Wendell Jones, Ph.D.

Dexrazoxane enhances efficacy of all-trans retinoic acid in acute myeloid leukemia patient blast cells and cell lines

All trans retinoic acid (ATRA) has demonstrated curative activity in acute promyelocytic leukemia (APL), a distinct subtype of acute myeloid leukemia (AML), that is characterized by a chromosomal translocation t(15;17) involving the retinoic acid receptor alpha (RARα) and promyelocytic leukemia (PML) genes. When ATRA is used in combination with arsenic trioxide, most APL patients achieve complete remission. However, success with this relatively nontoxic strategy has not fully translated to other AML subtypes. Early clinical trials of ATRA with anthracycline-based chemotherapy or arsenic trioxide provided conflicting results with potential benefits being restricted to distinct AML subtypes. ATRA in combination with arsenic trioxide has been shown to induce apoptosis in NPM1-mutated AML cell. A 21 gene-expression model (ATRA-21) has been developed to predict AML sub-type specific sensitivity to ATRA. Recently it was shown that addition of ATRA to decitabine resulted in higher remission rates in elderly AML patients. These findings suggest that ATRA-based combination therapies have the potential of being clinically effective in non-APL AML and merit investigation of novel, less toxic combination strategies with ATRA, especially for treating older patients who may be ineligible for toxic induction chemotherapy. Previously we reported that the anti-proliferative effects of ATRA in AML and APL cell lines were potentiated when topoisomerase (topo) IIβ was depleted or when topo IIα/topo IIβ were catalytically inhibited by the bis (2,6 dioxypiperazine) derivative, ICRF-193. Since the clinically approved topo II catalytic inhibitor, dexrazoxane (Dex), is frequently used as an effective cardioprotectant in pediatric AML patients treated with anthracycline-based therapy and shown to lower treatment related mortality, in this study we examined the effectiveness and mechanisms of the combination of ATRA with Dex, in AML patient blast cells and established AML cell lines.

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