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The temporal and regional cytotoxic and proliferative potential of whole smoke or the vapor phase of smoke from reference cigarettes was investigated. Male F344 rats were exposed nose-only 1 h/ day for up to 20 weekdays to 500 mg/ m 3 whole smoke, the vapor-phase equivalent of 500 mg/ m 3 whole smoke ( generated by electrostatic precipitation of particulates) , or filtered air. Histopathology ( 1, 2, 5, 10, or 20 exposures, 1 and 4 wk postexposure) and cell proliferation ( BrdU incorporation after 5 or 20 exposures and at 4 wk postexposure) were assessed in the nose and larynx. Blood nicotine, cotinine, and carboxyhemoglobin were monitored to substantiate exposure. Nicotine and cotinine levels were significantly elevated ( p £ .05) in whole-smoke-exposed rats relative to both filtered-air-and vapor-phase-exposed rats, while blood carboxyhemoglobin was comparably increased in both whole-smoke-and vapor-phase-exposed groups. Respiratory epithelial cell necrosis was observed in the anterior nose after only a single exposure to either whole smoke or its vapor phase. Hyperplasia subsequently developed after additional exposures to whole smoke or vapor phase, with squamous metaplasia occurring in whole-smoke-exposed animals. After 20 exposures, the cell proliferation index was increased in the nasal respiratory epithelium of rats exposed to either whole smoke or smoke vapor phase, with a greater response noted in wholesmoke-exposed rats. A minimal increase in the cell proliferation index, without significant histopathology, was noted in the olfactory epithelium. Necrosis of the laryngeal epithelium was an immediate response to whole-smoke exposure. This was eventually followed by squamous metaplasia. Hyperplasia, without initial cell necrosis, was seen in the larynges of smoke vapor-phase-exposed rats. Only minimal squamous metaplasia occurred in the larynges of the vapor-phase-exposed rats. Histopathologic and proliferative responses were markedly reduced in all respiratory-tract tissues at 1 and 4 wk postexposure. These data suggest that the morphologic changes commonly seen in the upper respiratory tract of whole-smoke-exposed rats are early adaptations related, in part, to components of the vapor phase of mainstream cigarette smoke.

Cancer and many other serious diseases are characterized by the uncontrolled growth of new blood vessels. Recently, RNA interference (RNAi) has reinvigorated the therapeutic prospects for inhibiting gene expression and promises many advantages over binding inhibitors, including high specificity, which is essential for targeted therapeutics. The modulation of angiogenesis pathways using small interfering RNA (siRNA) inhibitors of gene expression has proven to be a powerful approach which would be applied for treatment of multiple cancers. Using a nanoparticle-mediated systemic delivery of siRNA with a dual targeting specificity to both neovasculature and VEGF receptor 2 (KDR), we were able to achieve anti-tumor efficacies in multiple tumor models. We further tested this potential anticancer drug candidate, ICS-283, in combination with Genentech's Avastin, a mAb against VEGF A in colorectal tumor cell DLD-1 xenograft model. The combined regimen resulted stronger anticancer efficacy than either of the component alone with significant evidence of anti-angiogenesis activities. We will report the latest results of this novel approach, further discuss the underlined mechanism action of this mAb-siRNA combination for potent anti-angiogenesis therapy and its clinical implication for cancer treatment. The dual-targeted therapeutics and the combination of siRNAs targeting multiple pro-angiogenesis factors have further demonstrated the advantages of this novel therapeutic modality. As with any emerging technologies, many issues related to siRNA therapeutics must be addressed diligently before the success of this novel approach can be achieved in clinics.

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