Carcinogenesis Advance Access originally published online on January 21, 2008
Carcinogenesis 2008 29(5):887-888; doi:10.1093/carcin/bgm272
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Dr Jagadeesan Nair, Senior Scientist at the German Cancer Research Center (DKFZ) 1953–2007
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 290, Heidelberg, Germany
To whom correspondence should be addressed. Email: h.bartsch{at}dkfz.de
Jagadeesan Nair died unexpectedly and prematurely on 28 August 2007 in Mumbai, India, as the consequence of a heart attack while returning from home leave to his research institute in Heidelberg, Germany. He was an internationally recognized pioneer in the field of cancer biomarkers and tobacco carcinogenesis. As he had always wondered why progress toward a cure of cancer had been slow, despite impressive international efforts, he set his hope on preventive measures, the efficacy of which could be assessed at an early stage by the application of the ultrasensitive, specific biomarkers that he had developed. We will miss him as a person of great kindness, modesty and integrity.
Jagadeesan Nair, born in 1953 in Pallipuram (Kerala), India, received his MSc (gold medalist) in 1975 and his PhD degree in chemistry in 1981 at Ravishankar University, Raipur, India. He started his research and professional experience in 1980 as a scientific officer in the Carcinogenesis Division of the Cancer Research Institute, Tata Memorial Centre, Parel, Mumbai, India, under the guidance of the late Dr S.V.Bhide. In 1983, he received a prestigious research fellowship from the International Agency for Research on Cancer (IARC), Lyon, France, which allowed him to spend 2 years in the laboratories of that institute. It was there that I met Jagadeesan Nair for the first time. He was surprised that his future boss, a Unit Chief at IARC, personally picked him up at the Lyon airport. And, as it was December, he confessed that he had never seen snow before. This encounter was the beginning of a long-lasting friendship and collaboration in various projects on chemical carcinogenesis, molecular epidemiology and biomarker application. Although he returned to the Cancer Research Institute in Mumbai in 1985, he rejoined IARC in Lyon in 1992.
During this period, Jagadeesan Nair, with his colleague Hiroshi Ohshima and his wife Urmila Nair, published several seminal laboratory studies on the mechanisms whereby smokeless tobacco induces oral cancer. He found that unusually high levels of carcinogenic tobacco-specific nitrosamines occurred in snuff used in Sudan and were found in the saliva of users of the snuff (1,2). For this work, Jagadeesan Nair received the R.J.Jaju Award from the Indian Association of Cancer Research. Using the test for N-nitrosoproline [developed in our IARC laboratory by Ohshima et al. (3)], he showed that endogenous nitrosamine formation occurred in the saliva of users of betel quid with or without tobacco (4). A third finding was that reactive oxygen species are generated by betel quid ingredients, forming 8-hydroxydeoxyguanine in DNA in vitro (5); he also found hydroxylation of phenylalanine, used as a probe drug, in the saliva of quid chewers (6). Lastly, he identified two synthetic nitroarenes, musk ambrette and musk xylene as mutagens in Indian chewing tobacco (7); these were later shown to be carcinogens in rodents although the packaging of the tobacco products did not state that they contained these genotoxic flavoring agents.
In 1993, after I had accepted a professorship (Chair in Toxicology) at Heidelberg University joined with a position at the DKFZ as Division Head, Jagadeesan Nair decided in 1994 to follow me from Lyon to Heidelberg (the ZIP code for both is 69!) and later became a permanent staff member and team leader in our Division. On the basis of earlier work started by Alain Barbin, Yves Guichard and Fatia El Ghisassi at IARC to quantify etheno-DNA adducts (formed by the human carcinogen vinyl chloride), with essential contributions by Jagadeesan Nair, he developed and validated an ultrasensitive, specific method for detecting exocyclic DNA damage in man. This immunoaffinity/32P-postlabelling method, which is applicable for human biomonitoring by analyzing etheno base adducts in tissue and white blood cell DNA, had a detection limit of approximatelyfive adducts per 1010 parent nucleotides. Monoclonal antibodies against etheno-dA and etheno-dC were jointly developed with Manfred Rajewsky et al. at the University of Essen.
From that time, Jagadeesan Nair’s work focused mainly on gathering evidence that the promutagenic etheno-DNA adduct, when formed by persistent oxidative stress and lipid peroxidation, can drive cells to malignancy. By applying this method systematically to various tissues and white blood cells from asymptomatic humans and untreated rodents, he obtained unequivocal evidence that background levels of etheno adducts exist, probably resulting from physiological processes (8).
