Abstract
Previously, we described FGF-1- or FGF-4-transfected MCF-7 breast carcinoma cells which are tumorigenic and metastatic in untreated or tamoxifen-treated ovariectomised nude mice. In this study, we have assessed the effects of AGM-1470, an antiangiogenic agent, and pentosan polysulphate (PPS), an agent that abrogates the effects of FGFs, on tumour growth and metastasis produced by these FGF-transfected MCF-7 cells. Untreated or tamoxifen-treated ovariectomised mice were injected with FGF-transfected cells, treated with AGM-1470 or PPS, and tumour growth and metastasis analysed. The sensitivity of FGF-transfected and parental MCF-7 cells to AGM-1470 or PPS was also determined in vitro. Both AGM-1470 and PPS inhibited tumour growth in otherwise untreated or tamoxifen-treated mice injected with either FGF- or FGF-4-transfected MCF-7 cells. This effect was more reliably seen in tamoxifen-treated animals. AGM-1470 was about 10(5) times less potent in inhibiting the anchorage-dependent growth of parental MCF-7 or FGF-transfected MCF-7 cells than in inhibiting the growth of human umbilical vein endothelial cells. PPS did not affect the in vitro growth of the transfectants or parental cells. Thus, the growth-inhibitory effect on tumours was in excess of the effect of either drug on the same cells in tissue culture, implying that stromal elements are important determinants of the effects of these drugs. There was a positive correlation between tumour size and the extent of proximal lymph node metastasis. However, neither drug had a significant effect on the extent of metastasis to proximal or distal lymph nodes or lungs. AGM-1470 or PPS may be helpful in cases of breast carcinoma in which angiogenesis is due to expression of FGFs by the tumour cells and may be more effective when combined with tamoxifen.
Highlights
Tumours produced by FGF-J- or FGF-4-transfected MCF-7 cells in nude mice are growth-inhibited by treatment with pentosan polysulphate or AGM-1470
We treated ovariectomised mice injected with FGF-transfected MCF-7 cells with pentosan polysulphate (PPS), an agent which is capable of abrogating the effects of FGFs and other heparin-binding growth factors in vitro and in vivo (Wellstein et al, 1991; Zugmaier et al, 1992)
Since FGFs are known angiogenic factors, we examined the contribution of the angiogenic component to the tumorigenic phenotype of the transfectants by treating ovariectomised mice injected with FGF-transfected cells with AGM-1470
Summary
Cell linesMKL-4 cells are MCF-7 cells sequentially transfected with expression vectors for FGF-4 and lacZ as described (McLeskey et al, 1993; Kurebayashi et al, 1993). oa-21 and a-10 cells are clonal G-418-resistant cell lines isolated from a transfection of ML-20 cells [MCF-7 cells first transfected with an expression vector for lacZ (Kurebayashi et al, 1993)] with an expression vector encoding amino acids 21-145 of FGF-l (Burgess et al, 1986; Burgess and Maciag, 1989), and further characterised as producing high levels of the transfected protein and forming tumours in nude mice (Zhang et al, 1995). MKL-4 cells are MCF-7 cells sequentially transfected with expression vectors for FGF-4 and lacZ as described (McLeskey et al, 1993; Kurebayashi et al, 1993). Oa-21 and a-10 cells are clonal G-418-resistant cell lines isolated from a transfection of ML-20 cells [MCF-7 cells first transfected with an expression vector for lacZ (Kurebayashi et al, 1993)] with an expression vector encoding amino acids 21-145 of FGF-l (Burgess et al, 1986; Burgess and Maciag, 1989), and further characterised as producing high levels of the transfected protein and forming tumours in nude mice (Zhang et al, 1995). Pentosan polysulphate (PPS) was obtained from beneChemie, Munich, Germany. Tamoxifen pellets (5 mg, 60 day release) were obtained from Innovative Research, Toledo, OH, USA.
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