Daily variation in non-protein sulfhydryl levels of human bone marrow

There is increasing evidence that the dosing of certain antineoplastic agents based on a circadian type of schedule may have a beneficial effect on the outcome of patient therapy. Such regimens allow for a more intensive course of drugs to be administered due to a reduction in the toxicities associated with these agents. Since many of the antineoplastics in use today either form reactive intermediates or generate toxic free radical species within the cell, cellular thiols such as glutathione may play a role in their detoxification. Our studies were designed to investigate whether there exists a consistent daily fluctuation in the thiol content in human bone marrow samples. Five normal male volunteers, ages 26-32 years, underwent repeat bone marrow aspirations at approx. 8 a.m. and 8 p.m. Mean peak non-protein sulfhydryl (NPSH) levels of 47.7 nmole/mg protein occurred in morning bone marrow aspirates while evening aspirates showed markedly reduced mean levels of 7.9 nmole/mg protein. Reduced glutathione was used as a standard in these assays which measured sulfhydryls spectrophotometrically using Ellman's reagent. Our findings may help to explain the observed reduction in myelotoxicity in chemotherapy designed to take advantage of human circadian rhythms. These results support the proposition that the administration of certain cytotoxic drugs to match peak levels of thiols in the marrow may facilitate more intensive and active chemotherapy regimens.