Latent hematopoietic stem cell toxicity associated with protracted drug administration

Objective. The protracted administration of near-conventional daily doses o f chemotherapeutic agents is a strategy to increase dose intensity and, pot entially, efficacy as well. However, protracted therapy carries the risk of damage to stem cells in proliferative tissues that are not targeted by int ermittent schedules. Therefore, we have investigated the effects produced b y the protracted administration of two anticancer drugs on hematopoietic st em cell function. Materials and Methods. We used the competitive repopulating assay to assess stem cell damage caused by protracted daily drug treatment of mice. Results. Treatment with acetyldinaline for 10 consecutive days mediated a m odest effect on the short-term repopulating cells (STRCs) but spared the lo ng-term repopulating cells (LTRCs). Gemcitabine for 10 days led to a modest decline in both the STRCs and LTRCs. Extending treatment with gemcitabine for 28 days resulted in more severe repopulating cell (RC) damage, which wa s much worse than in acetyldinaline-treated mice. As expected, melphalan fo r 10 or 28 days mediated a marked reduction in all of the RCs of treated mi ce. The analysis of the RCs from mice that were allowed a 1-year recovery p eriod after completing the 28-day treatment with either acetyldinaline or g emcitabine showed normal levels of neutrophils and bone marrow (BM) progeni tors. However, a reduction in the RCs was observed in both groups, with lar ger reductions in gemcitabine-treated mice. Conclusions. Our data show that protracted treatment with gemcitabine, but not acetyldinaline, of mice caused severe permanent damage to the stem cell components. Therefore, although 28-day therapy with acetyldinaline or gemc itabine appeared to be well tolerated at the level of peripheral blood and bone marrow progenitors, gemcitabine produces permanent stem cell damage wh en used in long-term administration regimens that should perhaps only be ex plored clinically with stem cell support available. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science Inc.