Tumor Growth Rate Determines the Timing of Optimal Chronomodulated Treatment Schedules

In host and cancer tissues, drug metabolism and susceptibility to drugs vary in a circadian (24 h) manner. In particular, the efficacy of a cell cycle specific (CCS) cytotoxic agent is affected by the daily modulation of cell cycle activity in the target tissues. Anti-cancer chronotherapy, in which treatments are administered at a particular time each day, aims at exploiting these biological rhythms to reduce toxicity and improve efficacy of the treatment. The circadian status, which is the timing of physiological and behavioral activity relative to daily environmental cues, largely determines the best timing of treatments. However, the influence of variations in tumor kinetics has not been considered in determining appropriate treatment schedules. We used a simple model for cell populations under chronomodulated treatment to identify which biological parameters are important for the successful design of a chronotherapy strategy. We show that the duration of the phase of the cell cycle targeted by the treatment and the cell proliferation rate are crucial in determining the best times to administer CCS drugs. Thus, optimal treatment times depend not only on the circadian status of the patient but also on the cell cycle kinetics of the tumor. Then, we developed a theoretical analysis of treatment outcome (TATO) to relate the circadian status and cell cycle kinetic parameters to the treatment outcomes. We show that the best and the worst CCS drug administration schedules are those with 24 h intervals, implying that 24 h chronomodulated treatments can be ineffective or even harmful if administered at wrong circadian times. We show that for certain tumors, administration times at intervals different from 24 h may reduce these risks without compromising overall efficacy

Effects of two infectious bursal disease vaccine virus strains on hepatic microsomal enzyme activities in chickens

The influence of two infectious bursal disease vaccines on the activities of hepatic microsomal enzymes aniline hydroxylase, ethylmorphine N-demethylase, NADPH-cytochrome c reductase, aryl sulphotransferase and p-nitrophenol UDP-glucuronyltransferase was investigated in chickens. The vaccines contained attenuated Winterfield 2512 and VMG-91 strains, respectively. The activities of enzymes were determined on postvaccination days 0, 2, 5 and 7. At the same time, post-mitochondrial supernatant, cytosolic and microsomal pellet protein concentrations were determined. As expected. the antibody titres against infectious bursal disease virus in the serum were increased in both tested groups in relation to each administered vaccine. Using RT-PCR, the presence of the VP2 gene fragment of virus in the liver of chicken was demonstrated 4 and 6 h after vaccination. The results of this study suggest that the two commercial vaccines modulate the activities of five enzymes tested, and that the two attenuated vaccines applied triggered induction and/or inhibition of phases I and II of biotransformation enzyme activities