A major limitation of radiolabeled monoclonal antibodies (MAbs) for cancer imaging and therapy is their low accumulation within solid tumors. We, and others, have previously shown that pretreatment of a tumor mass with gamma radiation can increase the level of radiolabeled MAb at the tumor site. Unlike that of conventional radiation, the dose distribution of protons allows for increasing the dose to the cancer volume while reducing the normal tissue dose. The Proton Radiation Therapy Facility at LLUMC treats patients and conducts research. In this study, we sought to determine if preirradiation with proton beam can enhance the localization of radiolabeled MAb within xenotransplanted human colon tumors. T380 colon tumors, implanted s.c. into athymic mice, were subjected to proton irradiation (10 Gy, single dose) when mean tumor volume was 125-135 mm3/group. 111In-ZCE025, a murine MAb directed against carcinoembryonic antigen, was injected i.p. 2 h later, and biodistribution studies were performed 38 h thereafter. Animals irradiated with 60Co and given either 111In-ZCE025 or 111In-MOPC21, an irrelevant MAb, served as controls. The mean percentage of injected radioactivity localized within tumors was highest in the group treated with protons + 111In-ZCE025 when expressed on a per gram basis (%ID/g = 19.3). Somewhat unexpectedly, higher radioactivity was also noted in the normal tissues of these animals compared to other groups. The mean %ID/g tumor values for those given 60Co + 111In-ZCE025 or the antibody alone were 12.5 and 9.0. Our data show that preirradiation of solid tumors increases the localization of tumor-specific radiolabeled MAb at the tumor site.(ABSTRACT TRUNCATED AT 250 WORDS)