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 DP cases carry a specific t(17;22) translocation, resulting in a COL1A1/PDGFB rearrangement. The subsequently deregulated production of PDGFB generates autocrine stimulation of PDGFrbeta, leading to malignant transformation. Using NIH-3T3 cells transformed by the COL1A1/PDGFB rearrangement (5A cell line), we explored the possibility of blocking the PDGFB autocrine loop, both in vitro and in vivo, using STI571, 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 5A cells. In the presence of STI571, 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 STI571 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 STI571 on BCR-ABL-induced tumors. Our data indicate that STI571 might be a candidate compound for the pharmacological treatment of DP 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 PDGFrbeta.
Greco
A
A
Department of Experimental Oncology, Operative Unit 3, Istituto Nazionale Tumori, Milan, Italy. greco@istitutotumori.mi.it
Roccato
E
E
Miranda
C
C
Cleris
L
L
Formelli
F
F
Pierotti
M A
MA
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018223:Dermatofibrosarcoma / Q000473:pathology; D004195:Disease Models, Animal; D015321:Gene Rearrangement; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000517:prevention & control*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; C120892:COLIA1-PDGFB fusion protein, human; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta