Cycling characteristics of endogenous spleen colony-forming cells as measured with cytosine arabinoside and methotrexate.

Abstract

Abstract Single injections of the cycle-active drugs cytosine arabinoside and methotrexate induced a profound reduction in endogenous spleen colonies when given either shortly before or after irradiation. This is in marked contrast to the relative lack of effect of these drugs on normal exogenous (transplanted spleen colony-forming units) and more like their effect on rapidly replicating exogenous colony-forming cells. These data suggest that the normal endogenous colony-forming compartment is composed primarily of cells in rapid cell cycle as opposed to the nonreplicating state thought to be most common for exogenous colony-forming cells. The data did not support the concept that cytosine arabinoside remained in circulation until after irradiation and then killed cells as they began to divide. Plasma disappearance rate of cytosine arabinoside was the same (T12 about 32 minutes) in normal or irradiated mice. Neither large doses of cytosine arabinoside or methotrexate nor minimal doses (expected to leave the plasma very quickly) were more effective given after than before irradiation. The most likely explanation for the different response of endogenous colony-forming cells as compared to exogenous is that these were in the same stage of cell cycle (probably S-phase) shortly before and after irradiation and that they survived irradiation better than cells in other stages. Maximum killing was obtained when the drugs were given within 15 minutes of irradiation as compared to 1 to 4 hours before or after, suggesting that some synchronization was induced by irradiation. Different responses of endogenous and exogenous colony-forming cells have been noted before and the present data suggest a possible reason. It is still not clear whether these are different stem-cell compartments and endogenous colony-forming cells are rapidly turning over and relatively less radiosensitive or whether these cells represent the cycling portion of the exogenous colony-forming compartment.