Smaaland R, Sothern R B, Lote K, Sandberg S, Aakvaag A, Laerum O D
Department of Oncology, Haukeland Hospital, University of Bergen, Norway.
In Vivo. 1995 Jul-Aug;9(4):379-89.
Potential life-threatening drug induced side effects to the bone marrow (BM) may be reduced by the proper timing of chemotherapy (chronotherapy) according to circadian stage. Blood and BM samples were obtained concomitantly every 4h for 24h from 16 healthy men (19 series total) to compare circadian patterns in peripheral blood (PB) as reference rhythms for BM DNA. Circadian rhythm characteristics from population mean cosinor summary follow (phi = acrophase): in PB: cortisol, p = 0.014, phi = 13:04h; leukocytes (/mm3), p = 0.001, phi = 00:16h; neutrophils (%WBC), p = 0.001, phi = 15:36h; neutrophils (/mm3), p = 0.101, phi = 22:36h; lymphocytes (%WBC), p = 0.009, phi = 03:24h; lymphocytes (/mm3), p = 0.001, phi = 0.1:40h; in BM:DNA, p = 0.014, phi = 13:04h; and CFU-GM, p = 0.041, phi = 13:12h. When all DNA synthesis (S-phase) values were correlated with PB values by repeatedly advancing the DNA values by 4h, significant correlations with cortisol were found by advancing S-phase by 8h (r = 0.19, p = 0.050). Lymphocytes correlated best with S-phase when shifted by 12h (r = 0.37, p < 0.001), while neutrophils as % of leukocytes (but not absolute counts) correlated significantly when S-phase was delayed by 4h (r = 0.35, p < 0.001). These correlations confirm the phase relationships determined for the circadian rhythms. These findings suggest that the proper timing of an optimized anticancer cytotoxic chronotherapy can be confirmed and guided via sampling of marker rhythms (such as lymphocytes) in peripheral blood which have been found to demonstrate a relatively fixed relation to the circadian stage-dependent variation in unaffected BM proliferative activity.
根据昼夜节律阶段进行化疗（时间疗法）的适当时间安排，可能会降低对骨髓（BM）有潜在生命威胁的药物诱导副作用。从16名健康男性（共19组）身上每4小时同时采集一次血液和骨髓样本，持续24小时，以比较外周血（PB）中的昼夜节律模式，作为骨髓DNA的参考节律。群体均值余弦分析总结的昼夜节律特征如下（φ = 峰值相位）：在外周血中：皮质醇，p = 0.014，φ = 13:04时；白细胞（/mm³），p = 0.001，φ = 00:16时；中性粒细胞（%白细胞），p = 0.001，φ = 15:36时；中性粒细胞（/mm³），p = 0.101，φ = 22:36时；淋巴细胞（%白细胞），p = 0.009，φ = 03:24时；淋巴细胞（/mm³），p = 0.001，φ = 01:40时；在骨髓中：DNA，p = 0.014，φ = 13:04时；以及集落形成单位 - 粒细胞巨噬细胞（CFU - GM），p = 0.041，φ = 13:12时。当通过将DNA值反复提前4小时，使所有DNA合成（S期）值与外周血值相关联时，将S期提前8小时发现与皮质醇有显著相关性（r = 0.19，p = 0.050）。淋巴细胞在提前12小时时与S期相关性最佳（r = 0.37，p < 0.001），而当中性粒细胞占白细胞的百分比（而非绝对计数）在S期延迟4小时时有显著相关性（r = 0.35，p < 0.001）。这些相关性证实了所确定的昼夜节律的相位关系。这些发现表明，通过在外周血中对标记节律（如淋巴细胞）进行采样，可以确认并指导优化的抗癌细胞毒性时间疗法的适当时间安排，已发现外周血中的标记节律与未受影响的骨髓增殖活性中依赖昼夜节律阶段的变化呈现相对固定的关系。
