Tumor growth dependent on Kaposi's sarcoma-derived fibroblast growth factor inhibited by pentosan polysulfate.
A neoangiogenic response is critical for the unrestricted growth of solid tumors beyond a few millimeters in diameter. Release of adequate growth-stimulating activity from tumor cells is obviously required for the stimulation of blood vessel growth, and blockade of such stimulatory activity should repress tumor growth at the microscopic level. To test this hypothesis and to study appropriate inhibitors, we used a human adrenal cancer cell line (SW-13/K-fgf) engineered to secrete Kaposi's sarcoma-derived fibroblast growth factor (K-FGF), which we previously showed to induce growth of highly vascularized subcutaneous tumors in animals by autocrine and paracrine stimuli. In the present study, we tested different polysulfates for their selective inhibition of proliferation induced by K-FGF versus proliferation independent of K-FGF. Suramin and dextran sulfate showed slight selective inhibition of K-FGF-induced proliferation, ie, inhibition three- and five-fold greater, respectively, than the inhibition of proliferation independent of K-FGF. In contrast, heparin was inactive. The heparin analogue pentosan polysulfate (PPS), however, showed selective inhibition that was more than 2000-fold greater. The inhibitory effects of PPS on growth of SW-13/K-fgf cells, as well as endothelial cells, were fully reversible by an excess of added FGF. Daily intraperitoneal injections of PPS were tolerated well by athymic nude mice and prevented growth of subcutaneous SW-13/K-fgf tumor xenografts. PPS will be a useful tool to elucidate the effects of FGFs in vitro and in vivo and appears to be a prototype for the development of tumoricidal therapy based on targeting of growth factors.
Wellstein
A
A
Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, DC 20007.
Zugmaier
G
G
Califano
J A
JA
Kern
F
F
Paik
S
S
Lippman
M E
ME
D000310:Adrenal Gland Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005260:Female; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology* / Q000633:toxicity; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology*; D013498:Suramin / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
C496445:FGF4 protein, human; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D011518:Proto-Oncogene Proteins; D010426:Pentosan Sulfuric Polyester; D013498:Suramin; D005346:Fibroblast Growth Factors; D006493:Heparin