass tube. This is to me a symbol of our times, in which genome sequence analysis has revealed that rodents and humans, although separated evolutionarily, are not so different in toxicological terms. As noted decades ago, this is the basis for predicting susceptibility to carcinogenic stimuli and evaluation of human risks (Tomatis, 1979).
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Judged retrospectively, the meeting held in 1981, its participants and the proceedings volume all substantially contributed to further development of a multidisciplinary approach. This approach was first called `geographical pathology' by J. Higginson (Higginson, 1972
), then `biochemical epidemiology' by E. Wynder (Wynder and Reddy, 1974) and `molecular epidemiology' by B. Weinstein (Perera and Weinstein, 1982), one of the meeting's participants. Successful application of mutagenicity screening assays in drug safety testing
Although I hate to dwell too much on my own career, I shall briefly summarize three research achievements which I think would have pleased Frits Sobels. The first relates to the pre-clinical genotoxicity testing of an antischistosomal drug called Praziquantel (or Embay 8440, Droncit), a product developed by Bayer AG (Leverkusen, Germany) and Merck (Darmstadt, Germany). Because the two drugs in use at that time, Niridazole and Hycanthone, gave rise to serious side-effects, the companies asked the WHO division on Malaria and other Parasite diseases in Geneva, headed by Dr A. Davis, to have Praziquantel tested in a battery of short-term tests that have shown predictive value for the detection of potential carcinogens. Only if it was found to be devoid of any genetic effects would the drug companies proceed with further safety evaluations. With my distinguished colleagues T. Kuroki (Tokyo), C. Malaveille (Lyon), N. Loprieno (Lyon), R. Barale (Pisa), A.G. Abbondandolo (Pisa) and E. Vogel (Leiden), we tested this drug in the best assays available at that time. The indicator organisms Salmonella typhimurium strains, Schizosaccharomyces pombe, Saccharomyces cerevisiae, cultured V79 Chinese hamster cells, human heteroploid cells and Drosophila melanogaster were treated with Praziquantel, and tests for the induction of reverse and forward mutations, mitotic gene conversion, X-linked recessive lethal mutation, sister chromatid exchanges and unscheduled DNA repair synthesis were scored. Cell- and host-mediated assays were also performed. Hycanthone was included as a positive control. The uniform absence of any genetic activity of Praziquantel confirmed the assumption that its antischistosomal effectiveness is not a prerequisite for mutagenic activity (Bartsch et al., 1978). These results led the companies to implement the necessary rodent bioassays and clinical trials; later, the drug was approved by the US Food and Drug Administration and other drug control agencies. This very efficient antischistosomal drug is now used world wide and has and will continue to save millions of lives. An unexpected outcome of our work was that our laboratory in Lyon was one of the first in the West to receive visits by numerous Chinese guest scientists, who were allowed to come to WHO/IARC because the drug had been licensed and was produced in China at lower cost. All my Chinese visitors wanted to learn genotoxicity testing.
Field and laboratory studies on risk factors for esophageal cancer in Iran and China
My next example relates to investigations of the causative factors in esophageal cancer in the Islamic Republic of Iran and China, as the highest incidence rates in the world in both males and females were found in Gonbad in Iran and the next highest in Linxian County, China. The studies on risk factors for esophageal cancer in the Caspian littoral of Iran carried out by IARC researchers, headed by Dr N. Day, confirmed that the risk factors included nutritional deficiencies, drinking hot tea and chewing opium pipe residues (reviewed by Ghadirian et al., 1985). The opium dross, a black tarry material, is known locally as sukteh. In the 1970s we started laboratory investigations to characterize the nature of the DNA-damaging agents that we had shown to be present in opium dross (Hewer et al., 1978). We then produced pyrolysates of opium and of morphine, its major alkaloid, in a glass apparatus and these materials were investigated for their genetic and carcinogenic effects (Malaveille et al., 1982). We were able to isolate and characterize potent mutagens from these pyrolysates and showed that, although they have different structures, most have a hydroxyphenanthrene moiety (Figure 3), all of which can be derived from the parent compound, morphine, by mild heating (Friesen et al., 1985). The high DNA reactivity of this novel class of heterocyclic aromatic compounds was attributed to highly electrophilic metabolites, phenol epoxides, (Figure 3), which can attack DNA (Friesen et al., 1987).
