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The efficacy of the ribonucleotide reductase inhibitor Didox in preclinical models of AML.

Cook GJ, Caudell DL, Elford HL, Pardee TS - PLoS ONE (2014)

Bottom Line: In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit.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.

View Article: PubMed Central - PubMed

Affiliation: Wake Forest University Health Sciences, Department of Internal Medicine, Section on Hematology and Oncology, Winston-Salem, North Carolina, United States of America.

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.

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Related in: MedlinePlus

Didox has activity in AML models in vivo.A. Schema. 1.0×106 luciferase tagged AML cells were injected into sublethally irradiated (4.5 Gy) recipients and allowed to engraft. Engraftment was monitored by bioluminescent imaging (IVIS 100 imager). Animals received 5 days of Didox at 425 mg/kg or D5 water control via intraperitoneal injection (IP). Animals were followed for survival. B. Representative bioluminescent images from NrasG12D (MR2) mice pre- and post-treatment. C. Quantitation of bioluminescence post-treatment. D. Kaplan-Meier survival curves of Didox in vivo studies from start of treatment. *  = p of value less than 0.05.
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pone-0112619-g005: Didox has activity in AML models in vivo.A. Schema. 1.0×106 luciferase tagged AML cells were injected into sublethally irradiated (4.5 Gy) recipients and allowed to engraft. Engraftment was monitored by bioluminescent imaging (IVIS 100 imager). Animals received 5 days of Didox at 425 mg/kg or D5 water control via intraperitoneal injection (IP). Animals were followed for survival. B. Representative bioluminescent images from NrasG12D (MR2) mice pre- and post-treatment. C. Quantitation of bioluminescence post-treatment. D. Kaplan-Meier survival curves of Didox in vivo studies from start of treatment. *  = p of value less than 0.05.

Mentions: Both in vivo models express the poor prognostic fusion protein MLL-ENL. The second genetic alteration needed for leukemogenesis was provided by either the NrasG12D (MR2) or the Flt3 internal tandem duplication (Flt3 ITD). Luciferase tagged AML cells were injected into sublethally irradiated (4.5 Gy) recipients and allowed to engraft. Once engraftment was established by bioluminescent imaging, the animals received daily administrations of Didox at 425 mg/kg via IP injection (Figure 5A) over 5 days. Didox treatment significantly reduced leukemic burden compared to vehicle treated controls (Figure 5 B–C, p = 0.0026 and p = 0.0342). More importantly, Didox provided a significant survival benefit (Figure 5D, p<0.0001 and p = 0.0094). This data demonstrates that Didox has activity against syngeneic AML models in vivo.


The efficacy of the ribonucleotide reductase inhibitor Didox in preclinical models of AML.

Cook GJ, Caudell DL, Elford HL, Pardee TS - PLoS ONE (2014)

Didox has activity in AML models in vivo.A. Schema. 1.0×106 luciferase tagged AML cells were injected into sublethally irradiated (4.5 Gy) recipients and allowed to engraft. Engraftment was monitored by bioluminescent imaging (IVIS 100 imager). Animals received 5 days of Didox at 425 mg/kg or D5 water control via intraperitoneal injection (IP). Animals were followed for survival. B. Representative bioluminescent images from NrasG12D (MR2) mice pre- and post-treatment. C. Quantitation of bioluminescence post-treatment. D. Kaplan-Meier survival curves of Didox in vivo studies from start of treatment. *  = p of value less than 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4234372&req=5

pone-0112619-g005: Didox has activity in AML models in vivo.A. Schema. 1.0×106 luciferase tagged AML cells were injected into sublethally irradiated (4.5 Gy) recipients and allowed to engraft. Engraftment was monitored by bioluminescent imaging (IVIS 100 imager). Animals received 5 days of Didox at 425 mg/kg or D5 water control via intraperitoneal injection (IP). Animals were followed for survival. B. Representative bioluminescent images from NrasG12D (MR2) mice pre- and post-treatment. C. Quantitation of bioluminescence post-treatment. D. Kaplan-Meier survival curves of Didox in vivo studies from start of treatment. *  = p of value less than 0.05.
Mentions: Both in vivo models express the poor prognostic fusion protein MLL-ENL. The second genetic alteration needed for leukemogenesis was provided by either the NrasG12D (MR2) or the Flt3 internal tandem duplication (Flt3 ITD). Luciferase tagged AML cells were injected into sublethally irradiated (4.5 Gy) recipients and allowed to engraft. Once engraftment was established by bioluminescent imaging, the animals received daily administrations of Didox at 425 mg/kg via IP injection (Figure 5A) over 5 days. Didox treatment significantly reduced leukemic burden compared to vehicle treated controls (Figure 5 B–C, p = 0.0026 and p = 0.0342). More importantly, Didox provided a significant survival benefit (Figure 5D, p<0.0001 and p = 0.0094). This data demonstrates that Didox has activity against syngeneic AML models in vivo.

Bottom Line: In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit.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.

View Article: PubMed Central - PubMed

Affiliation: Wake Forest University Health Sciences, Department of Internal Medicine, Section on Hematology and Oncology, Winston-Salem, North Carolina, United States of America.

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.

Show MeSH
Related in: MedlinePlus