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

Abstract Local hyperthermia and the hypoxic cytotoxin SR 4233 were administered to nude mice with 693 ± 47 mm 3 (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 90 Y-NR-Lu-10 significantly inhibited tumor growth (control versus 90 Y-NR-Lu-10: P = 0.048). The administration of hyperthermia at 41.5°C for 1 h immediately following the injection of 111 In-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 90 Y-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 90 Y-NR-Lu-10 ( P = 0.01). SR 4233 also enhanced the tumor growth delay produced by 90 Y-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 90 Y-NR-Lu-10 ( P = 0.002). No toxicity was produced by the local hyperthermia, and the only toxicities produced by 90 Y-NR-Lu-10 and SR 4233 were neutropenia and weight loss.