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The Use of Daunomycin-Antibody Immunoconjugates in Managing Soft Tissue Sarcomas: Nude Mouse Xenograft Model¹

Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60612

² To whom requests for reprints should be addressed, at Specialized Cancer Center (M/C820), 840 South Wood Street, Chicago, IL 60612.

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 pl02 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 daunomycimtotal protein molar ratio ranged from 1.9 to 6.1. in vitro cytotoxicity studies using human fibrosarcoma cells showed that, at 10 µg/ml concentration, this immunoconjugate was 79.4% as efficient as free daunomycin and, at 1 µg/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.

¹ Supported by USPHS Grant CA 57164-02 from National Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/ 7/93. Accepted 9/21/93.