BACKGROUND RS7 is a murine monoclonal antibody immunoglobulin G1 with pan-carcinoma reactivity, which was raised against human squamous cell carcinoma of the lung. To optimize the use of monoclonal antibody RS7 as a carrier of radionuclides for tumor targeting and therapeutic applications, whole RS7 immunoglobulin G and its F(ab')2 fragment were radiolabeled, and their biodistribution and effectiveness as radioimmunotherapeutic agents in nude mice bearing established human tumor xenografts were evaluated. The contributions of the tumor model, monoclonal antibody form (fragment vs. intact), radioisotope (131I, 111In, 90Y, and 188Re), and antigen target were evaluated. METHODS Cumulative absorbed radiation doses were calculated from biodistribution data, and doses were normalized to blood to estimate expected relative toxicities. Two tumor models expressing different levels of RS7-antigen were studied: ME180, a cervical carcinoma cell line, and Calu-3, an adenocarcinoma of the lung cell line. In addition, the therapeutic effectiveness of 131I-RS7-F(ab')2 was compared to that of 131I-RS7-IgG. CONCLUSIONS Doses delivered to tumor (normalized to blood) calculated for 131I-RS7-F(ab')2 and 90Y-RS7-IgG were 4.7 times and 1.8 times greater, respectively, than 131I-RS7-IgG, and therefore would be expected to yield greater therapeutic efficacy when equitoxic doses are administered. This expectation was confirmed in the radioimmunotherapy study with 131I-RS7-F(ab')2. At equivalent absorbed dose to tumor, 131I-RS7-F(ab')2 was found to effect a slightly longer suppression of tumor growth than the intact 131I-RS7 IgG, and a 50% dose escalation yielded tumor regression for a prolonged period with the fragment, whereas a similar 50% dose escalation with 131I-RS7-IgG could not be tolerated.