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Local Hyperthermia and SR 4233 Enhance the Antitumor Effects of Radioimmunotherapy in Nude Mice with Human Colonic Adenocarcinoma Xenografts¹

Departments of Radiation Oncology [R. B. W., S. J. K.] and Nuclear Medicine [M. L. G.], Stanford University, Stanford, California 94305, and Laboratory of Cell and Molecular Biology, SRI International, Menlo Park, California 94025 [V. K. L., H. L. M.]

Local hyperthermia and the hypoxic cytotoxin SR 4233 were administered to nude mice with 693 ± 47 mm³ (mean ± SE) s.c. HCT-8 human colonic adenocarcinoma xenografts in an attempt to enhance the antitumor effects of radioimmunotherapy. Biodistribution studies revealed preferential binding of NR-Lu-10, a murine monoclonal antibody, to the tumors compared with an isotype-matched control antibody, CCOO16-3. A single injection of 25 µCi ⁹⁰Y-NR-Lu-10 significantly inhibited tumor growth (control versus ⁹⁰Y-NR-Lu-10: P = 0.048). The administration of hyperthermia at 41.5°C for 1 h immediately following the injection of ¹¹¹In-labeled NR-Lu-10 up-regulated tumor-associated antigen expression and increased antibody uptake in the tumors by 73% (P = 0.001) without significantly affecting antibody uptake in normal tissues. However, the heat treatment did not produce a more homogeneous distribution of the antibodies in the tumors and did not significantly enhance the tumor growth delay produced by ⁹⁰Y-NR-Lu-10 (P = 0.07). The administration of local hyperthermia at 43.0°C for 1 h, on the other hand, had direct cytotoxic effects (P = 0.03) and enhanced the tumor growth delay produced by ⁹⁰Y-NR-Lu-10 (P = 0.01). SR 4233 also enhanced the tumor growth delay produced by ⁹⁰Y-NR-Lu-10 (P = 0.03). The greatest antitumor effects were observed when both hyperthermia at 43.0°C and SR 4233 were administered in combination with ⁹⁰Y-NR-Lu-10 (P = 0.002). No toxicity was produced by the local hyperthermia, and the only toxicities produced by ⁹⁰Y-NR-Lu-10 and SR 4233 were neutropenia and weight loss.

¹ Supported in part by an American Society for Therapeutic Radiology and Oncology Fellowship, a stipend from the Robert D. Plageman Memorial Fund, an American Cancer Society Career Development Award, NIH Research Grant CA 56464, and a gift from The Friends of Radiology.

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA 94305.

Received 9/15/92. Accepted 4/22/93.

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