Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
PLoS One. 2019 May 6;14(5):e0216328. doi: 10.1371/journal.pone.0216328. eCollection 2019.
Combination therapy for acute lymphoblastic leukemia (ALL) is highly effective but results in significant toxicity including osteonecrosis. Asparaginase is known to potentiate both the antileukemic and osteonecrosis-inducing effects of dexamethasone. The schedule of dexamethasone alters osteonecrosis risk. However, the effects of the interaction with asparaginase are unknown when dexamethasone is given on a discontinuous schedule.
Using the murine model of osteonecrosis, we compared the frequency of osteonecrosis in mice receiving discontinuous dexamethasone (3.5 days/ week) with mice receiving asparaginase and discontinuous dexamethasone. We then tested the effect on antileukemic efficacy using six pediatric ALL xenografts.
The addition of asparaginase to discontinuous dexamethasone did not alter the rate of osteonecrosis compared to dexamethasone alone (7/35 in dexamethasone with asparaginase combination vs. 10/36 in dexamethasone alone, p = 0.62) despite increasing steady-state plasma dexamethasone levels (103.9 nM vs. 33.4 nM, p = 9.2x10-7). Combination therapy with asparaginase and dexamethasone demonstrated synergistic antileukemic effects across all six xenografts studied.
When discontinuous dexamethasone was given, its anti-leukemic activity synergized with asparaginase but the osteonecrosis-worsening effects of asparaginase (above dexamethasone alone) were not observed. Thus, there is a favorable drug interaction (unchanged toxicity, synergistic efficacy) between discontinuous dexamethasone and asparaginase.
急性淋巴细胞白血病（ALL）的联合治疗非常有效，但会导致严重的毒性，包括骨坏死。门冬酰胺酶已知可增强地塞米松的抗白血病和诱导骨坏死作用。地塞米松的给药方案改变了骨坏死的风险。然而，当地塞米松以不连续方案给药时，与门冬酰胺酶的相互作用的影响尚不清楚。
我们使用骨坏死的小鼠模型，比较了接受不连续地塞米松（每周 3.5 天）的小鼠与接受门冬酰胺酶和不连续地塞米松的小鼠的骨坏死频率。然后，我们使用六种儿科 ALL 异种移植来测试对抗白血病疗效的影响。
与单独使用地塞米松相比，门冬酰胺酶的加入并未改变不连续地塞米松的骨坏死率（地塞米松与门冬酰胺酶联合组有 7/35 例，而单独地塞米松组有 10/36 例，p=0.62），尽管稳态血浆地塞米松水平升高（103.9 nM 比 33.4 nM，p=9.2x10-7）。门冬酰胺酶和地塞米松联合治疗在所有六种研究的异种移植中均显示出协同的抗白血病作用。
当给予不连续地塞米松时，其抗白血病活性与门冬酰胺酶协同作用，但门冬酰胺酶（高于单独使用地塞米松）的骨坏死恶化作用并未观察到。因此，不连续地塞米松和门冬酰胺酶之间存在有利的药物相互作用（无毒性增加，协同疗效）。
