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These studies demonstrate the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using ²¹²Pb-labeled Herceptin as an in vivo generator of ²¹²Bi. In vitro studies compare the potential of the bismuth radioisotopes, ²¹³Bi and ²¹²Bi, to that of ²¹²Pb. Overall, ²¹²Pb results in a higher therapeutic index than either bismuth radioisotope, requiring lower radioactivity (µCi) for effective cytotoxic response. A pilot radioimmunotherapy (RIT) experiment treating mice bearing 5 d LS-174T intraperitoneally (i.p.) xenografts determined a maximum tolerated dose (MTD) of 20–40 µCi with i.p. administration. A specific dose response was observed and 10 µCi was selected as the effective operating dose for future experiments. Median survival of tumor-bearing mice receiving 10 µCi increased from 19 to 56 days (p = 0.008). The efficacy of ²¹²Pb-Herceptin was also assessed in a human pancreatic carcinoma xenograft (Shaw; i.p.) animal model previously reported as unresponsive to 213Bi-Herceptin (p = 0.002). Multiple dosing of ²¹²Pb-Herceptin was evaluated in both animal models. The median survival of mice bearing 3 d LS-174T i.p. xenografts increased to 110 days, with up to 3 doses of ²¹²Pb-Herceptin given at approximately monthly intervals; however, there was no evidence of a correlation with the second and third doses (p = 0.98). No improvement in median survival was noted with a similar regimen in the Shaw xenograft model.