Autocrine down-regulation of basic fibroblast growth factor receptors causes mitotoxin resistance in a human melanoma cell line.
The ability of melanoma to develop resistance to mitotoxins, growth-factor-directed anti-neoplastic agents that offer potential for the treatment of this highly refractory disease, may limit therapeutic efficacy. To address this problem, we developed a subcloned human melanoma cell line that is resistant to the mitotoxin composed of basic fibroblast growth factor conjugated to the ribosome-inactivating protein saporin. Resistance was caused by autocrine FGF ligands, which down-regulate bFGF receptors and reduce bFGF-saporin binding. Inhibiting the autocrine loop with suramin or with neutralizing antibodies to FGF up-regulated receptors and decreased resistance in vitro. Furthermore, suramin restored sensitivity in resistant tumor xenografts. These results suggest the potential of therapeutic modalities combining agents that neutralize growth factors with receptor-directed mitotoxins for targeting malignant melanoma either to prevent emergence of resistance or to circumvent resistance once it occurs.
Davol
P
P
Department of Medicine, Roger Williams Medical Center, Providence, RI 02908, USA.
Beitz
J G
JG
Frackelton
A R
AR
D015536:Down-Regulation / Q000502:physiology*; D004351:Drug Resistance; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000503:physiopathology*; D010940:Plant Proteins / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013498:Suramin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000378:metabolism
D010940:Plant Proteins; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C078442:basic fibroblast growth factor-saporin mitotoxin, recombinant; D016222:Fibroblast Growth Factor 2; D013498:Suramin; D000076985:Saporins