5-Iododeoxyuridine increases the efficacy of the radioimmunotherapy of human tumors growing in nude mice.
Recently, there has been much interest in the use of radionuclide conjugated monoclonal antibodies for the treatment of human malignancies. One way to potentially maximize the therapeutic effectiveness of radioimmunotherapy would be to sensitize tumor cells to the radiation dose delivered by the antibody. Since radioimmunotherapy can potentially treat disseminated disease, including micrometastasis, we chose to study a halogenated pyrimidine radiosensitizer, a class of compounds that affect nonhypoxic cells. 5-Iododeoxyuridine, administered with pyrimidine metabolism modulators, increased the therapeutic effectiveness of radioimmunotherapy, resulting in individual cures of human tumors growing in BALB/c nu/nu (nude) mice. 5-Iododeoxyuridine was administered with N-(phosphonacetyl)-L-aspartic acid and 5-fluoro-deoxycytidine plus tetrahydrouridine. This drug treatment was combined with radioimmunotherapy using 131I conjugated to a monoclonal antibody, Mc5. Mc5 binds to a mucin component of the human milk fat globule. This antigen is expressed on the surface of MX-1 cells, the transplantable human tumor used in this study. Tumor-bearing mice treated with both the drug protocol and 131I-Mc5 (540 microCi, 10 microCi/micrograms) showed a regression in average tumor volume. The average tumor volume was reduced below the initial size at treatment for 50 days; two of five cures were obtained. Neither cures nor regressions were observed with either the drug or antibody treatments alone. Our results indicate the potential for increasing the therapeutic effectiveness of radioimmunotherapy of human solid tumors with halogenated pyrimidines.
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John Muir Cancer & Aging Research Institute, Walnut Creek, California.
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D000818:Animals; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000532:radiotherapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D007065:Idoxuridine / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000379:methods*; D013767:Tetrahydrouridine / Q000008:administration & dosage / Q000627:therapeutic use; D014183:Transplantation, Heterologous
D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D013767:Tetrahydrouridine; D001224:Aspartic Acid; C013195:sparfosic acid; C007746:5-fluoro-2'-deoxycytidine; D007065:Idoxuridine; D010746:Phosphonoacetic Acid