The effect of anti-alpha-fetoprotein-adriamycin conjugate on a human hepatoma.
Conjugates between chemotherapeutic agents and antibodies, linked by a dextran bridge, were previously shown to be effective in suppression of hepatoma growth in vitro and in vivo. However, scaling up of production of such conjugates may lead to a high degree of variation in molar ratios of drug to antibody in different batches. In this study, an alternative link between drug and antibody was evaluated. A conjugate between adriamycin and murine IgGI monoclonal antibodies to human alpha-fetoprotein was prepared using a polyglutamic-acid bridge. The simple and reproducible method of linking adriamycin to a specific site on the antibody enabled the binding of the drug to alpha-fetoprotein with a high yield (63% to 68%); the molar ratio of drug/antibody was in the range of 110:1 to 120:1. The conjugate retained its capacity to bind to purified alpha-fetoprotein. Incorporation of [3H]-thymidine or [3H]-leucine into hepatoma cells, which express alpha-fetoprotein, was inhibited by the conjugate, compared with unconjugated antibody. Furthermore, 90% of this pharmacological activity was preserved, compared with free adriamycin. In vitro, the inhibitory activity of the polyglutamic acid conjugate was higher than that of a conjugate in which dextran was used as the linker between drug and antibody. In vivo, both conjugates were equally effective in suppression of hepatoma growth transplanted subcutaneously in athymic mice. However, this effect lasted only during the treatment period of 2 to 3 wk. Six days after discontinuation of therapy, reacceleration of tumor growth was observed regardless of the conjugate used.(ABSTRACT TRUNCATED AT 250 WORDS)
Galun
E
E
Department of Medicine A, Hadassah University Hospital, Jerusalem, Israel.
Shouval
D
D
Adler
R
R
Shahaar
M
M
Wilchek
M
M
Hurwitz
E
E
Sela
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D003432:Cross-Linking Reagents; D003911:Dextrans; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007930:Leucine / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011099:Polyglutamic Acid; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D003911:Dextrans; D000922:Immunotoxins; D000509:alpha-Fetoproteins; D011099:Polyglutamic Acid; D004317:Doxorubicin; D007930:Leucine; D013936:Thymidine