Subsequently, in many mechanistic and clinical studies (which would have not been possible without many contributions and collaborative efforts, see names in Acknowledgements), several inherited and acquired human cancer risk factors were shown to increase the level of promutagenic etheno adducts in target organs in which tumors later develop as a consequence of increased oxidative stress and lipid peroxidation. The factors include metal storage diseases, overproduction of nitric oxides (as a consequence of chronic infections and inflammatory processes), chronic inflammatory bowel disease, pancreatitis, persistent hepatitis B virus infection, atherosclerosis, high intake of 
-6 polyunsaturated fatty acids and alcohol abuse (9). While quantification of etheno-DNA adducts in tissue homogenates was an initial breakthrough, Jagadeesan Nair refined the adduct detection assay and developed a semiquantitative immunohistochemical method for etheno-dA that allows scoring of stained nuclei in human tissue slices (10). To facilitate molecular epidemiological studies, a non-invasive urinalysis procedure for excreted etheno-dA was also set up and successfully applied in human dietary intervention and etiology studies (11).
Dr Nair reported the occurrence of lipid peroxidation-induced miscoding etheno-DNA adducts in mitochondrial DNA for the first time and demonstrated their link to apoptosis (12). He also found significantly elevated levels of etheno-DNA adducts in organs affected by cancer-prone inflammatory diseases such as ulcerative colitis, Crohn’s disease and chronic pancreatitis (13). A new sensitive method for determining etheno-dC in human urine was developed on the basis of his original idea of using a specific deoxynucleoside kinase (cloned from Drosophila) for 32P-labeling deoxynucleosides (14). Dr Nair and his team then investigated the synergistic effect of estradiol metabolism on the formation of etheno-DNA adducts in breast epithelial cells and lymphocytes of women. He determined that the pathway leading to DNA damage involves 4-hydroxyestradiol, a catechol estrogen involved in breast carcinogenesis through induction of redox cycling (the last work presented by him at the AACR annual meeting in Los Angeles).
Dr Nair et al. published close to 90 articles in scientific journals and books (and many manuscripts are still to be written) covering important areas such as the development and application of biomarkers for quantification of exposure to carcinogens, for risk prediction and for measuring the efficacy of preventive measures. His last contribution, together with his wife Urmila, was a review of published literature on the above topics (15). Not surprisingly, Jagadeesan Nair was consistently oriented toward public health and cared about equity in human health. He was an invited member of two working groups for the preparation of IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 85, on betel quid and areca nut chewing and some areca nut-derived nitrosamines (2004) and, Volume 89, on smokeless tobacco and some related nitrosamines (see commentary in Lancet Oncology, December 2004).
On the occasion of my 65th anniversary (and official retirement), Dr Nair organized an international conference ‘Chronic Oxidative Stress and Cancer: Mechanisms, Biomarkers and Prevention’, which was held at the DKFZ on 23–26 October 2005. Selected articles from the 35 invited conference participants were published as highlights in the form of minireviews in the journal Biological Chemistry (April issue, 2006), with Dr Nair as guest editor. In 2007, Jagadeesan Nair acted as the local co-organizer of an Indo-German workshop held in Heidelberg from 12 to 14 July 2007, where the photograph shown was taken, on 13 July 2007, shortly before he left for home leave to Mumbai.
Jagadeesan Nair was a member of a European Union Scientific Committee on Emerging and Newly Identified Health Risks, from which a report on ‘Health effects of smokeless tobacco products’ has just been published. He was also a highly esteemed partner in several past and current EU-supported research projects. The last included ECNIS (Network of Excellence) and NewGeneris (European Integrated Project), but, sadly, he could not complete his contributions.
His many visiting postdoctoral fellows and the many diploma and doctoral students he supervised over the years will remember him as a person of the highest integrity, who rarely lost his good sense of humor. As one of them said, he was a person who had the capacity to make you feel good! So, not surprisingly, Jagadeesan Nair had many friends and admirers in all parts of the world, who will miss him greatly. We all extend our sympathy and condolences to his wife Urmila and his son Rahul.
