Circadian phase relationships between peripheral blood variables and bone marrow proliferative activity in clinical...

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.