Tumors of the nervous system including glioblastoma multiforme (GBM) are the most frequent and aggressive form of brain tumors; however, little is known about the impact of the circadian timing system on the formation, growth, and treatment of these tumors. We investigated day/night differences in tumor growth after injection of A530 glioma cells isolated from malignant peripheral nerve sheath tumor (MPNSTs) of NPcis (Trp53+/- ; Nf1+/- ) mice. Synchronized A530 cell cultures expressing typical glial markers were injected at the beginning of the day or night into the sciatic nerve zone of C57BL/6 mice subject to a 12:12 hours light/dark (LD) cycle or after being released to constant darkness (DD). Tumors generated in animals injected early at night in the LD cycle or in DD showed higher growth rates than in animals injected diurnally. No differences were found when animals were injected at the same time with cultures synchronized 12 hours apart. Similar experiments performed with B16 melanoma cells showed higher tumor growth rates in animals injected at the beginning of the night compared to those injected in the daytime. A higher tumor growth rate than that in controls was observed when mice were injected with knocked-down clock gene Bmal1 cells. Finally, when we compared day/night administration of different doses of the proteasome inhibitor Bortezomib (0.5-1.5 mg/kg) in tumor-bearing animals, we found that low-dose chemotherapy displayed higher efficacy when administered at night. Results suggest the existence of a precise temporal control of tumor growth and of drug efficacy in which the host state and susceptibility are critical.

中文翻译：

---

夜间哺乳动物肿瘤生长的时间调控：体内研究和化疗潜力

包括多形性胶质母细胞瘤 (GBM) 在内的神经系统肿瘤是最常见和最具侵袭性的脑肿瘤形式。然而，人们对昼夜节律计时系统对这些肿瘤的形成、生长和治疗的影响知之甚少。我们研究了注射从 NPcis (Trp53+/-; Nf1+/-) 小鼠的恶性外周神经鞘瘤 (MPNSTs) 分离的 A530 神经胶质瘤细胞后肿瘤生长的昼夜差异。在白天或夜晚开始时，将表达典型神经胶质标志物的同步 A530 细胞培养物注射到 C57BL/6 小鼠的坐骨神经区中，进行 12:12 小时的光/暗 (LD) 循环或在被释放到持续黑暗后。 DD）。在 LD 循环或 DD 的夜间早期注射的动物中产生的肿瘤显示出比昼夜注射的动物更高的生长速率。当动物同时注射间隔 12 小时同步的培养物时，没有发现差异。用 B16 黑色素瘤细胞进行的类似实验表明，与白天注射的动物相比，在夜间开始注射的动物的肿瘤生长率更高。当小鼠注射敲低的时钟基因 Bmal1 细胞时，观察到比对照组更高的肿瘤生长率。最后，当我们比较不同剂量蛋白酶体抑制剂硼替佐米 (0.5-1.5 mg/kg) 在荷瘤动物中的日夜给药时，我们发现低剂量化疗在夜间给药时表现出更高的疗效。结果表明存在对肿瘤生长和药物功效的精确时间控制，其中宿主状态和易感性至关重要。