Purpose: The efficacy of solid tumor radioimmunotherapy is reduced by heterogeneous tumor distribution of the radionuclide, with dose mainly deposited in the normoxic region and by the relative radioresistance of hypoxic tumor cells. In an attempt to overcome these challenges, radioimmunotherapy was combined with 2-deoxy-D-glucose (2DG), a hypoxia-selective cytotoxic inhibitor of glucose metabolism. Experimental Design: In vitro toxicity of 2DG in LS174T cultures was tested using a colonyforming assay. The effect of combining 2DG with radioimmunotherapy in vivo was tested by administering radiolabeled anti^carcinoembryonic antigen antibody ([ 131 I]A5B7 IgG1 whole monoclonal) to nude mice bearing s.c. LS174T tumors, followed by 10 daily injections of 2DG (2.0 g/kg). Tumors were measured to assess therapeutic efficacy. Results: Data from in vitro studies confirmed 2DG cytotoxicity in this cell line. Greater toxicity was observed under standard laboratory conditions and in hypoxic cultures than at intermediate, physiologically relevant levels of glucose and oxygen. Alone, 2DG had no effect on in vivo tumor growth (P = 0.377 compared with saline-treated controls). Combination of radioimmunotherapy with 2DG reduced the therapeutic effect of radioimmunotherapy (e.g., 150 ACi 131 I alone mean survival time, 48.33 F 16.83 days; combined with 2DG, 30.67 F 5.62 days, P = 0.038). Conclusions: The combination investigated had a detrimental effect on survival. It is suggested that a cellular metabolic response to more aggressive therapy, previously reported in vitro, caused this. The results of this study have implications for the clinical application of combined cancer therapies with an antimetabolic modality component.Radioimmunotherapy is a cancer treatment that uses a tumorspecific antibody to deliver a cytotoxic radionuclide. Delivered systemically, this therapy can access and treat tumor sites throughout the body, which might evade other therapies, such as surgery or locoregional external beam radiotherapy. Radioimmunotherapy has shown efficacy in model systems (1), lymphomas (2), and some common carcinomas (3), but has yet to achieve its clinical potential in solid tumors in which its effect has been suboptimal (4, 5).Despite advances in antibody formats and radionuclide availability, use, and selection, radioimmunotherapy of common epithelial tumors is yet to achieve the success seen in the treatment of hematologic malignancies. Reasons for this include difficulty in delivering sufficient radiation dose to kill the tumor. Common epithelial tumors often have an abnormal vascular system leading to poor delivery of systemically delivered therapeutic molecules. Moreover, once the radionuclide has been delivered, its effect is hindered by heterogeneous resistance of tumor cells to therapy. Addressing these mechanisms of therapeutic resistance is critical to successful treatment in the clinic.Oxygen is a potent radiosensitizer. Hypoxic cells require up to a 3-fold higher radiation dose than their aerobic cou...