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By activity-guided isolation and biological testing, we were able to demonstrate that these aromatic compounds differed with regard to their mutagenic activity, and some were 1000-fold more potent in bacteria than benzo[a]pyrene (Perry et al., 1983
; Friesen et al., 1987). In bioassays in rodents, the pyrolysate mixtures were also shown to produce tumors (Tsuda et al., 1993). In an attempt to link these opium pipe residues to esophageal cancer, we measured morphine metabolites in urine as an indicator of opium use, which in this area of the Caspian littoral was by ingestion of opium pipe residues. Morphine metabolites were thus determined in the urine of persons in households where there was a case of esophageal cancer and in control households. The results for over 1500 individuals showed that high urinary concentrations of morphine metabolites were more prevalent in high than in low incidence areas for esophageal cancer, with a 6-fold difference in both men and women. Members of households with a case had a higher prevalence of positive morphine metabolite findings than members for the control household in the same village (Ghadirian et al., 1985). This study was conducted at the end of the 1970s and therefore had to be halted when the civil disturbances began in Iran. Nevertheless, these initial results provided support for the hypothesis that opium use, in particular chewing of its pyrolysates, is a factor in the etiology of esophageal cancer in this region, probably acting together with nutritional deficiencies and thermal injury.
It also became clear, however, that opium pyrolysates alone could not account for the incidence of esophageal cancer type II in the rest of the Asian `cancer belt', such as in China. Our attention was directed to the hypothesis that endogenously produced carcinogenic N-nitroso compounds (NOC), either from dietary precursors and/or as a result of chronic inflammatory processes, were possible candidates (reviewed by Ohshima et al., 1982; Bartsch and Montesano, 1984). We considered that, if they are formed in vivo, they probably escaped detection by conventional biomonitoring and epidemiological techniques. Therefore, new non-invasive detection methods were required to establish their causal role in human cancer. There are three main pathways by which NOC could be produced in vivo (reviewed by Bartsch et al., 1992). First, intragastric acid can catalyze formation of nitrosamide-type carcinogens from ingested dietary precursors, which are probably relevant for cancer of the digestive tract. Second, activated macrophages and other cell types in inflamed or infected organs can produce DNA-reactive nitrogen oxides and nitrosamines via the enzyme inducible nitric oxide synthase (iNOS), providing carcinogenic stimuli in inflammation-associated malignancies (Ohshima and Bartsch, 1994). Third, bacteria isolated from human urinary tract infections were found to contain enzymes that also produce nitrosamines at neutral pH from precursor amines in situ, possibly relevant for bladder cancer causation.
To measure endogenous NOC formation in humans, the N-nitrosoproline (NPRO) test was developed in our laboratory in 1981 (Ohshima and Bartsch, 1981). Much credit goes to Dr H. Ohshima, who figures on the cover page of the journal Cancer Research (Figure 4). This novel, non-invasive test is based on the fact that amino acids such as proline, when given orally, scavenge nitrosating agents to form a nitrosated product, NPRO (Figure 4), which is excreted unchanged in the urine within 24 h. The test can be applied to humans by collecting two urine samples from the same person: one after ingestion of proline (A) and a second 1 day later after ingestion of proline with vitamin C, an inhibitor of nitrosation (B). The difference in NPRO excretion (A – B) reflects the nitrosation potential of the person, i.e. the rate at which amine precursors, when present in body fluids (gastric juice), could be nitrosated. With this assay in hand, we tried to determine whether endogenous NOC play a role in esophageal cancer in China, where, in the 1970s, this tumor was the second most important cause among all deaths from cancer.
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Initial studies by Dr S.H. Lu in areas of high and low risk for esophageal cancer provided some support for the involvement of NOC in causation of this disease (Lu et al., 1986
). After an exploratory visit with Dr H. Ohshima to Linxian County in Henan Province (Figure 5), we decided to participate in a large survey on diet, lifestyle and mortality in China, coordinated by Drs J. Chen (Beijing), R. Peto (Oxford, UK) and T.C. Campbell (Cornell University, Ithaca, NY). This ecological study covered 69 counties throughout China which were selected to represent a 300-fold range of mortality rates from esophageal cancer. Then, biological specimens were collected from over 4000 subjects and markers for exposure to carcinogens were measured, with 280 other variables. The NPRO test was used to measure NOC in pooled urine examples, as an index of exposure to endogenous and environmental nitrosamines. Finally, the biomarker data were correlated with mortality rates in the 69 counties.
