The moderately differentiated human colon tumor cell line, HT-29, constitutively expresses low levels of the high molecular weight mucin, tumor-associated glycoprotein 72 (TAG-72), and the M(r) 180,000 carcinoembryonic antigen (CEA) when grown as s.c. tumors in athymic mice. We report that the in vivo administration of gamma-interferon (IFN-gamma) resulted in a time- and dose-dependent increase in both TAG-72 and CEA expression in the HT-29 tumors. Immunohistochemical staining revealed a more homogeneous TAG-72-positive tumor cell population after IFN-gamma. Furthermore, both anti-TAG-72 and anti-CEA monoclonal antibodies (MAbs) showed enhanced localization to the HT-29 tumors in mice treated with IFN-gamma. Using that experimental model, subsequent studies presented evidence showing that the combination of IFN-gamma with 131I-CC49, an anti-TAG-72 MAb, resulted in a statistically significant improvement in therapeutic efficacy when compared with 131I-CC49 alone. For example, treatment with 300 microCi of 131I-CC49 initially suppressed HT-29 tumor growth; however, that reduction in tumor growth was transient as evidenced by the emergence of additional tumor growth at later time points. In contrast, an 8-day treatment with IFN-gamma in combination with 300 microCi 131I-CC49 resulted in sustained suppression of HT-29 tumor growth. Thus, IFN-gamma in vivo can substantially increase the TAG-72 expression in human colon tumor xenografts which leads to an increased tumor localization of anti-TAG-72 MAbs and seems to be responsible for the enhanced antitumor effects when IFN-gamma was combined with 131I-CC49. The results provide further evidence for including a biological response modifier, such as IFN-gamma, which can increase the expression of specific tumor antigens (i.e., TAG-72 and CEA) subsequently leading to a dramatic improvement in the antitumor efficacy of a radionuclide-conjugated MAb.