Circadian and ultradian cytokinetic rhythms of spontaneous human cancer.
Circadian and ultradian cytokinetic rhythms of spontaneous human cancer.
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自发性人类癌症的昼夜节律和超节律细胞分裂节律。
DOI：
10.1111/j.1749-6632.1991.tb27248.x
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发表时间：
1991
影响因子：
5.2
通讯作者：
Braly,PS
中科院分区：
文献类型：
--
作者：
Klevecz,RR;Braly,PS
几年前，基于治疗策略的失败，细胞动力学定向化疗被驳回，这些治疗策略假设肿瘤细胞在体内的增殖是一个随机过程，独立于宿主的稳定的内源性节律性，或不受宿主的稳定的内源性节律性的影响。未能理解细胞动力学的昼夜节律调节的一个后果是治疗策略从细胞周期特异性药物转向延长终端半衰期的药物，如阿霉素。一个新的、同样严重的问题来自于试图实现全天候高水平抗癌药物持续高水平给药方案的运动。后一种策略不仅颠覆了细胞动力学的时间生物学，而且颠覆了药物毒性的时间药理学。最后，许多抗癌药物都是强有力的相移剂。可以认为，这种相位扰动可能通过过度复制早期复制的DNA而增加耐药性，注意时机和使用非相移剂的药物可能会将耐药性的发展降至最低。我们错误地认为，通常被视为不考虑细胞动力学癌症化疗方法的基础是分段标记研究，其中标记的核或标记的中期细胞的比例是放射自显影计分。最近，来自一个或几个流式细胞DNA直方图的S相估计已经取代了标记方法，但没有应用时间生物学原理来解释它们。分段标记研究中，“HDT或其他DNA前体在一天中的一次或几次给药，很少会具体说明这些时间。”这种方法将得出当时正在复制的细胞的比例，如果遵循标记中期的曲线，则将得出添加标记时处于S期的细胞队列的染色体复制周期时间。尽管早晨和晚上复制DNA的细胞数量可能有很大差异，但即使S的相变时间延长，标记的中期分裂曲线的比例也是相似的。在非常活跃的增殖组织中，通常在体外，原始标记细胞的每个子细胞在尽可能短的时间内开始DNA合成，可以很好地估计细胞周期持续时间。在以下情况下
Cell kinetic directed chemotherapy was dismissed some years ago based on the failure of treatment strategies that assumed tumor cell proliferation in vivo to be a random process independent of, or unentrained by, the stable, endogenous rhythmicity of the host.'" One consequence of this failure to understand the circadian modulation of cell kinetics has been the evolution of treatment strate-gies away from cell cycle specific drugs and toward drugs, such as Adriamycin, that have prolonged terminal half-lives. A new and equally serious problem comes from the movement toward drug delivery regimens that attempted to achieve constant high levels of anticancer agents around the clock. This latter strategy subverts not only the chronobiology of cell kinetics but the chronopharmacology of drug toxicity. Finally, many anticancer drugs are powerful phase-shifting agents. It can be argued that such phase perturbation may act to increase drug resistance through overreplication of early replicating DNA, and that attention to timing and the use of drugs that are not phase-shifting agents may minimize the development of resistance.What is often, and mistakenly we believe, taken to be the basis for dismissing cell kinetic approaches to cancer chemotherapy are fractional labeling studies, where the fraction of labeled nuclei, or labeled metaphase cells, is scored autoradiographically. More recently Sphase estimates from one or a few flow cytometric DNA histograms have replaced labeling methods but have not applied chronobiologic principles to their interpretation. Fractional labeling studies in which" HdT or other DNA precursors are given at one or a few times of day, rarely if ever specify those times." This approach will yield the fraction of cells that are replicating at that time and, if the curve for labeled metaphases is followed, the chromosome replication cycle time of the cohort of cells in Sphase when the label was added. In spite of the fact that there may be great differences in the number of cells replicating DNA between morning and evening, the fraction of labeled metaphase (FLM) curves are similar even though S phase transit times are length-ened." In very actively proliferating tissues, usually in vitro, where each daughter cell of the original labeled cell begins DNA synthesis in the minimum possible time, a good estimate of cell cycle duration may be obtained. In the case where