Recent clinical results suggest that higher anti-tumor efficacy may be achieved with internalizing monoclonal antibodies (MAbs) at lower toxicity when labeled with Auger-electron, as compared to conventional beta-emitters. The aim of our study was to compare the toxicity and anti-tumor efficacy of the 125I-labeled internalizing MAb, CO17-1A, with its 131I-labeled form in a human colon cancer model in nude mice. Biodistribution studies were performed in nude mice bearing s.c. human colon cancer xenografts. For therapy, the mice were injected either with unlabeled 125I- or 131I-labeled C017-1A at equitoxic doses. Control groups were left untreated, were given a radiolabeled isotype-matched irrelevant antibody or a tumor-specific, but noninternalizing antibody. The maximum tolerated activities (MTD) of 131I-and 125I-CO17-1A without artificial support were 300 microCi and 3 mCi, respectively. Myelotoxicity was dose-limiting; bone marrow transplantation allowed for an increase of the MTD to 400 microCi of 131I-17-1A, whereas the MTD of 125I-17-1A with bone marrow support had not been reached at 5 mCi. Whereas no significant therapeutic effects were seen with unlabeled C017-1A, tumor growth was retarded with 131I-CO17-1A. With the 125I-label, however, therapeutic results were clearly superior. In contrast, no significant difference was observed in the therapeutic efficacy of the 131I- vs. 125I-labeled, noninternalizing antibodies. Our data indicate a superiority of Auger-electron emitters, such as 125I, as compared to therapy with conventional beta-emitters with internalizing antibodies. The lower toxicity of Auger emitters may be due to the short path length of their low-energy electrons, which can reach the nuclear DNA only if the antibody is internalized (as is the case in antigen-expressing tumor tissue, but not in the stem cells of the red marrow).