Chronobiology, chronotoxicity, chronoefficacy!

Just picked up this article on Wee1 expression in the circadian rhythm dependent intestinal damage induced by docetaxel from Fujimura’s group which identifies increased expression of Wee1 (controlled by the clock gene complex clock/bmal), phosphorylated CDK1, and cleaved Caspase-3 and lower levels of survivin in animals dosed with docetaxel 14 hours after lights on (HALO) compared with those dosed 2 HALO. The 14 HALO group showed increased intestinal damage compared with the 2 HALO group although the mechanistic relationship of the changes in protein expression and intestinal damage is unclear. Drug exposures were the same from the two dosing protocols. It has previously been suggested that docetaxel is more efficacious when dosed during the light period time point while another recent report highlighted the circadian nature of toxicity and efficacy of oxaliplatin. The idea of chronotherapy is, of course, not new with various reviews written on the field . Finally chronotoxicity as determined by MTD and efficacy for celecoxib is discussed with respect to efficacy in a breast cancer mouse xenograft model I found the results quite impressive.

However, this did set me thinking a few thoughts. Do we as research scientists consider sufficiently the timing of drug dosing either for efficacy or for minimising side effects either preclinically or clinically? Is this a variable that needs tighter control in the preclinical setting? What are the consequences on drug efficacy for those who suffer from disrupted sleep patterns (be it due to ill health, life style or required work patterns)? Could co-administration (or with a 12hr off-set) of an appropriate hypnotic (and its not entirely clear what would be an appropriate hypnotic) or improved sleep hygiene improve efficacy of some therapeutics?