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The results of this study on diet, lifestyle and mortality in China (Chen et al., 1990
) were printed as a monograph (in Chinese and English), and some of the most important results were published separately (Wu et al., 1993). These included the following: (i) a significant positive correlation between mortality rates from esophageal cancer and exposure to endogenously formed NOC, suggesting that endogenous synthesis of carcinogens may be implicated; (ii) correlations between exposure to NOC and mortality rates from cancers at other sites (nasopharynx and leukemia), although these were less strong and consistent; (iii) with respect to prevention, endogenous nitrosamine synthesis could be reduced markedly by ingestion of the nitrosation inhibitor vitamin C. To be effective in inhabitants of this high risk area, this dietary preventive measure would have to start early and be maintained for life.
Several international studies were subsequently conducted on exposure to NOC and gastrointestinal tract cancer among inhabitants of high risk areas in Japan, Poland and Costa Rica (reviewed by Bartsch et al., 1992). The results suggested that the burden of NOC in humans is determined not only by ingestion of preformed NOC and their precursors but also by synthesis in the body through inflammatory processes via the iNOS pathway, leading to overproduction of NO. Chronic inflammatory processes like esophagitis, gastritis and chronic infections are common world wide, but particularly in China. We therefore hypothesized, in a now widely quoted article (Ohshima and Bartsch, 1994), that chronic inflammatory conditions lead, via overproduction of NO in situ or via activated macrophages, to a cascade of adverse reactions, including (i) formation of carcinogenic nitrosamines, (ii) production of reactive oxygen and nitrogen species that attack DNA and (iii) additional DNA damage by base deamination and strand breaks. Such DNA damage, when generated in cancer-prone tissues by endogenously formed reactants and processes, may contribute to genetic instability, which is a driving force in the progression of carcinogenesis. We are currently pursuing this hypothesis in research which is summarized briefly below.
Biomarkers for persistent oxidative stress and increasing loads of promutagenic DNA damage, driving forces in carcinogenesis
As malignant growth is increasingly recognized as a pathological consequence of persistent oxidative stress, sensitive and specific markers for evaluating oxidative DNA damage are needed that can be used in human molecular epidemiological studies. At present, the availability of such biomarkers is limited, either because the method is insensitive or because of artefactual formation of oxidized DNA bases. We therefore investigated use of exocyclic (etheno) DNA adducts, which are chemically stable, secondary oxidation products. These turned out to be reliable markers of oxidative stress-derived DNA damage. A monograph summarizes the role of this type of exocyclic DNA lesions in mutagenesis and carcinogenesis (Singer and Bartsch, 1999).
Etheno adducts are formed from the carcinogens vinyl chloride and urethane and also from the major lipid peroxidation product of -6 polyunsaturated fatty acids (PUFA) (linoleic acid, and arachidonic acid), trans-4-hydroxy-2-nonenal (El-Ghissassi et al., 1995; Chung et al., 1996). This intermediate can react via its 2,3-epoxide with DNA to form the etheno-bridged base adducts (
dA, dC and dG) (Figure 6). With seminal contributions from my co-workers Drs J. Nair and A. Barbin at IARC, we developed a sensitive, specific method that allows detection of etheno-DNA adducts at levels as low as 1–2 adducts/1010 parent nucleotides, which permitted us to study their role in experimental and human carcinogenesis.
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Using this ultrasensitive immunoaffinity 32P-post-labeling procedure (Nair et al., 1995
), we unambiguously and quantitatively revealed for the first time the existence of background levels of dA and dC adducts in liver and other tissues from unexposed rodents and humans (reviewed by Bartsch et al., 1994; Nair et al., 1999a). Three research groups in the USA, headed by L. Marnett, F.L. Chung and J. Swenberg, independently identified the presence of lipid peroxidation (LPO)-derived background DNA adducts using different methods of detection (reviewed by Bartsch, 1999; Weisburger, 1999).
