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Optimizing the Sequence of Combination Therapy with Radiolabeled Antibodies and Fractionated External Beam

Department of Medical Physics and Nuclear Medicine, Department of Radiology, and The Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York

The purpose of this study was to determine the optimum sequence for combined modality therapy with radiolabeled antibodies and fractionated external beam radiation. Methods: The uptake and distribution of a nontherapeutic activity of ¹²⁵I-labeled tumor-associated A33 monoclonal antibody was determined in SW1222 human colon carcinoma xenografts in nude mice for 4 study groups: group 1, radiolabeled antibody alone; group 2, radiolabeled antibody administered (day 0) immediately before the first of 5 daily fractions of 2-Gy, 320-kilovolt peak x-rays; group 3, radiolabeled antibody administered after the fifth radiation fraction (day 5); and group 4, radiolabeled antibody administered 5 d after irradiation (day 10). Tumors were excised 5 d after antibody administration. Tumors were frozen and sectioned for histology and phosphor plate autoradiography. The percentage of A33 antigen-expressing cells was estimated by immunohistochemical staining. Results: The average tumor uptake values relative to control group 1 were 1.47 (group 2), 0.78 (group 3), and 0.21 (group 4), which illustrates that tumor uptake is increased by almost 50% when the antibody is present in the blood at the start of irradiation. Five days into a fractionated irradiation protocol, antibody uptake was reduced, falling more significantly on day 10. Phosphor plate autoradiographs showed decreased uptake uniformity for groups 3 and 4. Immunohistochemical data showed a reduction in A33 antigen-positive cells from 85%, 64%, 50%, to 41% for groups 1–4, respectively. Conclusion: Maximum radiolabeled antibody tumor uptake was achieved when the antibody was administered just before radiation therapy. This might be explained by a transient increase in capillary leakage to macromolecules, followed by a reduction at later times, possibly the result of capillary damage and occlusion.

Key Words: radioimmunotherapy • radiation therapy • A33 antibody • immunohistochemistry • phosphor plate autoradiography

Received Oct. 29, 1999; revision accepted May 5, 2000.

For correspondence or reprints contact: John L. Humm, PhD, Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.

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