Effect of fibroblast growth factor saporin mitotoxins on human bladder cell lines.
Mitotoxins targeted via high-affinity growth factor receptors on the cell surface are a potential means of anticancer therapy. We have evaluated the effect of a chemically conjugated (FGF2-SAP) and a fusion protein (rFGF2-SAP) mitotoxin containing FGF-2 and saporin on normal (FHs 738B1) and malignant bladder cell lines (HT1197, TCCSUP, EJ-6, and RT4). The FGF-saporins demonstrated potent cytotoxicity in malignant bladder cell lines with an ID50 range of 0.13-13.6 nM, whereas cells derived from normal fetal bladder (FHs 738B1) were less sensitive to FGF2-saporins (ID50 > 100 nM). Greater than a 100-fold difference in cytotoxicity between FGF-saporins and unconjugated saporin was observed. Assessment of cellular FGF-2 content and secretion showed that FHs 738B1 and TCCSUP contained and secreted significantly more FGF-2 compared to other cell lines tested. (125)I-FGF-2 receptor binding studies showed the presence of high-affinity (pM) FGF receptors on all bladder cell lines. Cross-linking studies revealed the presence of a major receptor-ligand complex of 90 kDa on FHs 738B1 and 160-170 kDa on the other bladder cell lines. All cell lines studied, except RT4, expressed solely FGFR-1. These studies demonstrate that FGF2-saporins have antiproliferative activity on human bladder cancer cell lines. However, the number of high-affinity FGF receptors, and FGF-2 cellular content and secretion are not absolute determinants of cellular sensitivity to FGF2-saporins.
Tetzke
T A
TA
Prizm Pharmaceuticals Inc., San Diego, California, USA.
Caton
M C
MC
Maher
P A
PA
Parandoosh
Z
Z
D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006801:Humans; D000922:Immunotoxins; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D014407:Tumor Cells, Cultured; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
D000922:Immunotoxins; D010940:Plant Proteins; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D005346:Fibroblast Growth Factors; D009699:N-Glycosyl Hydrolases; D000076985:Saporins