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Radioimmunotherapy of Human Colon Carcinomatosis Xenograft with ⁹⁰Y-ZCE025 Monoclonal Antibody: Toxicity and Tumor Phenotype Studies¹

Divisions of Pathology and General Oncologic Surgery, City of Hope National Medical Center, Duarte, California 91010, and Hybritech, Inc., San Diego, California 92126

Monoclonal antibody ZCE025 recognizes an epitope of the carcinoembryonic molecule (CEA). We have shown that when linked to ⁹⁰Y, its localization in the tumor was sufficient to result in a significant tumoricidal effect in human colon carcinomatosis grown in the peritoneum of athymic mice. Intraperitoneal tumors were present 7 days after inoculation of the CEA-producing human colon carcinoma cell line LSI74T, when the mice received i.p. injections with 40 to 160 µCi of ⁹⁰Y-labeled ZCE025 or 96.5c (nonspecific monoclonal antibody). The animals that were autopsied 12 days after treatment displayed a significant (P < 0.001) inhibition of tumor growth when compared to the control animals that received no treatment or similar doses of nonspecific monoclonal antibody. Microscopically, the treated tumors showed extensive radiation effect and they became progressively necrotic until only a rim of viable tissue remained in the periphery of the nodules. CEA expression was practically absent on the newly grown nodules that began to appear 3 weeks after therapy, and remained so 6 weeks thereafter. In contrast, over 80% of the tumor cells from the untreated animals expressed CEA. There was no mortality due to treatment; however, the hematopoietic organs were markedly depleted at the higher doses. The marrow and the spleen recovery began 2 weeks after treatment, and it was completed by the 4th week. No evidence of toxicity was present in any of the other organs examined. These studies suggest that ⁹⁰Y-ZCE025 therapy results in clonal selection of cells lacking or minimally expressing CEA. The inherent implications of these findings are discussed.