title: 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 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 microCi 90Y-NR-Lu-10 significantly inhibited tumor growth (control versus 90Y-NR-Lu-10: P = 0.048). The administration of hyperthermia at 41.5 degrees 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 degrees 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 degrees 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.
authors.affiliation: Department of Radiation Oncology, Stanford University, California 94305.
authors.forename: R B
authors.initials: RB
authors.lastname: Wilder
authors.forename: V K
authors.initials: VK
authors.lastname: Langmuir
authors.forename: H L
authors.initials: HL
authors.lastname: Mendonca
authors.forename: M L
authors.initials: ML
authors.lastname: Goris
authors.forename: S J
authors.initials: SJ
authors.lastname: Knox
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology; D001345:Autoradiography; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011863:Radioimmunoassay; D016499:Radioimmunotherapy / Q000379:methods*; D000077704:Tirapazamine; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014227:Triazines / Q000494:pharmacology* / Q000633:toxicity; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000922:Immunotoxins; D007205:Indium Radioisotopes; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D015021:Yttrium Radioisotopes; D000077704:Tirapazamine