Growth-inhibitory effect of STI571 on cells transformed by the COL1A1/PDGFB rearrangement

Dermatofibrosarcoma protuberans (DP) is a skin tumor of intermediate malignancy characterized by high recurrence rates, for which surgical excision is the main therapy, All Up cases carry a specific t(17;22) translocation, resulting in a COLIAI/PDCFB rearrangement, The subsequently deregulated production of PDGFB generates autocrine stimulation of PDGFr beta, leading to malignant transformation, Using NIH-3T3 cells transformed by the COLIAI/PDGFB rearrangement (5A cell line), we explored the possibility of blocking the PDGFB autocrine loop, both in vitro and in vivo using ST1571, an inhibitor of the PDGF receptor and of ABL kinase activity, The presence of small amounts of serum in the culture medium was required for the in vitro growth and morphological transformation of SA cells, In the presence of ST1571, the growth rate was reduced and the associated transformed phenotype changed to a flattened one, This effect could be reversed on removal of the inhibitor. The growth rate of tumors induced by 5A cells in nude mice was reduced by ST1571 administration. Interestingly, this effect was also evident on pre-existing tumors, but no tumor eradication was observed, This is consistent with the reversible effects of the inhibitor observed in vitro but differs from the eradication effect of ST1571 on BCR-ABL-induced tumors, Our data indicate that ST1571 might be a candidate compound for the pharmacological treatment of Up and demonstrate that the same compound may act in different ways (cytotoxic vs, cytostatic), according to the specificity of the inhibited tyrosine kinase, namely, ABL or PDGFr beta, (C) 2001 Wile-Liss. Inc.