Targeting human prostatic carcinoma through basic fibroblast growth factor receptors in an animal model: characterizing and circumventing mechanisms of tumor resistance.
BACKGROUND
Basic fibroblast growth factor receptors on DU145 human prostatic carcinoma xenografts serve as targets for the delivery of a growth factor-toxin chimera, basic fibroblast growth factor-saporin (bFGF-SAP), which produces significant antitumor activity in a nude mouse model. However, DU145 tumors often become resistant to prolonged treatment.


METHODS
Nude mice bearing DU145 xenografts were intravenously administered bFGF-SAP (0.05 microg/kg weekly for 4 weeks), and a panel of eight tumors was isolated from the treated animals and established in monolayer culture.


RESULTS
In cell-survival assays, sensitivity of the treated tumor-derived cell lines to bFGF-SAP (IC50 = 12-100 nM) varied widely from cells derived from a vehicle-treated control tumor (IC50 = 10 nM). A significant inverse correlation was observed between increased IC50 values in vitro and increased tumor growth delay in vivo. Pretreatment of tumor cells with suramin or neutralizing antibodies to bFGF or keratinocyte growth factor (KGF) circumvented resistance in one of the tumor lines, confirming autocrine-mediated resistance. In another tumor subline, a 3-fold decrease in bFGF high-affinity receptor sites, which concurred with a 4-fold decrease in ability to internalize the bFGF ligand, was consistent with a decrease in total cellular expression of the FGF2 receptor (Bek). Resistance was circumvented by alternatively targeting FGF1 receptor (Flg) on these cells with a saporin immunotoxin.


CONCLUSIONS
These studies identify alterations in the ligand-targeted receptor as a frequent contributor to resistance arising in DU145 tumors to in vivo treatment with a bFGF receptor-directed-toxin chimera, and provide the basis for designing methods to circumvent resistance for the purpose of enhancing efficacy of receptor-directed therapies in the treatment of prostate cancer.
Department of Medicine, Roger Williams Medical Center and Brown University, Providence, Rhode Island 02908, USA.
P A
PA
Davol
A R
AR
Frackelton
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000627:therapeutic use* / Q000633:toxicity; D000091344:Filaggrin Proteins; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010940:Plant Proteins / Q000627:therapeutic use* / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D012044:Regression Analysis; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D003603:Cytotoxins; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; 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; D000076985:Saporins