Persistence of the Chromosome End Regions at Low Copy Number in Mutant Strains of Streptomyces rimosus and Streptomyces lividans

Streptomycetes are important antibiotic producing bacteria that often exhibit genetic instability. One or both ends of the linear Streptomyces chromosome are lost spontaneously, resulting in viable mutant strains sometimes lacking hundreds of genes. We examined some strains of Streptomyces rimosus and Streptomyces lividans, which had been classified as »deletion mutants« and appeared to have lost chromosome end sequences. We discovered that the »deleted« sequences were still present in vegetative mycelium at a very low copy number so that they were normally not detected. The copy number in S. rimosus was estimated as 0.1–1.0 10–3/chromosome. Streptomyces spores contain the disappearing chromosome end sequences at a higher copy number than the vegetative mycelium, promoting their inheritance via spore preparations. This, in effect, represents a separation between germ line and deleted vegetative genomes, which has not been recognised before in Streptomyces, and has practical implications both for strain preservation and genetic studies

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