Having available an ultrasensitive detection method, we then investigated which pathological conditions, most of them known as cancer risk factors causing oxidative and nitrosative stress, could significantly increase the background etheno-DNA adduct levels in cancer-prone organs. Table I lists some of our findings in humans (A) and experimental animals (B): in affected organs from patients with metal storage diseases or rodents with an iron or copper overload; in organs that later develop tumors and show overexpression of `emergency enzymes' such as iNOS, LOX or COX-2. Increased levels of etheno-DNA adducts were found to be present in colonic polyps of patients with familial adenomatous polyposis (FAP) and in affected organs of persons with chronic inflammatory conditions, such as inflammatory bowel disease (Crohn's disease or ulcerative colitis) or chronic pancreatitis. These initial results suggested that LPO-derived DNA damage could play a major role in the development of human cancers associated with chronic infections and/or those which have an inflammatory component in their etiopathogenesis, whereby iNOS, LOX and COX-2 are often overexpressed. Finally, and most surprisingly, high levels of etheno-adducts were found in leukocyte DNA of women, but not of men, on a diet with a high concentration of linoleic acid (sunflower oil). This PUFA and also arachidonic acid are very good substrates for LPO, and may be triggered by redox cycling of hydroxylated estrodiol metabolites (Nair et al., 1997).
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What is the significance of these latest studies (Figure 7
)? The level of miscoding etheno-DNA adducts was found to increase progressively in target organs and preneoplastic lesions of cancer-prone patients and rodents, suggesting that these markers of increased oxidative stress and elevated LPO cause genetic instability and drive cells to malignancy. We measured such accumulation of miscoding lesions, for the first time, in cancer-prone organs such as the human colon (FAP, Crohn's disease and ulcerative colitis), pancreas (chronic pancreatitis) and liver (Wilson's disease) and in mouse skin papillomas (after initiation and promotion with chemicals). Etheno-DNA adducts are therefore promising means for quantifying increasing loads of promutagenic DNA damage in the early stages of the carcinogenesis process and should thus be useful for verifying the efficacy of chemopreventive measures in humans. In order to facilitate clinical and molecular epidemiological studies of this type, which we are now pursuing, we have also developed a non-invasive assay based on immunoaffinity HPLC–fluorescence to quantify excreted etheno-bridged nucleosides (such as dA) in a few milliliters of urine (Nair, 1999).
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I close with an excerpt from the rapporteur's report, written by the late C. Heidelberger, from the book Host Factors in Human Carcinogenesis, referred to earlier (Bartsch and Armstrong, 1982
), in which he summarized the future directions for cancer research: `... there was emphasis on the need to shift from semantic to mechanistic considerations. Many believed that a common soil for epidemiologists and laboratory scientists to till is metabolic or molecular epidemiology, in which meaningful laboratory tests will be done in individuals at epidemiologically defined risk or lack of risk to cancer ... Papers presented in later sessions provided evidence that powerful tools and methodologies are becoming available for metabolic or molecular epidemiology, which should lead to a rapprochement between epidemiologists and experimentalists. Hand-in-hand, they will follow these new golden threads, which will lead them, as they did Theseus, out of the maze and will enable them to evade the dread Minotaur, cancer. And Zeus, the IARC, and all the peoples of this and other lands will rejoice.' Frits Sobels, through his school of thought and his many talented associates, undoubtedly contributed to that goal (see Sankaranarayanan and Lohmann, 1993). This lecture is dedicated to his memory.
Acknowledgments
In relation to this article, the author acknowledges in particular the scientific contributions of Drs J.Nair and N.Frank (DKFZ, Heidelberg, Germany) and collaboration with H.G.Beger, P.L.Carmichael, P.Dolara, F.Kadlubar, M.Mutanen, M.Nagao, P.J.O'Connor, D.H.Phillips, M.Rajewsky, S.Tannenbaum, C.Vaca, E.Vogel, J.Laval, G.Winde and G.Wogan. I thank my ex-co-workers A.Barbin, A.-M.Camus, M.Castegnaro, C.Malaveille, M.Friesen, H.Ohshima, I.O'Neill and B.Pignatelli, as well as numerous PhD students and visiting scientists, for their enthusiasm and motivation when working with me between 1973 and 1993 at IARC, Lyon, France. Mrs Susanna Fuladdjusch is thanked for her skilled secretarial help and Mrs Elisabeth Heseltine for editing. The author's research in this area was supported in part by EU contracts ENV4-CT97-0505 and QL-RT-2000-00286.
Notes
1 Tel: +49 6221 423300; Fax: +49 6221 423359; Email: h.bartsch{at}dkfz.deDelivered on 4 September 2001 at the 31st EEMS Meeting, Ghent, Belgium. 
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Received on March 25, 2002; accepted on April 25, 2002.
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