Effects of modulation of basic fibroblast growth factor on tumor growth in vivo.
BACKGROUND
Recombinant human basic fibroblast growth factor (rHu-bFGF) is known to stimulate proliferation in some tumor cells and to modulate tumor vascularization.


OBJECTIVE
The purpose of this study was to examine the possible role of this agent in the development of tumors. The study was designed to determine the effects of modulating bFGF activity in vivo in tumor models from cell lines with different responses to bFGF and with different content and receptor levels of bFGF.


METHODS
Two tumor cell lines (human DLD-2 colon carcinoma and rat C6 glioma) were characterized for bFGF content and bFGF receptor levels by Western blot analysis in cultured cells and by studies of [125I]rHu-bFGF binding to sections from xenografts grown in nude mice. Tumor cell proliferation was monitored after treatment with rHu-bFGF or the DG2 or DE6 IgG monoclonal antibody to rHu-bFGF in culture and in vivo.


RESULTS
C6 cells exhibited 7800 high-affinity receptors for rHu-bFGF per cell (dissociation constant [Kd] = 46 pM), while DLD-2 cells lacked high-affinity receptors. rHu-bFGF stimulated [3H]thymidine uptake by C6 cells, but the addition of DG2 IgG prevented this stimulation; rHu-bFGF had no effect on [3H]thymidine incorporation by DLD-2 cells. C6 cells had higher levels of immunoreactive bFGF than did DLD-2 cells. The xenografts from both cell lines exhibited high-affinity [125I]rHu-bFGF binding that was concentrated on vascular-like structures. rHu-bFGF at a dosage of 0.25 mg/kg given intraperitoneally daily for 18 days caused a twofold increase in DLD-2 tumor weight but had little effect on the growth of C6 xenografts. In contrast, daily intravenous injections of DG2 IgG given to mice had no effect on DLD-2 tumor growth but reduced growth of C6 tumors by approximately 30%--a statistically significant difference.


CONCLUSIONS
The addition of exogenous rHu-bFGF or of a neutralizing antibody resulted in significant alterations in tumor growth in vivo, which were specific for tumor type and bFGF characteristics. While some of these effects may be mediated by the bFGF-responsive endothelial cells of the tumor vasculature (DLD-2 colon carcinoma), others may result from inhibition of bFGF-dependent tumor cell proliferation (C6 glioma).


CONCLUSIONS
Studies that measure tumor blood flow are necessary to confirm that these effects are mediated by changes in tumor vasculature.
Gross
J L
JL
Du Pont Merck Pharmaceutical Co., Wilmington, Del.
Herblin
W F
WF
Dusak
B A
BA
Czerniak
P
P
Diamond
M D
MD
Sun
T
T
Eidsvoog
K
K
Dexter
D L
DL
Yayon
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000918:Antibody Specificity; D001345:Autoradiography; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology* / Q000628:therapy; D003600:Cytosol / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000493:pharmacokinetics / Q000494:pharmacology*; D005910:Glioma / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D051379:Mice; D008819:Mice, Nude; D009500:Neutralization Tests; D051381:Rats; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2