Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines

Michael Pearlman, David Jendiroba, Lance Pagliaro, Afsaneh Keyhani, Baoshun Liu, Emil J. Freireich

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

In an attempt to improve current therapeutic strategies for acute myelogenous leukemia (AML), we studied the effects of a commercially available drug, dexrazoxane (DEX), which protects against anthracycline-induced cardiotoxicity. The rationale was that DEX would permit higher doses of cardiotoxic drugs to be given. The drug itself may have therapeutic potential as well. Finally, there are concerns that the drug may, as a protective agent, diminish the effectiveness of various chemotherapeutics. To help resolve the question about potential drug antagonism, we undertook a series of in vitro analyses of DEX and various combinations with anthracyclines and other agents. Colony-forming assays were used to evaluate stem-cell renewal of myeloid cells in vitro, and median-effect analysis was used to evaluate antagonism, synergism, and additivity. The anthracyclines doxorubicin, daunorubicin, and idarubicin were individually combined with DEX to study in vitro effects in leukemic myeloid cell lines. In the hope, we could extend the findings to non-anthracyclines, etoposide and cytosine arabinoside were also evaluated in combination with DEX using the same in vitro model and method. We found that the effects of DEX in combination with any of the anthracyclines were schedule dependent. The antitumor effect was greater for each combination than for any anthracycline alone except when DEX was administered 24h before doxorubicin or daunorubicin. These data were corroborated through median-effect analysis. Etoposide in combination with DEX was synergistic for all combinations and schedules, and the combination of cytosine arabinoside and DEX was effective depending on the schedule used. DEX appears to be a promising drug in the treatment of AML and warrants further clinical study involving novel drug combinations.

Original languageEnglish (US)
Pages (from-to)617-626
Number of pages10
JournalLeukemia Research
Volume27
Issue number7
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

Fingerprint

Dexrazoxane
Anthracyclines
Acute Myeloid Leukemia
Cell Line
Appointments and Schedules
Daunorubicin
Pharmaceutical Preparations
Cytarabine
Etoposide
Myeloid Cells
Doxorubicin
Drug Antagonism
Idarubicin
Protective Agents
Drug Combinations

Keywords

  • Acute leukemia therapy
  • Cytotoxicity
  • Dexrazoxane
  • Doxorubicin
  • In vitro

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines. / Pearlman, Michael; Jendiroba, David; Pagliaro, Lance; Keyhani, Afsaneh; Liu, Baoshun; Freireich, Emil J.

In: Leukemia Research, Vol. 27, No. 7, 01.07.2003, p. 617-626.

Research output: Contribution to journalArticle

Pearlman, Michael ; Jendiroba, David ; Pagliaro, Lance ; Keyhani, Afsaneh ; Liu, Baoshun ; Freireich, Emil J. / Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines. In: Leukemia Research. 2003 ; Vol. 27, No. 7. pp. 617-626.
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