The effect of an anti-membrane antibody-methotrexate conjugate on the human prostatic tumour line PC3.
Methotrexate (MTX) was linked, via an active ester intermediate, to a purified IgG fraction of rabbit polyclonal antiserum raised against a cell membrane preparation from the human prostatic cell line PC3. The resulting conjugates contained an average of 0.044 mg of MTX per mg of antibody with acceptable losses in both the binding activity of the immunoglobulin (27.5%) and the enzyme inhibitory activity of the drug (32% at a MTX concentration of 3 x 10(-7) M). Using cultures of PC3 cells the antibody-MTX (Ab-MTX) conjugates were observed to be as effective as free drug in causing cell death and more effective than non-immune IgG-MTX (NIgG-MTX) conjugates. When athymic nude mice bearing PC3 tumours were administered with Ab-MTX conjugates, significant reductions in tumour growth rates were observed compared to animals given saline, MTX alone or NIgG-MTX conjugates (P less than 0.01 in all cases). Furthermore, the accumulation of radioactive MTX in the tumour tissue of animals injected with these Ab-MTX conjugates was 16-fold greater than those given free drug and 8.6-fold greater than those administered with NIgG-MTX conjugates. Uptake by the reticuloendothelial system, however, was not significantly different when animals from each treatment group were compared.
Rowland
A J
AJ
Tenovus Institute for Cancer Research, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Harper
M E
ME
Wilson
D W
DW
Griffiths
K
K
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000648:ultrastructure; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004337:Drug Carriers; D007074:Immunoglobulin G; D008727:Methotrexate