Hyaluronidase-induced periodic modulation of the interstitial fluid pressure increases selective antibody uptake in human osteosarcoma xenografts.
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.
Brekken
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C
Department of Physics, Norwegian University of Science and Technology, N-7491 Trondheim, Norway. Christian.Brekken@phys.ntnu.no
Hjelstuen
M H
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Bruland
Ø S
ØS
de Lange Davies
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C
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
D000911:Antibodies, Monoclonal; D000939:Epitopes; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D006821:Hyaluronoglucosaminidase