Abstract
Our previous studies showed that carboxymethyl benzylamide dextran (CMDB7) blocks basic fibroblast growth factor (FGF-2)-dependent cell proliferation of a human breast epithelial line (HBL100), suggesting its potential role as a potent antiangiogenic substance. The derived cell line (HH9), which was transformed with the hst/FGF4 gene, has been shown to be highly proliferative in vitro and to induce angiogenic tumours in nude mice. We show here that CMDB7 inhibits the mitogenic activities of the conditioned media from HBL 100 and HH9 cells in a dose-dependent manner. When HH9 cells were injected s.c. into nude mice, CMDB7 treatment (300 mg kg(-1) week(-1)) suppressed the tumour take and the tumour growth by about 50% and 80% respectively. Immunohistochemical analysis showed a highly significant decrease, by more than threefold, in the endothelial density of viable tumour regions, together with a significant increase in the necrosis area. This antiangiogenic activity of CMDB7 was further demonstrated by direct inhibition of calf pulmonary artery (CPAE) and human umbilical vein (HUVEC) endothelial cell proliferation and migration in vitro. In addition, we showed that CMDB7 inhibits specifically the mitogenic effects of the growth factors that bind to heparin such as FGF-2, FGF-4, platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGF-beta1), but not those of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1). These results demonstrate that CMDB7 inhibits FGF-2/FGF-4-dependent tumour growth and angiogenesis, most likely by disrupting the autocrine and paracrine effects of growth factors released from the tumour cells.
Highlights
When CMDB7 was removed from the culture medium after a 4-day treatment cell growth resumed at a rate similar to that observed in untreated cells
HH9 cells cultured with CMDB7 appeared otherwise healthy: they remained attached to the plastic tissue culture flask and did not undergo any noticeable morphological changes
In order to confirm the specific effects of CMDB7 on FGF-2 and FGF-4. we tested the effect of CMDB7 on ras transformed HBLlOO-cells
Summary
W'ater-soluble dextran derivatixve (CMDB7) >-as prepared from dextran T40 as prexiously described (Chaubet et al 1995). CMDB7 >-as prepared by a statistical substitution of dextran in twxo steps: carboxymethylation. This derixatixve >-as purified by ultrafiltration and ly ophilized. 30%c: mass apparent molecular weight = 80 000 g molFI) Cell lines. The breast epithelial cell line HBL100 obtained from Dr R Cassingena The HH9 cell line used in this studx is a clone of HBL 100 cells transformed wxith the FGF-4 oncogene (Souttou et al 1996). All epithelial cell lines and Balb/c 3T3 fibroblasts )-ATCC) were grown in Dulbecco's modified Ea2le's medium ( DIENM ) Gibco. France) supplemented wxith 2 m2\ L-glutamine. 50 IU ml-l penicillin and 50 .ga ml- streptomycin. and 10% fetal calf serum FCS
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
