Based on current evidence, the majority of cancers have aberrant hypermethylation in the promoters of TSGs, although the whole genome may appear to be hypomethylated. Our study was limited to 24 promoters, and the results could only identify methylation changes in a small number of the potential targets relevant to lung cancer. Ongoing efforts in our laboratory are focused on whole genome methylation screening using additional animal models to look at spontaneously occurring lung tumors as well as inhaled carcinogen-induced lung cancer. These studies are expected to yield much more Sorafenib valuable information on the biology of lung carcinogenesis, which should guide the development of improved therapeutic strategies. Reed et al. have recently reported a similar study using aerosol Aza for the treatment of an orthotopic lung cancer model in nude rats. They concluded that their aerosol and systemic deliveries are equally effective in terms of antitumor efficacy as well as gene demethylation. Although the methodologies, tumor models, and endpoints used in Reed study and our study are significantly different, the fact that both studies lead to some similar conclusions using aerosol Aza represents strong proof of concept of the potential of aerosol demethylation therapy as a novel strategy for the management of lung cancer and bronchial premalignancy. In our study, we found that the effective dose was much lower than the optimal IV dose, indicating that targeted aerosol delivery of the minimal effective dose rather than the maximum tolerated dose of an epigenetic agent is a potentially effective therapeutic strategy. In addition, our aerosol formulation showed a very good aerodynamic size range that makes it suitable for use in humans. We have recently completed preclinical toxicity studies of aerosol Vidaza in mice and FDA approved us to initiate a Phase I clinical study with aerosol Vidaza in patients with advanced lung cancer with disease mostly confined to the lung parenchyma that are not candidates for therapies of a higher priority. In this study, in addition to determining the toxicity profile of aerosol Vidaza, we will investigate by sequential bronchoscopy whether aerosol Vidaza can lead to TSG reexpression in the bronchial epithelium and or/tumor tissue. We expect that the results of this study will determine whether inhaled demethylation therapy should be further developed both as an early intervention or even prevention strategy. If that is the case, significant effort will have to be devoted to explore the use of other candidate agents as Aza is potentially carcinogenic and therefore not an ideal candidate as a preventive agent. It has been hypothesized in the literature that exposure to extremely low frequency electromagnetic fields may lead to human health effects such as childhood leukemia or brain tumors. However, this hypothesis was derived from epidemiological studies which per se do not implicate causal relationships. The latter can only be addressed with experiments carried out under carefully controlled conditions. Among the experiments on rats and mice listed in the ‘BioInitiative Report’
, the following results related to brain cells seem to be of particular importance: Lai and Singh ; found nuclear DNA singlestrand breaks and double-strand breaks from 0.01 mT magnetic field exposure onwards in a dosedependent manner in rats. It is of note that these effects could be blocked by pretreating rats with a vitamin E analog, a nitric oxide synthase inhibitor, or an iron chelator. From these data, the authors concluded that MF exposure might lead to increased generation of free radicals via the so-called Fenton reaction within mitochondria which, thereafter, cause nuclear DNA damage.