Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex
Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex
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DOI：
10.1073/pnas.0409897102
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发表时间：
2005-03-01
影响因子：
11.1
通讯作者：
Antoch, MP
中科院分区：
文献类型：
--
作者：
Gorbacheva, VY;Kondratov, RV;Antoch, MP
生物钟控制着哺乳动物生理学的许多方面，包括对癌症治疗的反应。我们发现野生型和生物钟突变型小鼠在对抗癌药物环磷酰胺（CY）的反应上表现出显著差异。野生型小鼠的敏感性差异很大，这取决于给药时间，而Clock突变型和Bmal1基因敲除型小鼠在所有测试时间对治疗都高度敏感。相反，隐花色素功能缺失突变小鼠（Cry1（ - / - ）Cry2（ - / - ）双基因敲除型）与它们的野生型同窝小鼠相比，对CY更具抗性。因此，对化疗反应的每日时间差异和等位基因依赖性变化都与生物钟CLOCK/BMAL1反式激活复合物的功能状态相关。对不同CY代谢产物血浆浓度的药代动力学分析表明，与传统观点相反，药物敏感性的生物钟变化不能归因于CY代谢激活和/或解毒速率的变化。同时，不同生物钟基因型的小鼠在B细胞对有毒CY代谢产物的反应上表现出显著差异：B细胞存活/恢复率与体内药物敏感性直接相关。基于这些结果，我们提出CLOCK/BMAL1转录复合物通过调节生物体生存所必需的靶细胞的存活来影响化疗药物的致死性。
The circadian clock controls many aspects of mammalian physiology, including responses to cancer therapy. We find that wild-type and circadian mutant mice demonstrate striking differences in their response to the anticancer drug cyclophosphamide (CY). While, the sensitivity of wild-type mice varies greatly, depending on the time of drug administration, Clock mutant and Bmal1 knockout mice are highly sensitive to treatment at all times tested. On the contrary, mice with loss-of-function mutations in Cryptochrome (Cry1(-/-)Cry2(-/-) double knockouts) were more resistant to CY compared with their wild-type littermates. Thus, both time-of-day and allelic-dependent variations in response to chemotherapy correlate with the functional status of the circadian CLOCK/BMAL1 transactivation complex. Pharmacokinetic analysis of plasma concentration of different CY metabolites shows that, in contrast to the traditional view, circadian variations in drug sensitivity cannot be attributed to the changes in the rates of CY metabolic activation and/or detoxification. At the same time, mice of different circadian genotypes demonstrate significant differences in B cell responses to toxic CY metabolites: B cell survival/recovery rate was directly correlated with the in vivo drug sensitivity. Based on these results, we propose that the CLOCK/BMAL1 transcriptional complex affects the lethality of chemotherapeutic agents by modulating the survival of the target cells necessary for the viability of the organism.