Area of Pathobiology, University of Missouri-Columbia, MO, U.S.A.
Anticancer Res. 2011 Oct;31(10):3143-9.
The BCL2 proto-oncogene in non-Hodgkin's lymphoma is a dominant inhibitor of apoptosis. The goal of this work was to develop a (177)Lu-labeled anti-BCL2-peptide nucleic acid (PNA) conjugate designed for dual modality NHL therapy, i.e., simultaneous down-regulation of BCL2-mediated resistance to apoptosis and delivery of cytotoxic internally emitted radiation.
The effect of 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetra-acetic acid (DOTA)-anti-BCL2-Tyr(3)-octreotate was evaluated by uptake, efflux, proliferation, and viability assays, using Mec-1 lymphoma cells. In vitro dosimetry was modeled with a Monte Carlo projection.
Cellular efflux indicated moderate retention of radioactivity in the Mec-1 cells. Viability studies using the (177)Lu-labeled PNA conjugate indicated a mass-dose dependence and strongly additive statistical effect in reducing cellular viability.
These studies demonstrate the ability of a BCL2 antisense PNA conjugate to specifically target, be retained in, and reduce cellular viability in Mec-1 NHL cells. The results also hold promise for the development of a therapeutic radiopharmaceutical with potential dual modality function.
非霍奇金淋巴瘤中的 BCL2 原癌基因是凋亡的主要抑制剂。这项工作的目的是开发一种（177）Lu 标记的抗 BCL2-肽核酸（PNA）缀合物，用于双重模式 NHL 治疗，即同时下调 BCL2 介导的凋亡抵抗和细胞内发射的细胞毒性辐射。
采用 Mec-1 淋巴瘤细胞，通过摄取、外排、增殖和活力测定评估 1,4,7,10-四氮杂环十二烷-N,N',N",N"'-四乙酸（DOTA）-抗 BCL2-Tyr（3）-奥曲肽的作用。使用蒙特卡罗投影进行体外剂量测定。
细胞外排表明放射性物质在 Mec-1 细胞中有中等程度的保留。使用（177）Lu 标记的 PNA 缀合物进行的活力研究表明，细胞活力降低具有质量剂量依赖性和统计学上的强烈相加效应。
这些研究表明，BCL2 反义 PNA 缀合物能够特异性靶向、保留在 Mec-1 NHL 细胞中，并降低其细胞活力。研究结果也为开发具有潜在双重模式功能的治疗放射性药物提供了希望。
