title: Hyaluronidase-induced periodic modulation of the interstitial fluid pressure increases selective antibody uptake in human osteosarcoma xenografts.
abstract: Periodic modulation of the elevated interstitial fluid pressure might improve filtration and uptake of tumor-targeting macromolecules (e.g. radioimmunoconjugates) in solid tumors. Cycling of the tumor interstitial fluid pressure was initiated by intratumoral injections of bovine testicular hyaluronidase (BTH, 1,600 U) in osteosarcoma-bearing nude mice. BTH injection was repeated at 3-day intervals up to 9 days, in conjunction with tail vein injections of 125I-labeled TP-3 monoclonal antibody against an osteosarcoma-associated antigen (n = 9) or non-specific 125I-labeled UPC-10 antibody (n = 9). Control mice received intratumoral injections of phosphate buffered saline (n = 18). The radioactivities of tumor and normal tissues (blood, liver, kidney and spleen) were measured and compared between the different groups. BTH injections increased the tumor uptake of specific 125I-labeled TP-3 significantly by approximately 70% in mice receiving 3 fractions compared to 1-2 fractions of the antibody (p < 0.05). The tumor/normal tissue ratio in mice receiving 3 fractions of 125I-labeled TP-3 (n = 5) was significantly higher for all tissues, compared with mice receiving 1-2 fractions (n = 4) (p < 0.05). Control injections did not affect the tumor/blood ratio, but increased the uptake of 125I-labeled TP-3 significantly in kidney and spleen (p < 0.05). Also, BTH reduced the uptake of 125I-labeled UPC-10 in tumor and liver by approximately 20% compared with controls (p < 0.05). The results indicate that periodic lowering of the tumor interstitial fluid pressure might increase the specificity of blood-borne monoclonal antibodies to solid tumors in vivo.
authors.affiliation: Department of Physics, Norwegian University of Science and Technology, N-7491 Trondheim, Norway. Christian.Brekken@phys.ntnu.no
authors.forename: C
authors.initials: C
authors.lastname: Brekken
authors.forename: M H
authors.initials: MH
authors.lastname: Hjelstuen
authors.forename: Ø S
authors.initials: ØS
authors.lastname: Bruland
authors.forename: C
authors.initials: C
authors.lastname: de Lange Davies
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D000918:Antibody Specificity; D001345:Autoradiography; D002417:Cattle; D000939:Epitopes / Q000096:biosynthesis / Q000276:immunology; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology*; D018796:Immunoconjugates / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D015552:Injections, Intralesional; D007457:Iodine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D012516:Osteosarcoma / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D006821:Hyaluronoglucosaminidase