调节精氨酸代谢途径作为重组精氨酸脱亚氨酶的潜在抗肿瘤机制。

Modulation of arginine metabolic pathways as the potential anti-tumor mechanism of recombinant arginine deiminase.

作者信息

Shen Li-Jiuan, Beloussow Karin, Shen Wei-Chiang

机构信息

Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, 404B, Los Angeles, CA 90089-9121, USA.

出版信息

Cancer Lett. 2006 Jan 8;231(1):30-5. doi: 10.1016/j.canlet.2005.01.007.

DOI:10.1016/j.canlet.2005.01.007

PMID:16356828

Abstract

Arginine deiminase (ADI), currently in clinical trials, has various biological activities including anti-proliferation, anti-angiogenesis and inhibition of inducible nitric oxide synthase (iNOS). To recognize limitations and therapeutic applications, the mechanism of ADI modulation of arginine metabolic pathways was investigated. MCF-7 and A549 cells have notable different sensitivity to recombinant ADI (rADI) and express diverse argininosuccinate synthase (AS) activity, which regenerates arginine. Due to compartmentalization of arginine, utilization of arginine for protein synthesis occurs from either the intracellular arginine pool or the citrulline-arginine-regeneration pathway, whereas for polyamine synthesis, utilization is only from the intracellular arginine pool. Modulating AS activity or introducing rADI intracellularly to reduce intracellular arginine regeneration may expand therapeutic applications of rADI.

摘要

精氨酸脱亚氨酶（ADI）目前正处于临床试验阶段，具有多种生物学活性，包括抗增殖、抗血管生成以及抑制诱导型一氧化氮合酶（iNOS）。为了认识其局限性和治疗应用，对ADI调节精氨酸代谢途径的机制进行了研究。MCF-7细胞和A549细胞对重组ADI（rADI）具有显著不同的敏感性，并且表达不同的精氨琥珀酸合酶（AS）活性，该酶可使精氨酸再生。由于精氨酸的区室化，用于蛋白质合成的精氨酸利用来自细胞内精氨酸池或瓜氨酸-精氨酸再生途径，而对于多胺合成，利用仅来自细胞内精氨酸池。调节AS活性或在细胞内引入rADI以减少细胞内精氨酸再生可能会扩大rADI的治疗应用。