Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.
Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.
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DOI：
10.1016/j.jphs.2018.01.008
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发表时间：
2018-04
影响因子：
3.5
通讯作者：
Shoya Shiromizu;Naoki Kusunose;Naoya Matsunaga;S. Koyanagi;S. Ohdo
中科院分区：
文献类型：
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作者：
Shoya Shiromizu;Naoki Kusunose;Naoya Matsunaga;S. Koyanagi;S. Ohdo
急性淋巴细胞白血病细胞的增殖在营养上依赖于天冬酰胺的外部供应。l-天冬酰胺酶是一种水解血液中的l-天冬酰胺的酶，用于治疗急性淋巴细胞白血病和其他相关的血癌。虽然先前的研究表明，l-天冬酰胺酶抑制培养实体瘤细胞的增殖，但该酶是否能阻止实体瘤在体内的生长尚不清楚。在这项研究中，我们证明了优化给药方案对l-天冬酰胺酶在4T1乳腺荷瘤小鼠中的抗肿瘤活性的重要性。几种类型的小鼠实体瘤细胞的培养依赖于外部供应的天冬酰胺。其中，我们选择小鼠4T1乳腺癌细胞，将其植入BALB/c雌性小鼠体内，在标准化的光/暗周期条件下保存。在光照期静脉给药-天冬酰胺酶可显著抑制小鼠体内4T1肿瘤细胞的生长，而在暗期给药则未显示出明显的抗肿瘤活性。血浆天冬酰胺水平的降低与天冬酰胺抗肿瘤作用的给药时间依赖性密切相关。上述结果提示，优化给药方案可提高l-天冬酰胺酶对乳腺荷瘤小鼠的抗肿瘤作用。
Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine.l-asparaginase, an enzyme hydrolyzingl-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated thatl-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumorsin vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity ofl-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration ofl-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration ofl-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy ofl-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule.