Abstract
Acute Myeloid Leukemia (AML) is an aggressive malignancy which leads to marrow failure, and ultimately death. There is a desperate need for new therapeutics for these patients. Ribonucleotide reductase (RR) is the rate limiting enzyme in DNA synthesis. Didox (3,4-Dihydroxybenzohydroxamic acid) is a novel RR inhibitor noted to be more potent than hydroxyurea. In this report we detail the activity and toxicity of Didox in preclinical models of AML. RR was present in all AML cell lines and primary patient samples tested. Didox was active against all human and murine AML lines tested with IC50 values in the low micromolar range (mean IC50 37 µM [range 25.89–52.70 µM]). It was active against primary patient samples at concentrations that did not affect normal hematopoietic stem cells (HSCs). Didox exposure resulted in DNA damage and p53 induction culminating in apoptosis. In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit. Didox was well tolerated, as marrow from treated animals was morphologically indistinguishable from controls. Didox exposure at levels that impaired leukemia growth did not inhibit normal HSC engraftment. In summary, Didox was well tolerated and effective against preclinical models of AML.
Highlights
Acute Myeloid Leukemia (AML) is an aggressive, genetically heterogeneous malignancy of the marrow wherein neoplastic myeloid progenitors suppress healthy hematopoietic stem cells (HSCs) leading to marrow failure, and death
Didox is active against AML in vitro Ribonucleotide reductase (RR) has previously been shown to be upregulated in a variety of malignancies
Despite multiple distinct genetic abnormalities in the patient samples and cell lines we found detectable levels of RR in all samples tested (Figure 1A) consistent with RR being a final common pathway target
Summary
Acute Myeloid Leukemia (AML) is an aggressive, genetically heterogeneous malignancy of the marrow wherein neoplastic myeloid progenitors suppress healthy HSCs leading to marrow failure, and death. AML is a disease of the elderly, with a median onset age of 70 and more than 70% of patients are over the age of 60 at diagnosis [2]. For this population the incidence of AML has slowly been climbing over the past several decades; the one year survival rate remains virtually unchanged [5]. These patients desperately need new treatment strategies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
