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Nicotine per se is not a substantial cause of cancer. Any cancer-related risks during short-term nicotine therapy to aid smoking cessation are insignificant compared to the risks of smoking.

Carcinogenic nicotine-derived nitrosamines have been theorized to be formed in the body under certain conditions after administration of nicotine medications, and there is some evidence for this for N'-nitrosonornicotine (NNN). The level of this carcinogen is low, and further research is needed to determine whether this level could represent a health hazard during long-term nicotine therapy. Nicotine has been shown to inhibit apoptosis (cell death) and to enhance angiogenesis in cell and experimental animal test systems. These effects could in theory promote the spread of cancers. However this risk has not been documented in people.

Carcinogenicity studies carried out in mice, rats, and hamsters demonstrate that, under normal conditions, nicotine is not carcinogenic (US Department of Health and Human Services, 2001; Surgeon General's report 2010). One study does show a low, but significant, incidence of tumors in hamsters exposed to nicotine and maintained in 60% hyperoxia, and some others suggest a possible enhancing effect of nicotine on the activity of carcinogens (US Department of Health and Human Services, 2001; Schuller et al., 1995). Other tobacco smoke constituents, such as polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, aldehydes, acrolein, 1,3-butadiene, benzene and aromatic amines, are believed to be responsible for the induction of cancers associated with tobacco use (Hoffman & Hecht, 1990; Hecht, 1999). However, two metabolites of nicotine that are formed in humans, nornicotine and 4-methylamino-1-(3-pyridyl)-1-butanone can, under certain conditions, react with endogenous nitrosating agents producing the carcinogenic tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)  (Hecht  et al., 2000; Carmella  et al., 1997; Porubin et al., 2007).  While there is no evidence for endogenous production of NNK in NRT users, some NRT users do produce NNN, sometimes in amounts greater than delivered during smoking (Stepanov et al., 2009). Further research is necessary to determine whether endogenous formation of NNN in people undergoing long-term NRT would pose a significant carcinogenic risk.

Nicotine promotes metastasis in animals with implanted tumors, speculated to be a result of enhanced angiogenesis (Heeschen et al., 2001; Cooke, 2007). Nicotine has been demonstrated to affect cellular signal transduction in several critical pathways that involve inhibition of apoptosis and stimulation of cellular proliferation (West et al., 2003; Dasgupta et al., 2006). These studies concerning inhibition of apoptosis, stimulation of angiogenesis and cellular proliferation by nicotine have been done in animals. Relevant human data are not available. The generally negative results in animal carcinogenicity tests lead to the conclusion that nicotine itself is not a significant direct, cause of cancer in people who use tobacco products, although nicotine could possibly promote cancer once initiated. Short term nicotine use for tobacco cessation is undoubtedly much safer than persistent tobacco use.

US Department of Health and Human Services. Survey of compounds which have been tested for carcinogenic activity. Bethesda, MD: US Department of Health and Human Services, National Institute of Health, National Cancer Institute, 2001.

Centers for Disease Control and Prevention (US), National Center for Chronic Disease Prevention and Health Promotion (US), Office on Smoking and Health (US). How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2010.

Schuller HM, McGavin MD, Orloff M, Riechert A, Porter B. Simultaneous exposure to nicotine and hyperoxia causes tumors in hamsters. Lab Invest. 1995; 73: 448-456.

Hoffmann D, Hecht SS. Advances in tobacco carcinogenesis. In Handbook of Experimental Pharmacology, 1990; pp.63-102. Edited by CS Cooper and PL Grover. Heidelberg: Springer-Verlag.

Hecht SS
. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999; 91: 1194-1210.

Hecht SS, Hochlater JB, Villalta PW, Murphy SE. 2'-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: formation of a lung carcinogen precursor. Proc Natl Acad Sci USA. 2000; 97: 12493-12497.

Carmella S, Borukhova A, Desai D, Hecht SS. Evidence for endogenous formation of tobacco-specific nitrosamines in rats treated with tobacco alkaloids and sodium nitrite. Carcinogenesis. 1997; 18: 587-592.

Porubin D, Hecht SS, Li Z, Gonta M, Stepanov I. Endogenous formation of N’-nitrosonornicotine in F344 rats in the presence of some antioxidants and grape seed extract. J Agric Food Chem. 2007; 55: 7199-7204.

Stepanov I, Carmella SG, Han S, Pinto A, Strasser AA, Lerman C, Hecht SS. Evidence for endogenous formation of N'-nitrosonornicotine in some long-term nicotine patch users. Nicotine Tob Res. 2009; 11(1): 99-105.

Stepanov I, Carmella SG, Briggs A, Hertsgaard L, Lindgren B, Hatsukami D, Hecht SS
. Presence of the carcinogen N'-nitrosonornicotine in the urine of some users of oral nicotine replacement therapy products. Cancer Res. 2009; 69(21): 8236-8240.

Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, Tsao PS, Johnson FL, Cooke JP. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 2001; 7: 833-839.

Cooke JP. Angiogenesis and the role of the endothelial nicotinic acetylcholine receptor. Life Sci. 2007; 80: 2347-2351.

West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris C, Belinsky S, Dennis PA. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest. 2003; 111: 81-90.

Dasgupta P, Kinkade R, Joshi B, Decook C, Haura E, Chellappan S. Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc Natl Acad Sci USA. 2006; 103: 6332-6337. logo