The use of daunomycin-antibody immunoconjugates in managing soft tissue sarcomas: nude mouse xenograft model.
Analysis of human fibrosarcoma cells exposed to radiolabeled monoclonal antibody 19-24, which recognizes sarcoma-associated antigen p102, revealed that over 54% of the cell surface-bound radioactivity was internalized. No modulation of cell surface p102 antigen by monoclonal antibody 19-24 was observed in human fibrosarcoma cells. Monoclonal antibody 19-24 coupled to daunomycin via a dextran bridge was found to be most effective. In different preparations, the daunomycin:total protein molar ratio ranged from 1.9 to 6.1. In vitro cytotoxicity studies using human fibrosarcoma cells showed that, at 10 micrograms/ml concentration, this immunoconjugate was 79.4% as efficient as free daunomycin and, at 1 microgram/ml concentration, 36.8% as efficient. Control nonspecific murine monoclonal antibody P3 immunoconjugates were relatively ineffective. The distribution of 14C-Adriamycin, 125I-labeled monoclonal antibody 19-24, and 125I-labeled 19-24 immunoconjugate was also evaluated over a 24-h period in tumor and normal tissues of athymic mice bearing a human fibrosarcoma xenograft. Poor uptake of radiolabeled Adriamycin by the tumor tissue was observed. The level of 14C radioactivity in the tumor tissue never exceeded 1% of the total injected dose and was 24.8-fold lower than the radioactivity found in the spleen tissue. Tumor tissue uptake of radiolabeled monoclonal antibody 19-24 was characterized by the high tumor tissue:blood ratio of 1.62 +/- 0.28 (SD). However, for monoclonal antibody 19-24 immunoconjugates, this ratio decreased to 0.66 +/- 0.05, which was still higher than normal (liver, 0.48 +/- 0.02; lung, 0.48 +/- 0.07; spleen, 0.28 +/- 0.01) or nonspecific monoclonal antibody P3 immunoconjugates (0.22 +/- 0.03). Thus, it appears that, compared to free daunomycin, monoclonal antibody 19-24 immunoconjugates may be more efficient and less cytotoxic to normal tissues.
Stastny
J J
JJ
Cancer Center, University of Illinois at Chicago 60612.
Das Gupta
T K
TK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004317:Doxorubicin / Q000493:pharmacokinetics; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000628:therapy*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D004317:Doxorubicin; D003630:Daunorubicin