Greco A, Roccato E, Miranda C, Cleris L, Formelli F, Pierotti M A
Department of Experimental Oncology, Operative Unit 3, Istituto Nazionale Tumori, Milan, Italy.
Int J Cancer. 2001 May 1;92(3):354-60. doi: 10.1002/ijc.1190.
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.
隆突性皮肤纤维肉瘤（DP）是一种中度恶性的皮肤肿瘤，其特点是复发率高，手术切除是主要治疗方法。所有DP病例都存在特定的t(17;22)易位，导致COL1A1/PDGFB重排。随后PDGFB产生失调，对PDGFrβ产生自分泌刺激，导致恶性转化。我们使用通过COL1A1/PDGFB重排转化的NIH-3T3细胞（5A细胞系），探讨了使用STI571（一种PDGF受体和ABL激酶活性抑制剂）在体外和体内阻断PDGFB自分泌环的可能性。5A细胞的体外生长和形态转化需要培养基中存在少量血清。在STI571存在的情况下，生长速率降低，相关的转化表型变为扁平状。去除抑制剂后，这种效应可以逆转。给裸鼠注射STI571可降低5A细胞诱导的肿瘤生长速率。有趣的是，这种效应在已有的肿瘤上也很明显，但未观察到肿瘤根除。这与在体外观察到的抑制剂的可逆效应一致，但与STI571对BCR-ABL诱导的肿瘤的根除效应不同。我们的数据表明，STI571可能是DP药物治疗的候选化合物，并证明根据所抑制的酪氨酸激酶（即ABL或PDGFrβ）的特异性，同一化合物可能以不同方式起作用（细胞毒性与细胞抑制性）。
