UICC World Cancer Congress 2006

Although tobacco and environmental tobacco smoke are recognized to contain numerous carcinogens the role of these substances is unexplored in patients already diagnosed with cancer [e.g., determining the potential effects of benzo[a]pyrene and its up-regulatory effects on CYP1A1 or its ability to mutate p53 ]. Nicotine is safe when used in nicotine replacement products for tobacco cessation. However, the in vivo effects of long-term nicotine exposure could affect persistent cellular proliferation, inhibition of apoptosis, and stimulation of vascular endothelial growth factor, which can result in increased microvessel density within the tumor. In 1994, nicotine was found to reverse opioid-induced growth inhibition in lung cancer cells by activating protein kinase C through receptors on the cancer cells. Since then, nicotine has been found to have multiple effects on several proteins within the intracellular signal transduction pathways in vitro. For example, in lung cancer cells, nicotine activates the mitogen-activated protein kinase pathway, resulting in inhibition of apoptosis. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone have been shown to activate the Akt pathway in human airway epithelial cells, resulting in induction of downstream substrates that promote cell cycle progression and inhibition of apoptosis. Much effort has been made to identify the responsible nicotinic acetylcholine receptors and to date, these have been found to be that both a7 (nicotine) and a3 (4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone) subunits were involved.

Various research groups are currently studying nicotinic acetylcholine receptors and their functions. Such functions could include intracellular communication downstream from the epidermal growth factor receptor, thus modifying the effect of oncologic drugs. In a mouse lung cancer model, nicotine increased vascular endothelial growth factor levels, resulting in increased microvessel density and increased tumor growth, compared with levels in animals not exposed to nicotine. Nicotine also has been shown to induce extracellular signal-regulated protein kinase with resultant activation of cyclooxygenase-2 and increased vascular endothelial growth factor expression. Trials of cyclooxygenase- 2 inhibitors should investigate the influence of smoking on treatment efficacy. A recent laboratory study showed that exposure to tobacco smoke resulted in an increase in cyclooxygenase-2 expression due to stimulation of epidermal growth factor receptor. With the plethora of potential effects that nicotine alone could exert on cancer cells and the number of times per day that nicotine or known carcinogens are inhaled, it is critical that these effects be assessed, as such differences between smokers and nonsmokers may confound trial results.