Immunotargeting of daunomycin to localized and metastatic human colon adenocarcinoma in athymic mice.
A monoclonal antibody (designated SF25), which recognizes a protein antigen expressed on a large number of human colon carcinomas, was used for drug targeting. Daunomycin-antibody conjugates were prepared by two previously described procedures. In one, the drug was bound to the antibody through a spacer of small molecular mass (cis-aconitic acid), while in the other a dextran bridge served as the link between drug and antibody. High substitution rates of drug to antibody were obtained using the latter binding procedure. Both conjugates were tested in vitro against two human colon carcinoma cell lines, LS180 and KM-12. The efficacy of a daunomycin-dextran-SF25 antibody conjugate was tested against colon carcinoma LS180 tumors transplanted at different sites into athymic mice. The specific conjugate was significantly more inhibitory to a subcutaneous tumor growth than its components or their mixture. SF25 antibody alone showed antitumoral effects against all three forms of transplanted tumor tested, namely, local, metastatic or intrahepatic, whereas daunomycin, on its own, was effective only against the subcutaneous tumor. Binding of daunomycin to dextran partially improved its inhibitory activity against the metastatic tumor. The conjugate, daunomycin-dextran-SF25 antibody reduced the number of metastatic foci, increased the survival rate and delayed death. Yet against lymph node metastases it was not significantly better than a mixture of both constituents. However, results obtained with an intrahepatic tumor, a model that mimics the natural progression of the disease, resembled those described with the subcutaneous tumor. Daunomycin-dextran-SF25 antibody was significantly more effective than all components separately and than a mixture of drug and antibody, provided a highly drug-substituted conjugate was used.
Hurwitz
E
E
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Adler
R
R
Shouval
D
D
Takahashi
H
H
Wands
J R
JR
Sela
M
M
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003630:Daunorubicin / Q000008:administration & dosage*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D003630:Daunorubicin