Effect of the dosing interval on myelotoxicity and survival in mice treated by cytarabine

Many antineoplastic drugs are cell-cycle-phase-specific. These drugs are often highly toxic to the host, as they have the potential to impair replication, not only in the cancer cells, but also in the normal tissues. Using mathematical models it has been shown how selectivity of these drugs can be increased by exploiting the relatively large variability in cell-cycle parameters of the neoplasia. These models predict that toxicity to the host of cell-cycle-phase-specific drugs can be minimised if the dosing interval is an integer multiple of the average intermitotic interval of the susceptible host cells. Experimental evidence supporting this prediction is presented in this work. Our results show that a constant duration of the dosing interval yields higher survival rates in mice treated by cytarabine, as compared with random dosing intervals. Minimal myelotoxicity is exerted when the dosing interval is an exact multiple of the inter-mitotic time of bone marrow stem cells and erythroid progenitors (i.e. 7 h). Survival is significantly lower in mice treated every 8 h, or its multiple, as compared with that of mice treated at a 7 h or 10 h dosing interval.