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Polyethylene glycol (PEG) has been reported to inhibit the development of colonic lesions in carcinogen-treated rats when administered orally. However, the precise mechanism for the chemopreventive activity of PEG remains largely elusive. Based on a characteristic feature of PEG as a ‘fusogen’, we investigated its potential as a chemotherapeutic agent through the induction of multinucleated cell formation and apoptosis induction in PC-3 prostate cancer cells. When PC-3 cells were treated with 0.5 and 1.0% PEG 1000, multinucleated cells were induced at a frequency of 8.4 and 13%, respectively, 36 h after PEG treatment under high cell density (1 × 106 cells in 100 µL PEG solution) in vitro. Although abnormality of cell cycle progression was not evident in PEG-treated PC-3 cells, multinucleated cells substantially disappeared at around 38 h due to apoptosis. In contrast, no apparent growth suppression was observed when PC-3 cells were exposed to up to 1.0% PEG at a much lower cell density, namely under ordinary culture conditions. Furthermore, injection of 0.5% PEG solution in vivo into PC-3 xenografts implanted in BALB/c-nu/nu male mice significantly suppressed tumor growth compared to phosphate-buffered saline injection. Multinucleated TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells were observed inside the PEG-injected tumors. PEG was here demonstrated to have anticell proliferation and antitumor effects via induction of apoptosis, possibly by cell fusion. PEG injection therapy could therefore be adopted as an alternative chemotherapeutic strategy for localized prostate cancers, including those that become refractory to androgen-deprivation therapy. (Cancer Sci 2008; 99: 1055–1062)