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Acknowledgments |
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We gratefully acknowledge the contributions and collaborative efforts of a great number of colleagues (list not exhaustive), without whom the above work could not have been accomplished: X.Sun, A.Frank, N.Frank, Y.Yang, Q.Fang, T.Hagenlocher, K.Schmidt, K.-H.Adzersen and the late C.Ditrich (DKFZ, Heidelberg); A.Barbin, Y.Guichard (Lyon, France); D.H.Phillips, P.L.Carmichael (Sutton, UK); C.E.Vaca, M.Mutanen (Stockholm, Sweden); M.Nagao, T.Hanaoka, S.Tsugane (Tokyo, Japan); G.Fürstenberger (DKFZ, Heidelberg); S.Tannenbaum, G.Wogan (Cambridge, Massachusetts, USA); C.C.Harris, S.P.Hussain (Bethesda, MD, USA), M.Saparbaev, J.Laval (Villejuif, France), B.Tudek (Warsaw, Poland); G.Winde (Herford, Germany); S.de Flora, A.Izzotti (Genoa, Italy); P.Srivatanakul, M.Meerang, S.Fucharoen (Bangkok, Thailand); F.Gansauge, H.Beger (Ulm, Germany); P.Dolora (Florence, Italy); R.W.Godschalk, F.van Schooten (Maastricht, Netherlands); H.K.Seitz (Heidelberg, Germany) and S.Dechakhamphu, P.Yongvanit (Khon Kaen, Thailand). S.Fuladdjusch is thanked for excellent secretarial help.
Conflict of Interest Statement: None declared.
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 Top References |
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- Idris AM, et al. Unusually high levels of carcinogenic tobacco-specific nitrosamines in Sudan snuff (toombak). Carcinogenesis (1991) 12:1115–1118.
[Abstract/Free Full Text] - Idris AM, et al. Carcinogenic tobacco-specific nitrosamines are present at unusually high levels in the saliva of oral snuff users in Sudan. Carcinogenesis (1992) 13:1001–1005.
[Abstract/Free Full Text] - Ohshima H, et al. Quantitative estimation of endogenous nitrosation in humans by monitoring N-nitrosoproline excreted in the urine. Cancer Res. (1981) 41:3658–3662.
[Abstract/Free Full Text] - Nair J, et al. Tobacco-specific and betel-nut-specific N-nitroso compounds: occurrence in saliva and urine of betel quid chewers and formation in vitro by nitrosation of betel quid. Carcinogenesis (1985) 6:295–303.
[Abstract/Free Full Text] - Nair U, et al. Formation of reactive oxygen species and of 8-hydroxydeoxyguanosine in DNA in vitro with betel quid ingredients. Chem. Biol. Interact. (1987) 63:157–169.[CrossRef][Web of Science][Medline]
- Nair UJ, et al. Ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxy radical generation during betel quid chewing. Carcinogenesis (1995) 16:1195–1198.
[Abstract/Free Full Text] - Nair J, et al. Identification, occurrence and mutagenicity in S. typhimurium of two synthetic nitroarenes—musk ambrette and musk xylene—in Indian chewing tobacco and betel quid. Food Chem. Toxicol. (1986) 24:27–31.[CrossRef][Web of Science][Medline]
- Nair J, et al. 1,N6-Ethenodeoxyadenosine and 3,N4-ethenodeoxycytine in liver DNA from humans and untreated rodents detected by immunoaffinity/32P-postlabeling. Carcinogenesis (1995) 16:613–617.
[Abstract/Free Full Text] - Bartsch H, et al. Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair. Langenbecks Arch. Surg. (2006) 391:499–510.[CrossRef][Web of Science][Medline]
- Frank A, et al. Immunohistochemical detection of 1,N6-ethenodeoxadenosine in nuclei of human liver affected by diseases predisposing to hepato-carcinogenesis. Carcinogenesis (2004) 25:1027–1031.
[Abstract/Free Full Text] - Hanaoka T, et al. Urinary level of 1,N6-ethenodeoxyadenosine, a marker of oxidative stress, is associated with salt excretion and 6-polyunsaturated fatty acid intake in postmenopausal Japanese women. Int. J. Cancer (2002) 100:71–75.[Web of Science][Medline]
- Nair J, et al. Apoptosis and age-dependant induction of nuclear and mitochondrial etheno-DNA adducts in Long-Evans Cinnamon (LEC) rats: enhanced DNA damage by dietary curcumin upon copper accumulation. Carcinogenesis (2005) 26:1307–1315.
[Abstract/Free Full Text] - Nair J, et al. Increased etheno DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis and chronic pancreatitis. Antioxid. Redox Signal. (2006) 8:1003–1010.[CrossRef][Web of Science][Medline]
- Sun X, et al. A new ultrasensitive 32P-postlabeling method for the analysis of 3,N4-etheno-2‘-deoxycytidine in human urine. Biomarkers (2006) 11:329–340.[CrossRef][Web of Science][Medline]
- Nair U, et al. Lipid peroxidation-induced DNA damage in cancer-prone inflammatory diseases: a review of published adduct types and levels in humans. Free Radic. Biol. Med. (2007) 43:1109–1120.[CrossRef][Web of Science][Medline]
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