Phase III study of BCL-family inhibitors in lymphoma

Bcl-2家族蛋白是细胞凋亡途径的重要调控因子。Bcl-2癌基因首次在滤泡性淋巴瘤中被发现，在滤泡性淋巴瘤中，t（14;18）染色体易位导致b细胞中该蛋白显著过表达。与其他已知的癌基因相比，Bcl-2不刺激细胞增殖，而是通过保护细胞免受各种促凋亡刺激（包括细胞因子戒断、照射、细胞毒性药物、热量和不受调节的癌基因）来抑制程序性细胞死亡Bcl-2基因家族编码一个密切相关的蛋白家族，具有促凋亡或抗凋亡活性，并共享多达4个Bcl-2同源结构域（BH）抗凋亡家族成员（Bcl-XL, Bcl-2, Bcl-w, Bcl-B， A1和Mcl 1）具有四个BH结构域，命名为BH1-4。促凋亡家族成员可进一步细分为多结构域蛋白（Bax, Bak）和仅bh3蛋白（Bad, Bik, Bid, Bim Hrk, Bmf, Noxa, Puma）。这三组蛋白之间的相互作用作为内在凋亡途径的门户。ABT-263是一种新型的小分子Bcl-2家族蛋白抑制剂，具有高亲和力（Ki  1 nM）结合多种抗凋亡Bcl-2家族蛋白，包括Bcl-XL、Bcl-2、Bcl-w和Bcl-B。ABT-263对源自小细胞肺癌和淋巴细胞恶性肿瘤的人类肿瘤细胞系显示出强大的基于机制的细胞毒性（EC50  1 &#61549；M）。ABT-263对22种包括多种白血病和淋巴瘤类型（包括b细胞和t细胞恶性肿瘤）的细胞系中的10种表现出有效的单药活性。在两个侧翼弥漫性大b细胞淋巴瘤模型（DoHH-2和WSU-DLCL2）中，当ABT-263以100 mg/kg/天的剂量给药（p.o, q.d） 17天时，发现了显著的单药治疗活性。已知这两种肿瘤由于t（14;18）易位而表达高水平的Bcl-2。WSU-DLCL2系是从一位在化疗、放疗和骨髓移植后病情进展的患者中分离出来的，该患者被认为是治疗抵抗性淋巴瘤的模型。

The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway. The Bcl-2 oncogene was first identified in follicular lymphoma where the t(14;18) chromosomal translocation results in significant over-expression of the protein in B-cells. In contrast to other known oncogenes, Bcl-2 does not stimulate cellular proliferation, but rather inhibits programmed cell death by protecting cells from a wide variety of pro apoptotic stimuli, including cytokine withdrawal, irradiation, cytotoxic drugs, heat and deregulated oncogenes.1 The Bcl-2 family of genes encodes a family of closely related proteins that possess either pro apoptotic or anti-apoptotic activity and share up to four Bcl-2 Homology (BH) domains.2,3,4,5 The anti-apoptotic family members (Bcl-XL, Bcl-2, Bcl-w, Bcl-B, A1 and Mcl 1) are characterized by four BH domains that are designated BH1-4. The pro apoptotic family members can be further subdivided into multidomain proteins (Bax, Bak) and the BH3-only proteins (Bad, Bik, Bid, Bim Hrk, Bmf, Noxa, Puma). The interplay between these three groups of proteins serves as the gateway to the intrinsic apoptosis pathway. ABT-263 is a novel small molecule Bcl-2 family protein inhibitor that binds with high affinity (Ki  1 nM) to multiple anti-apoptotic Bcl-2 family proteins including Bcl-XL, Bcl-2, Bcl-w, and Bcl-B. ABT-263 displays potent mechanism-based cytotoxicity (EC50  1 M) against human tumor cell lines derived from small cell lung carcinomas and lymphoid malignancies. ABT-263 exhibits potent single agent activity against 10 of 22 cell lines consisting of multiple leukemia and lymphoma types spanning both B-cell and T-cell malignancies. In two flank models of diffuse large B-cell lymphoma (DoHH-2 and WSU-DLCL2), significant monotherapy activity was noted when ABT-263 was administered at a dose of 100 mg/kg/day given p.o., q.d.  17 days. Both of these tumors are known to express high levels of Bcl-2 due to the t(14;18) translocation. The WSU-DLCL2 line was isolated from a patient whose disease progressed following chemotherapy, radiation therapy and bone marrow transplantation and is recognized as a model of therapy-resistant lymphoma.