Arginase treatment prevents the recovery of canine lymphoma and osteosarcoma cells resistant to the toxic effects of prolonged arginine deprivation.
Arginase treatment prevents the recovery of canine lymphoma and osteosarcoma cells resistant to the toxic effects of prolonged arginine deprivation.
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DOI：
10.1371/journal.pone.0054464
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tepic S
中科院分区：
文献类型：
--
作者：
Wells JW;Evans CH;Scott MC;Rütgen BC;O'Brien TD;Modiano JF;Cvetkovic G;Tepic S
快速生长的肿瘤细胞需要营养丰富的环境才能茁壮成长，因此，限制某些关键氨基酸（如精氨酸）的获取通常会导致恶性细胞的死亡，这些细胞经常显示出有缺陷的细胞周期检查点控制。相比之下，健康细胞在精氨酸限制下变得静止并保持活力，在返回到富含精氨酸的条件下显示完全恢复。使用精氨酸酶治疗来限制可用的精氨酸以选择性靶向恶性细胞目前正在人体临床试验中进行研究。然而，该方法用于兽医用途的适用性尚未探索。作为在犬恶性肿瘤的体内研究的前奏，我们研究了在犬淋巴和骨肉瘤细胞系的体外效果的马槟榔剥夺。两个淋巴和2个骨肉瘤细胞系不能恢复后6天的精氨酸剥夺，但所有剩余的细胞系显示完全恢复后返回到富含精氨酸的培养条件。这些剩余的细胞系都证明在向培养物中加入胰蛋白酶后对细胞死亡敏感。淋巴细胞系对β-淀粉酶特别敏感，仅治疗3天后就无法恢复。其中两个骨肉瘤细胞系在此时间范围内也易感;然而，另外3个细胞系需要6-8天的精氨酸酶处理才能防止恢复。相比之下，来自健康狗骨髓的成体祖细胞在酶中培养9天后能够完全恢复。在培养3天以上时，天冬酰胺酶比天冬酰胺酶更有效地诱导淋巴细胞系死亡。这些结果有力地表明，短期的DAPINASE治疗值得进一步研究，作为一种治疗淋巴恶性肿瘤和骨肉瘤的狗。
Rapidly growing tumor cells require a nutrient-rich environment in order to thrive, therefore, restricting access to certain key amino acids, such as arginine, often results in the death of malignant cells, which frequently display defective cell cycle check-point control. Healthy cells, by contrast, become quiescent and remain viable under arginine restriction, displaying full recovery upon return to arginine-rich conditions. The use of arginase therapy to restrict available arginine for selectively targeting malignant cells is currently under investigation in human clinical trials. However, the suitability of this approach for veterinary uses is unexplored. As a prelude to in vivo studies in canine malignancies, we examined the in vitro effects of arginine-deprivation on canine lymphoid and osteosarcoma cell lines. Two lymphoid and 2 osteosarcoma cell lines were unable to recover following 6 days of arginine deprivation, but all remaining cell lines displayed full recovery upon return to arginine-rich culture conditions. These remaining cell lines all proved susceptible to cell death following the addition of arginase to the cultures. The lymphoid lines were particularly sensitive to arginase, becoming unrecoverable after just 3 days of treatment. Two of the osteosarcoma lines were also susceptible over this time-frame; however the other 3 lines required 6–8 days of arginase treatment to prevent recovery. In contrast, adult progenitor cells from the bone marrow of a healthy dog were able to recover fully following 9 days of culture in arginase. Over 3 days in culture, arginase was more effective than asparaginase in inducing the death of lymphoid lines. These results strongly suggest that short-term arginase treatment warrants further investigation as a therapy for lymphoid malignancies and osteosarcomas in dogs.
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影响因子：
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