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.


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.
Karmanos Cancer Institute, Wayne State University, Detroit, Mich., USA. keyes_kristan_a@lilly.com
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Keyes
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Segovia
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Bueren
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Parchment
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Albella
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001549:Benzamides; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D003114:Colony-Forming Units Assay; D003433:Crosses, Genetic; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010655:Phenylenediamines / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D001549:Benzamides; D010655:Phenylenediamines; D003841:Deoxycytidine; D008558:Melphalan; C081895:tacedinaline; D000093542:Gemcitabine