George Daniel
Dana-Farber Cancer Institute, Boston, MA, USA.
Adv Exp Med Biol. 2003;532:141-51. doi: 10.1007/978-1-4615-0081-0_12.
The platelet-derived growth factors (PDGF) are a pleotrophic family of peptide growth factors that signal through cell surface, tyrosine kinase receptors (PDGFR) and stimulate various cellular functions including growth, proliferation, and differentiation. To date, PDGF expression has been demonstrated in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to subtler paracrine interactions involving adjacent stroma and vasculature. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) blocks activity of the Bcr-Abl oncoprotein and the cell surface tyrosine kinase receptor c-Kit, and as such was recently approved for several indications in the treatment on chronic myeloid leukemia and gastrointestinal stromal tumors. In both of these examples the target protein was identified by an oncogenic, activating mutation. Imatinib mesylate is also a potent inhibitor of PDGFR kinase and is currently being evaluated for the treatment of chronic myelomonocytic leukemia and glioblastoma multiforme, based upon evidence in these diseases of activating mutations in PDGFR. However, the PDGF pathway may represent a therapeutic target in other solid tumors in which it is not part of the oncogenic transformation. In order to investigate the potential biologic implications of inhibiting PDGFR in these tumor types, clinical trials that investigate both established clinical endpoints of response and benefit, as well as surrogate endpoints that describe the biologic significance of PDGF inhibition in vivo are needed.
血小板衍生生长因子（PDGF）是一类多效性的肽生长因子家族，通过细胞表面酪氨酸激酶受体（PDGFR）发出信号，刺激包括生长、增殖和分化在内的各种细胞功能。迄今为止，已在多种不同的实体瘤中证实了PDGF的表达，从胶质母细胞瘤到前列腺癌。在这些不同的肿瘤类型中，PDGF信号传导的生物学作用可能各不相同，从自分泌刺激癌细胞生长到涉及相邻基质和脉管系统的更微妙的旁分泌相互作用。酪氨酸激酶抑制剂甲磺酸伊马替尼（以前称为STI571、格列卫，诺华制药公司，新泽西州东哈嫩）可阻断Bcr-Abl癌蛋白和细胞表面酪氨酸激酶受体c-Kit的活性，因此最近被批准用于治疗慢性粒细胞白血病和胃肠道间质瘤的多种适应症。在这两个例子中，靶蛋白都是通过致癌的激活突变鉴定出来的。甲磺酸伊马替尼也是PDGFR激酶的有效抑制剂，基于这些疾病中PDGFR激活突变的证据，目前正在评估其用于治疗慢性粒单核细胞白血病和多形性胶质母细胞瘤。然而，PDGF通路可能是其他实体瘤的治疗靶点，而在这些实体瘤中它并非致癌转化的一部分。为了研究在这些肿瘤类型中抑制PDGFR的潜在生物学意义，需要开展临床试验，既要研究既定的临床反应和获益终点，也要研究描述PDGF体内抑制生物学意义的替代终点。
