Circannual rhythm in DNA synthesis (S‐phase) in healthy human bone marrow and rectal mucosa 1

Abstract

Cytotoxic anti-cancer drugs are meant to interact with tumor cells to impair the replicative and/or transcriptional functions of DNA in order to reduce proliferative rate and cause cell death. These drugs also affect rapidly proliferating healthy tissues such as the bone marrow and the gastrointestinal tract, thereby resulting in toxicity-related dose reductions and/or delays in treatment. We previously demonstrated a circadian rhythm in DNA synthesis (S-phase) of total bone marrow (BM) nucleated cells in 16 healthy, diurnally active men sampled every 4 h for 24 h (19 series). Highest values determined by flow cytometry were found near midday. We also reported a circadian rhythm in DNA synthesis of the rectal mucosa (RM) in 16 healthy men sampled every 2-3 h for 24 h under fed and fasting conditions (24 series). Highest proliferative activity as reflected by in vitro [3H]Tdr uptake, was found near the time of awakening. Circannual (about yearly) rhythmicity in cell division rates may also influence treatment effects. Our BM and RM DNA data, which were collected over several years, were reanalyzed for seasonality by ANOVA and for circannual rhythm by the least-squares fit of a 1 year cosine. Characteristics of circadian amplitudes and acrophases were also compared between seasons. In addition to a significant circadian rhythm, a significant circannual rhythm in cell proliferation in healthy BM (P = 0.008) and RM (P < 0.001) could be established on the basis of these serially independent data. The range between the lowest and highest points of the fitted 1 year cosine (circannual double amplitude) was comparable to the circadian range for BM (25%); it was at least doubled for RM (70%). Highest values occurred in the late summer for BM and mid-fall for RM. Based on limited data in some seasons, the circadian patterns were more prominent in the fall and winter, with larger amplitudes and later acrophases, when compared with summer for BM and spring and summer for RM. Thus, in addition to time of day, time of year may influence chemo- and immunotherapeutic strategies and should be considered in the design of preclinical and clinical treatment regimens and other procedures.