Lancet Jeffrey E, Karp Judith E
James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave, Box 704, Rochester, NY 14642, USA.
Blood. 2003 Dec 1;102(12):3880-9. doi: 10.1182/blood-2003-02-0633. Epub 2003 Aug 14.
Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth across a wide range of malignant phenotypes. Many hematologic malignancies appear to be reasonable disease targets, in that they express relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), AKT, and others that may depend on farnesyl protein transferase (FTase) activity to promote proliferation and survival. A host of phase 1 trials have been recently launched to assess the applicability of FTIs in hematologic malignancies, many of which demonstrate effective enzyme target inhibition, low toxicity, and some clinical responses. As a result, phase 2 trials have been initiated in a variety of hematologic malignancies and disease settings to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.
法尼基转移酶抑制剂（FTIs）是一类小分子抑制剂，可选择性抑制多种细胞内底物蛋白（如Ras）的法尼基化。临床前研究表明，它们能够有效抑制多种恶性表型的肿瘤生长。许多血液系统恶性肿瘤似乎是合理的疾病靶点，因为它们表达相关的生物学靶点，如Ras、丝裂原活化蛋白激酶（MAPK）、AKT等，这些靶点可能依赖法尼基蛋白转移酶（FTase）活性来促进增殖和存活。最近开展了一系列1期试验，以评估FTIs在血液系统恶性肿瘤中的适用性，其中许多试验显示出有效的酶靶点抑制、低毒性以及一些临床反应。因此，已在多种血液系统恶性肿瘤和疾病背景下启动了2期试验，以进一步验证临床活性，并确定可能被这些药物修饰的下游信号转导靶点。预计这些研究将有助于明确FTIs在血液系统恶性肿瘤患者中的最佳作用，并深入了解将FTIs与其他药物联合使用的有效方法。
