The highly tumorigenic human
breast cancer MCF-7ras line (Ha-ras-transfected MCF-7 cell line) loses
estrogen dependence and secretes diffusible
growth factors that support its own
tumor growth in vivo. Our previous studies showed that carboxymethyl benzylamide
dextran (
CMDB7) inhibits the growth of breast MCF-7 and MCF-7ras cell lines. In this study, we have shown that
conditioned medium (CM) from MCF-7 and MCF-7ras cells stimulated the
DNA synthesis of BALB/c3T3 fibroblasts and that
CMDB7 strongly inhibited these mitogenic effects in a dose-dependent manner.
Neutralizing antibodies against
platelet-derived growth factor (PDGF) partially inhibited the mitogenic effect of MCF-7ras CM. The flow cytometry analysis of the cell cycle showed that the CM of
tumor cells increased the percentage of fibroblasts in S phase and that
CMDB7 blocked them in G0/G1 phase.
CMDB7 inhibited the mitogenic effect of
PDGF-BB and
transforming growth factor (TGF) beta1 but not those of
epidermal growth factors and
insulin-like growth factor on BALB/c3T3 fibroblasts.
CMDB7 increased the electrophoretic mobility of radiolabeled
PDGF-BB and
TGF-beta1, apparently by forming a stable complex with these factors. On intact BALB/c3T3 fibroblasts, binding of iodinated
growth factors (125I-TGF-beta1 and 125I-PDGF) to their receptors was completely displaced by
CMDB7. In vivo studies demonstrated that s.c. injection of
CMDB7 inhibited by 66% the
tumor growth of MCF-7ras xenografts in nude mice. These results showed that
CMDB7 inhibits the mitogenic effect of
growth factors released from MCF-7 and MCF-7ras cells and suppresses
tumor growth in the MCF-7ras model.