Petrelli A, Giordano S
Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Str. Provinciale 142, 10060, Candiolo (Torino), Italy.
Curr Med Chem. 2008;15(5):422-32. doi: 10.2174/092986708783503212.
Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib--targeting VEGFR, PDGFR, FLT-3 and c-Kit--a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.
通过抑制特定靶分子的化合物进行的靶向治疗代表了癌症治疗的新视角。与作用于所有分裂细胞并产生毒性作用和损伤正常组织的传统化疗不同，靶向药物能够以更具特异性的方式作用于直接参与肿瘤进展的细胞亚群。控制细胞增殖和死亡的分子，如生长因子的酪氨酸激酶受体（RTKs），是这类治疗方法的最佳靶点之一。目前临床实践中使用的两类靶向RTKs的化合物是：单克隆抗体和酪氨酸激酶抑制剂。靶向治疗时代始于曲妥珠单抗（一种抗HER2的单克隆抗体）被批准用于治疗转移性乳腺癌，以及伊马替尼（一种靶向BCR-Abl的小分子酪氨酸激酶抑制剂）被批准用于治疗慢性粒细胞白血病。尽管最初人们对这些治疗的疗效充满热情，但临床医生很快就不得不面对复发问题，因为几乎所有癌症患者都会产生耐药性，这通常是由于替代RTK途径的激活。从这个角度来看，靶向药物的基本原理正在发生根本性转变。过去，主要努力方向是开发作用于单一RTK的高度特异性抑制剂。现在，人们普遍认为同时干扰多个RTK的分子可能比单一靶点药物更有效。随着美国食品药品监督管理局（FDA）最近批准索拉非尼和舒尼替尼——靶向VEGFR、PDGFR、FLT-3和c-Kit——一种不同的局面正在出现，新一代能够抑制多条途径的抗癌药物可能会发挥主要作用。
