Phase I/II study of BCL-family inhibitors in lymphoma

Bcl-2家族蛋白是内源性凋亡途径的重要调节因子。 Bcl-2癌基因首先在滤泡性淋巴瘤中发现，其中t（14;18）染色体 易位导致B细胞中蛋白质的显著过表达。相比 与其他已知的癌基因相比，Bcl-2不刺激细胞增殖，而是抑制细胞增殖。 通过保护细胞免受多种促凋亡刺激而导致程序性细胞死亡， 包括细胞因子戒断、辐射、细胞毒性药物、热和致癌基因失调。 Bcl-2基因家族编码一个密切相关的蛋白质家族， 凋亡或抗凋亡活性，并共享多达四个Bcl-2同源（BH）结构域。2，3，4，5 抗凋亡家族成员（Bcl-XL、Bcl-2、Bcl-w、Bcl-B、A1和Mcl 1）是 其特征在于被命名为BH 1 -4的四个BH结构域。促凋亡家族成员 可进一步细分为多结构域蛋白（Bax，巴克）和仅BH 3蛋白（Bad， Bik、Bid、Bim Hrk、Bmf、Noxa、Puma）。这三组蛋白质之间的相互作用 作为通向内在凋亡途径的通道。ABT-263是一种新型小分子药物 Bcl-2家族蛋白抑制剂，以高亲和力（Ki #61603; 1 nM）结合至 多种抗凋亡Bcl-2家族蛋白，包括Bcl-XL、Bcl-2、Bcl-w和Bcl-B。 ABT-263显示出有效的基于机制的细胞毒性（EC50#61603; 1 M）针对源自小细胞肺癌的人肿瘤细胞系 和淋巴恶性肿瘤。ABT-263对22种细胞中的10种表现出有效的单药活性 由跨越B细胞和T细胞的多种白血病和淋巴瘤类型组成的细胞系 恶性肿瘤。在弥漫性大B细胞淋巴瘤（DoHH-2和WSU-DLCL 2）的双侧模型中， 当ABT-263以100 mg/kg的剂量给药时， 经口给药mg/kg/天，q.d. &十七天。已知这两种肿瘤 由于t（14;18）易位而表达高水平的Bcl-2。WSU-DLCL 2系是 分离自在化疗、放疗和化疗后疾病进展的患者， 骨髓移植，并被认为是治疗抗性淋巴瘤的模型。

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.