Latent hematopoietic stem cell toxicity associated with protracted drug administration.

OBJECTIVE: The protracted administration of near-conventional daily doses of chemotherapeutic agents is a strategy to increase dose intensity and, potentially, efficacy as well. However, protracted therapy carries the risk of damage to stem cells in proliferative tissues that are not targeted by intermittent schedules. Therefore, we have investigated the effects produced by the protracted administration of two anticancer drugs on hematopoietic stem 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 modest effect on the short-term repopulating cells (STRCs) but spared the long-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 was much worse than in acetyldinaline-treated mice. As expected, melphalan for 10 or 28 days mediated a marked reduction in all of the RCs of treated mice. The analysis of the RCs from mice that were allowed a 1-year recovery period after completing the 28-day treatment with either acetyldinaline or gemcitabine showed normal levels of neutrophils and bone marrow (BM) progenitors. However, a reduction in the RCs was observed in both groups, with larger 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 gemcitabine appeared to be well tolerated at the level of peripheral blood and bone marrow progenitors, gemcitabine produces permanent stem cell damage when used in long-term administration regimens that should perhaps only be explored clinically with stem cell support available.

Cytotoxic chemotherapy regimens that increase dose per cycle (dose intensity) by extending daily dosing from 5 consecutive days to 28 consecutive days and beyond.

Dose intensity, defined as dose administered per unit time, has emerged as a potentially important measurement of anticancer drug exposure and determinant of efficacy. There are several strategies for increasing dose intensity, one being a protracted daily dosing strategy without major dose reduction for toxicity. This strategy involves continued therapy during periods of recovery from reversible toxicity, and it inherently challenges our understanding that renewing tissues cannot repopulate (recover) in the continued presence of cytotoxic drug. We have tested this idea directly in a murine preclinical trial. Specifically, we have tested whether acutely myelotoxic doses of gemcitabine (i.p. injection, 6.0 mg/m2/day), acetyldinaline [CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'-aminophenyl)-benzamide, 150 mg/m2/day p.o.], and/or melphalan (i.p. injection, 7.2 mg/m2/day) can be tolerated for 28 consecutive days and whether suppressed bone marrow function recovers despite this protracted daily therapy. The three drugs all caused acute neutropenia and suppression of medullary hematopoiesis. Damage to progenitor populations exposed to acetyldinaline and gemcitabine was not as severe as that caused by melphalan, in which case absolute neutrophil count, mature progenitors (colony-forming unit granulocyte/macrophage), and immature progenitors (colony-forming unit-S) progressively declined to severely depressed levels. Marrow recovery was observed during continued daily treatment with acetyldinaline and gemcitabine but not melphalan, and marrow function completely recovered after finishing the 28-day course. Pharmacology studies proved that protracted therapy causes little, if any, change in cellular drug tolerance or systemic exposure.